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1.  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
2.  In rats, oral oleoyl-DHEA is rapidly hydrolysed and converted to DHEA-sulphate 
BMC Pharmacology  2007;7:4.
Background
Dehydroepiandrosterone (DHEA) released by adrenal glands may be converted to androgens and estrogens mainly in the gonadal, adipose, mammary, hepatic and nervous tissue. DHEA is also a key neurosteroid and has antiglucocorticoid activity. DHEA has been used for the treatment of a number of diseases, including obesity; its pharmacological effects depend on large oral doses, which effect rapidly wanes in part because of its short half-life in plasma. Since steroid hormone esters circulate for longer periods, we have studied here whether the administration of DHEA oleoyl ester may extend its pharmacologic availability by keeping high circulating levels.
Results
Tritium-labelled oleoyl-DHEA was given to Wistar male and female rats by gastric tube. The kinetics of appearance of the label in plasma was unrelated to sex; the pattern being largely coincident with the levels of DHEA-sulfate only in females, and after 2 h undistinguishable from the results obtained using labelled DHEA gavages; in the short term, practically no lipophilic DHEA label was found in plasma. After 24 h only a small fraction of the label remained in the rat organs, with a different sex-related distribution pattern coincident for oleoyl- and free- DHEA gavages. The rapid conversion of oleoyl-DHEA into circulating DHEA-sulfate was investigated using stomach, liver and intestine homogenates; which hydrolysed oleoyl-DHEA optimally near pH 8. Duodenum and ileum contained the highest esterase activities. Pure hog pancreas cholesterol-esterase broke down oleoyl-DHEA at rates similar to those of oleoyl-cholesterol. The intestinal and liver esterases were differently activated by taurocholate and showed different pH-activity patterns than cholesterol esterase, suggesting that oleoyl-DHEA can be hydrolysed by a number of esterases in the lumen (e.g. cholesterol-esterase), in the intestinal wall and the liver.
Conclusion
The esterase activities found may condition the pharmacological availability (and depot effect) of orally administered steroid hormone fatty acid esters such as oleoyl-DHEA. The oral administration of oleoyl-DHEA in order to extend DHEA plasma availability has not been proved effective, since the ester is rapidly hydrolysed, probably in the intestine itself, and mainly converted to DHEA-sulfate at least in females.
doi:10.1186/1471-2210-7-4
PMCID: PMC1831771  PMID: 17346356
3.  Effects of 7-keto Dehydroepiandrosterone on Voluntary Ethanol Intake in Male Rats 
Alcohol (Fayetteville, N.Y.)  2010;45(4):349-354.
Administration of dehydroepiandrosterone (DHEA), a neurosteroid that can negatively modulate the GABAA receptor, has been shown to decrease voluntary intake of ethanol in rats. In vivo, DHEA can be metabolized to a variety of metabolites, including 7-keto DHEA, a metabolite without the prohormonal effects of DHEA. This study compared the effectiveness of 7-keto DHEA to DHEA for reducing ethanol intake in the same group of rats. The subjects, previously trained to drink ethanol using a saccharin-fading procedure, had access to ethanol for thirty minutes daily, and the amount consumed was recorded. Subjects were administered 10 and 56 mg/kg of DHEA or 7-keto DHEA intraperitoneally 15 minutes prior to drinking sessions. Subjects received each particular dose daily until one of two criteria was met; that is, either ethanol intake did not differ by more than 20% of the mean for three consecutive days, or for a maximum of eight days. Both 10 and 56 mg/kg of 7-keto DHEA significantly reduced the dose of ethanol consumed. While 10 mg/kg of 7-keto DHEA produced decreases similar to those found with DHEA, the 56-mg/kg dose of 7-keto DHEA was significantly more effective at decreasing the dose of ethanol consumed than the same dose of DHEA. These results show that 7-keto DHEA is comparable to, or possibly more effective than, DHEA at decreasing ethanol consumption in rats, and that 7-keto DHEA is a compound deserving further investigation as a possible clinical treatment for alcohol abuse without the prohormonal effects of DHEA.
doi:10.1016/j.alcohol.2010.08.020
PMCID: PMC3095668  PMID: 21051179
DHEA; 7-ketoDHEA; neurosteroid; GABAA receptor; ethanol intake; rats
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.  Perceived Stress at Work Is Associated with Lower Levels of DHEA-S 
PLoS ONE  2013;8(8):e72460.
Background
It is known that long-term psychosocial stress may cause or contribute to different diseases and symptoms and accelerate aging. One of the consequences of prolonged psychosocial stress may be a negative effect on the levels of dehydroepiandrosterone (DHEA) and its sulphated metabolite dehydroepiandrosterone sulphate (DHEA-S). The aim of this study is to investigate whether levels of DHEA and DHEA-S differ in individuals who report perceived stress at work compared to individuals who report no perceived stress at work.
Methods
Morning fasting DHEA-S and DHEA levels were measured in serum in a non-stressed group (n = 40) and a stressed group (n = 41). DHEA and DHEA-S levels were compared between the groups using ANCOVA, controlling for age.
Results
The mean DHEA-S levels were 23% lower in the subjects who reported stress at work compared to the non-stressed group. Statistical analysis (ANCOVA) showed a significant difference in DHEA-S levels between the groups (p = 0.010). There was no difference in DHEA level between the groups.
Conclusions
This study indicates that stressed individual have markedly lower levels of DHEA-S. Given the important and beneficial functions of DHEA and DHEA-S, lower levels of DHEA-S may constitute one link between psychosocial stress, ill health and accelerated ageing.
doi:10.1371/journal.pone.0072460
PMCID: PMC3756071  PMID: 24015247
6.  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
7.  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
8.  Administration of Dehydroepiandrosterone (DHEA) Enhances Visual-Spatial Performance in Post-Menopausal Women 
Behavioral neuroscience  2011;125(5):742-752.
The current paper examines the effect of administering Dehydroepiandrosterone (DHEA) on visual-spatial performance in post-menopausal women (N=24, ages 55-80). The concurrent reduction of serum DHEA levels and visual-spatial performance in this population, coupled with the documented effects of DHEA’s androgenic metabolites on visual-spatial performance, suggest that DHEA administration may enhance visual-spatial performance. The current experiment used a double-blind placebo-controlled crossover design in which 50 mg of oral DHEA was administered daily in the drug condition to explore this hypothesis. Performance on the Mental Rotation, Subject-Ordered Pointing, Fragmented Picture Identification, Perceptual Identification, Same-Different Judgment, and Visual Search tasks and serum levels of DHEA, DHEAS, testosterone, estrone and cortisol were measured in the DHEA and placebo conditions. In contrast to prior experiments using the current methodology that did not demonstrate effects of DHEA administration on episodic and short-term memory tasks, the current experiment demonstrated large beneficial effects of DHEA administration on Mental Rotation, Subject-Ordered Pointing, Fragmented Picture Identification, Perceptual Identification and Same-Different Judgment. Moreover, DHEA administration enhanced serum levels of DHEA, DHEAS, testosterone and estrone, and regression analyses demonstrated that levels of DHEA and its metabolites were positively related to cognitive performance on the visual-spatial tasks in the DHEA condition
doi:10.1037/a0025151
PMCID: PMC3715689  PMID: 21942436
Dehydroepiadrosterone (DHEA); post-menopausal women; cognition; visual-spatial tasks; androgens
9.  Testosterone Increases Circulating Dehydroepiandrosterone Sulfate Levels in the Male Rhesus Macaque 
The adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are two of the most abundant hormones in the human circulation. Furthermore, they are released in a circadian pattern and show a marked age-associated decline. Adult levels of DHEA and DHEAS are significantly higher in males than in females, but the reason for this sexual dimorphism is unclear. In the present study, we administered supplementary androgens [DHEA, testosterone and 5α-dihydrotestosterone (DHT)] to aged male rhesus macaques (Macaca mulatta). While this paradigm increased circulating DHEAS immediately after DHEA administration, an increase was also observed following either testosterone or DHT administration, resulting in hormonal profiles resembling levels observed in young males in terms of both amplitude and circadian pattern. This stimulatory effect was limited to DHEAS, as an increase in circulating cortisol was not observed. Taken together, these data demonstrate an influence of the hypothalamo-pituitary–testicular axis on adrenal function in males, possibly by sensitizing the zona reticularis to the stimulating action of adrenocorticopic hormone. This represents a plausible mechanism to explain sex differences in circulating DHEA and DHEAS levels, and may have important implications in the development of hormone therapies designed for elderly men and women.
doi:10.3389/fendo.2014.00101
PMCID: PMC4070064  PMID: 25009533
adrenal gland; aging; androgen; dehydroepiandrosterone; non-human primate; testosterone
10.  The Relationship between Dehydroepiandrosterone (DHEA), Working Memory and Distraction – A Behavioral and Electrophysiological Approach 
PLoS ONE  2014;9(8):e104869.
Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEAS) have been reported to have memory enhancement effects in humans. A neuro-stimulatory action and an anti-cortisol mechanism of action may contribute to that relation. In order to study DHEA, DHEAS and cortisol relations to working memory and distraction, we recorded the electroencephalogram of 23 young women performing a discrimination (no working memory load) or 1-back (working memory load) task in an audio-visual oddball paradigm. We measured salivary DHEA, DHEAS and cortisol both before each task and at 30 and 60 min. Under working memory load, a higher baseline cortisol/DHEA ratio was related to higher distraction as indexed by an enhanced novelty P3. This suggests that cortisol may lead to increased distraction whereas DHEA may hinder distraction by leading to less processing of the distractor. An increased DHEA production with consecutive cognitive tasks was found and higher DHEA responses attributed to working memory load were related to enhanced working memory processing as indexed by an enhanced visual P300. Overall, the results suggest that in women DHEA may oppose cortisol effects reducing distraction and that a higher DHEA response may enhance working memory at the electrophysiological level.
doi:10.1371/journal.pone.0104869
PMCID: PMC4126777  PMID: 25105970
11.  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
12.  OBSESSIVE–COMPULSIVE DISORDER VERSUS BODY DYSMORPHIC DISORDER: A COMPARISON STUDY OF TWO POSSIBLY RELATED DISORDERS 
Depression and anxiety  2007;24(6):399-409.
The relationship between obsessive–compulsive disorder (OCD) and body dysmorphic disorder (BDD) is unclear. BDD has been proposed to be an OCD-spectrum disorder or even a type of OCD. However, few studies have directly compared these disorders’ clinical features. We compared characteristics of subjects with OCD (n = 210), BDD (n = 45), and comorbid BDD/OCD (n = 40). OCD and BDD did not significantly differ in terms of demographic features, age of OCD or BDD onset, illness duration, and many other variables. However, subjects with BDD had significantly poorer insight than those with OCD and were more likely to be delusional. Subjects with BDD were also significantly more likely than those with OCD to have lifetime suicidal ideation, as well as lifetime major depressive disorder and a lifetime substance use disorder. The comorbid BDD/OCD group evidenced greater morbidity than subjects with OCD or BDD in a number of domains, but differences between the comorbid BDD/OCD group and the BDD group were no longer significant after controlling for BDD severity. However, differences between the comorbid BDD/OCD group and the OCD group remained significant after controlling for OCD severity. In summary, OCD and BDD did not significantly differ on many variables but did have some clinically important differences. These findings have implications for clinicians and for the classification of these disorders.
doi:10.1002/da.20232
PMCID: PMC2092450  PMID: 17041935
dysmorphophobia; phenomenology; OCD-spectrum disorders; somatoform disorders; insight; comorbidity
13.  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
14.  DHEA administration and exercise training improves insulin resistance in obese rats 
Background
Dehydroepiandrosterone (DHEA) is precursor of sex steroid hormone. We demonstrated that acute DHEA injection to type 1 diabetes model rats induced improvement of hyperglycemia. However, the effect of the combination of DHEA administration and exercise training on insulin resistance is still unclear. This study was undertaken to determine whether 6-weeks of DHEA administration and/or exercise training improve insulin resistance in obese male rats.
Methods
After 14 weeks of a high-sucrose diet, obese male Wistar rats were assigned randomly to one of four groups: control, DHEA administration, exercise training, and a combination of DHEA administration and exercise training (n = 10 each group).
Results
After 6-weeks of DHEA administration and/or exercise training, rats in the combination group weighed significantly less and had lower serum insulin levels than rats in the other groups. Moreover, the rats treated with DHEA alone or DHEA and exercise had significantly lower fasting glucose levels (combination, 84 ± 6.5 mg/dL; DHEA, 102 ± 9.5 mg/dL; control, 148 ± 10.5 mg/dL). In addition, insulin sensitivity check index showed significant improvements in the combination group (combination, 0.347 ± 0.11; exercise, 0.337 ± 0.16%; DHEA, 0.331 ± 0.14; control, 0.308 ± 0.12). Muscular DHEA and 5α-dihydrotestosterone (DHT) concentrations were significantly higher in the combination group, and closely correlated with the quantitative insulin-sensitivity check index (DHEA: r = 0.71, p < 0.01; DHT: r = 0.69, p < 0.01).
Conclusion
These results showed that a combination of DHEA administration and exercise training effectively improved fasting blood glucose and insulin levels, and insulin sensitivity, which may reflect increased muscular DHEA and DHT concentrations.
doi:10.1186/1743-7075-9-47
PMCID: PMC3433349  PMID: 22647230
Exercise training; Insulin sensitivity; Sex steroid hormone; Obesity
15.  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
16.  Interactions between dehydroepiandrosterone and glucocorticoid metabolism in pig kidney: Nuclear and microsomal 11β-hydroxysteroid dehydrogenases 
The 11β–hydroxysteroid dehydrogenase type 1 (11βHSD1) activates glucocorticoids (GC) by reversibly converting 11-keto-GC to 11-hydroxy-GC, while 11βHSD2 and 11βHSD3 only catalyzes the reverse reaction. Recently, rat and human 11βHSDs were shown to interconvert 7α- and 7β-hydroxy-dehydroepiandrosterone (7α- or 7β-OH-DHEA) with 7-oxo-DHEA. We report that pig kidney microsomes (PKMc) and nuclei (PKN) oxidize 7α-OH-DHEA to 7-oxo-DHEA at higher rates with NAD+, than with NADP+. Corticosterone (CS), dehydrocoticosterone (DHC), 11α- and 11β-hydroxyprogesterone, and carbenoxolone completely inhibited these reactions, while 7-oxo-DHEA only inhibited the NAD+-dependent reaction. Conversely, CS oxidation was not inhibited by 7α-OH-DHEA or 7-oxo-DHEA. PKMc and PKN did not convert 7-oxo-DHEA to 7-OH-DHEA with either NADPH or NADH. Finally, PKN contained a high affinity, NADPH-dependent 11βHSD that reduces DHC to CS. The GC effects on interconversion of DHEA metabolites may have clinical significance, since DHEA and its 7–oxidized derivatives have been proposed for treatment of human autoimmune and inflammatory disorders.
doi:10.1016/j.abb.2005.07.010
PMCID: PMC1363734  PMID: 16137639
Corticosterone; dehydrocorticosterone; dehydroepiandrosterone; DHEA; 7α-hydroxy-DHEA; 7β-hydroxy-DHEA; 7-oxo-DHEA; 11β-hydroxysteroid dehydrogenase; kidney; pig
17.  Effect of age and caloric restriction on circadian adrenal steroid rhythms in rhesus macaques 
Neurobiology of aging  2007;29(9):1412-1422.
Dietary caloric restriction (CR) slows aging, extends lifespan, and reduces the occurrence of age-related diseases in short-lived species. However, it is unclear whether CR can exert similar beneficial effects in long-lived species, like primates. Our objective was to determine if CR could attenuate purported age-related changes in the 24-h release of adrenal steroids. To this end, we examined 24-hour plasma profiles of cortisol, and dehydroepiandrosterone sulfate (DHEAS) in young and old, male and female rhesus macaques (Macaca mulatta) subjected to either ad libitum (AL)-feeding or CR (70% of AL) for 2–4 years. Hormone profiles from young monkeys showed pronounced 24-h rhythms. Cortisol concentrations were higher in old males but not females, whereas DHEAS rhythms were dampened with age in both sexes. The cortisol rhythms of old CR males resembled that of young control males. However, CR failed to prevent age-related declines in DHEAS and further dampened DHEAS rhythms in both sexes. Apart from the partial attenuation of the age-related cortisol elevation in the old males, 24-h adrenal steroid rhythms did not benefit from late-onset CR.
doi:10.1016/j.neurobiolaging.2007.03.011
PMCID: PMC2585543  PMID: 17420071
Adrenal steroids; Aging; Caloric restriction; Circadian; Cortisol; DHEAS; Endocrine rhythms; Primate
18.  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
19.  Cortisol and DHEA-S are associated with startle potentiation during aversive conditioning in humans 
Psychopharmacology  2005;186(3):434-441.
Rationale
Fear conditioning reliably increases the startle reflex and stress hormones, yet very little is known about the effect of stress hormones on fear-potentiated startle. Cortisol and the sulfate ester of dehydroepiandrosterone (DHEA-S) are involved in stress and anxiety. Evidence suggests that low cortisol/DHEA-S ratio has a buffering effect on stress and anxiety in preclinical and clinical studies, suggesting that there may be a relationship between fear-potentiated startle and cortisol and DHEA-S activity.
Objective
The aim of the study was to examine whether there is a relationship between cortisol/DHEA-S ratio and fear-potentiated startle.
Methods
Thirty healthy subjects participated in a differential aversive conditioning experiment during which one of two stimuli (CS+) was paired with a shock, and the other was not (CS-). Conditioned responses were assessed with the startle reflex, defined as startle potentiation during CS+ compared to CS-. DHEA-S and cortisol levels were assayed from blood samples collected in both a baseline and an aversive conditioning session. Subjective state anxiety, arousal, and valence were assessed at various times during testing.
Results
Fear-potentiated startle was larger in individuals with high compared to low cortisol/DHEA-S ratio. Multiple regression analyses revealed that fear-potentiated startle was positively associated with cortisol and negatively associated with DHEA-S. There was no significant correlation between DHEA-S and cortisol levels.
Conclusion
These data suggest that cortisol and DHEA-S are involved in fear conditioning.
doi:10.1007/s00213-005-0124-2
PMCID: PMC2702204  PMID: 16052364
Fear conditioning; Fear-potentiated startle; Cortisol; DHEA-S; Stress; HPA
20.  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
21.  Quality of life in children with OCD with and without comorbidity 
Background
Quality of life (QoL) is a well-established outcome measure. However, in contrast to adult obsessive-compulsive disorder (OCD), little is known about QoL in children with OCD. This study aimed to assess QoL, social competence and school functioning of paediatric patients with OCD by comparing them with the general population and assessing the relations between comorbidity, duration and severity of symptoms, family accommodation and QoL.
Methods
Children and adolescents (n = 135), aged 7–17 (mean 13 [SD 2.7] years; 48.1% female) were assessed at baseline for treatment. QoL was assessed by self-report and caregiver’s proxy report on the Questionnaire for Measuring Health-related Quality of Life in Children and Adolescents (KINDL-R) and compared with an age- and sex-matched sample from the general population. Social competence and school functioning were assessed with the Child Behavior Checklist, comorbidity with the Kiddie Schedule for Affective Disorders and Schizophrenia (Present and Lifetime Version), severity of OCD with the Children’s Yale-Brown Obsessive Compulsive Scale and the families’ involvement with the child’s OCD symptoms with the Family Accommodation Scale.
Results
QoL and social competence were reduced (p < .001) in patients with OCD compared with controls (KINDL-R mean score 62.40 [SD 13.00] versus 69.72 [12.38] in self-reports and 61.63 [SD 13.27] versus 74.68 [9.97] in parent reports). Patients with comorbidity had lower QoL (p = .001) in proxy ratings than those with OCD only (mean score 56.26 [SD 12.47] versus 64.30 [SD 12.75]). In parent proxy reports, severity of OCD (r = −.28) and family accommodation (r = −.40) correlated moderately negatively with QoL.
Conclusions
To our knowledge, this is the largest QoL study of paediatric OCD. QoL was markedly reduced in children with OCD, especially in those with comorbid psychiatric disorders. Based on our findings, we suggest employing QoL assessment in order to have a more comprehensive understanding of childhood OCD.
Clinical trials registration information
This study was registered in Current Controlled Trials; Nordic Long-term Obsessive Compulsive disorder (OCD) Treatment Study (ISRCTN66385119).
doi:10.1186/s12955-014-0152-x
PMCID: PMC4236467  PMID: 25358486
Pediatric OCD; Quality of life; Comorbidity; Assessment
22.  Oral dehydroepiandrosterone (DHEA) replacement in older adults: effects on central adiposity, glucose metabolism, and blood lipids 
Clinical endocrinology  2011;75(4):456-463.
Objective
The aim was to determine the effects of dehydroepiandrosterone (DHEA) therapy on changes in central adiposity, insulin action, and blood lipids. Many of the actions of DHEA in humans are thought to be mediated through its conversion to sex hormones, which are modulators of adiposity, muscularity, and insulin sensitivity. The effects of DHEA replacement on regional tissue composition, glucose metabolism, and blood lipid profile in older adults have been inconsistent.
Design
a randomized, double-blinded, placebo-controlled trial. The intervention was oral DHEA 50 mg/d or placebo for 12 months.
Participants
58 women and 61 men, aged 60–88 yr, with low serum DHEA sulfate (DHEAS) levels at study entry.
Measurements
Computed tomography measures of abdominal fat areas, thigh muscle and fat areas, DXA-derived trunk fat mass, serum glucose and insulin responses to an oral glucose challenge, and fasted serum total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides were assessed before and after the intervention.
Results
There were no significant (P > 0.05) differences between the DHEA and placebo groups in the changes in regional tissue composition or glucose metabolism. HDL-cholesterol (P =0.01) and fasted triglycerides (P =0.02) decreased in women and men taking DHEA.
Conclusion
Restoring serum DHEAS levels in older adults to young adult levels for 1 year does not appear to reduce central adiposity or improve insulin action. The benefit of DHEA on decreasing serum triglycerides must be weighed against the HDL-lowering effect.
doi:10.1111/j.1365-2265.2011.04073.x
PMCID: PMC3166648  PMID: 21521341
dehydroepiandrosterone; regional adiposity; insulin action
23.  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
24.  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
25.  Female social and sexual interest across the menstrual cycle: the roles of pain, sleep and hormones 
BMC Women's Health  2010;10:19.
Background
Although research suggests that socio-sexual behavior changes in conjunction with the menstrual cycle, several potential factors are rarely taken into consideration. We investigated the role of changing hormone concentrations on self-reported physical discomfort, sleep, exercise and socio-sexual interest in young, healthy women.
Methods
Salivary hormones (dehydroepiandrosterone sulfate-DHEAS, progesterone, cortisol, testosterone, estradiol and estriol) and socio-sexual variables were measured in 20 women taking oral contraceptives (OC group) and 20 not using OCs (control group). Outcome measures were adapted from questionnaires of menstrual cycle-related symptoms, physical activity, and interpersonal relations. Testing occurred during menstruation (T1), mid-cycle (T2), and during the luteal phase (T3). Changes in behavior were assessed across time points and between groups. Additionally, correlations between hormones and socio-behavioral characteristics were determined.
Results
Physical discomfort and sleep disturbances peaked at T1 for both groups. Exercise levels and overall socio-sexual interest did not change across the menstrual cycle for both groups combined. However, slight mid-cycle increases in general and physical attraction were noted among the control group, whereas the OC group experienced significantly greater socio-sexual interest across all phases compared to the control group. Associations with hormones differed by group and cycle phase. The estrogens were correlated with socio-sexual and physical variables at T1 and T3 in the control group; whereas progesterone, cortisol, and DHEAS were more closely associated with these variables in the OC group across test times. The direction of influence further varies by behavior, group, and time point. Among naturally cycling women, higher concentrations of estradiol and estriol are associated with lower attraction scores at T1 but higher scores at T3. Among OC users, DHEAS and progesterone exhibit opposing relationships with attraction scores at T1 and invert at T3.
Conclusions
Data from this study show no change across the cycle in socio-sexual interest among healthy, reproductive age women but higher social and physical attraction among OC users. Furthermore, a broader range of hormones may be associated with attraction than previously thought. Such relationships differ by use of oral contraceptives, and may either reflect endogenous hormone modulation by OCs and/or self-selection of sexually active women to practice contraceptive techniques.
doi:10.1186/1472-6874-10-19
PMCID: PMC2887768  PMID: 20507626

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