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1.  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
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.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  Androgen Supplementation During Aging: Development of a Physiologically Appropriate Protocol 
Rejuvenation Research  2014;17(2):150-153.
Abstract
Men show an age-related decline in the circulating levels of testosterone (T) and dehydroepiandrosterone sulfate (DHEAS). Consequently, there is interest in developing androgen supplementation paradigms for old men that replicate the hormone profiles of young adults. In the present study, we used old (21–26 years old) male rhesus monkeys as a model to examine the efficacy of an androgen supplementation paradigm that comprised oral T administration (12 mg/kg body weight, dissolved in sesame oil/chocolate) in the evening, and two oral DHEA administrations, 3 hr apart (0.04 mg/kg body weight, dissolved in sesame oil/chocolate) in the morning. After 5 days of repeated hormone supplementation, serial blood samples were remotely collected from each animal hourly across the 24-hr day, and assayed for cortisol, DHEAS, T, 5α-dihydrotestosterone (DHT), estrone (E1), and 17β-estradiol (E2). Following androgen supplementation, T levels were significantly elevated and this was associated with a more sustained nocturnal elevation of T's primary bioactive metabolites, DHT and E1 and E2. Plasma DHEAS levels were also significantly elevated after androgen supplementation; DHEAS levels rose in the early morning and gradually declined during the course of the day, closely mimicking the profiles observed in young adults (7–12 years old); in contrast, cortisol levels were unaltered by the supplementation. Together the data demonstrate a non-invasive androgen supplementation paradigm that restores youthful circulating androgen levels in old male primates. Because this paradigm preserves the natural circulating circadian hormone patterns, we predict that it will produce fewer adverse side effects, such as perturbed sleep or cognitive impairment.
doi:10.1089/rej.2013.1518
PMCID: PMC3995436  PMID: 24134213
12.  Effect of Interleukin-1beta and Dehydroepiandrosterone on the Expression of Lumican and Fibromodulin in Fibroblast-Like Synovial Cells of the Human Temporomandibular Joint 
Several epidemiological studies have reported that temporomandibular disorders (TMDs) are more prevalent in women than in men. It has recently been proposed that sex hormones such as estrogen, testosterone and dehydroepiandrosterone (DHEA) are involved with the pathogenesis of TMDs. Although studies have investigated the relationship between estrogen and testosterone and the restoration of TMDs, the relationship between DHEA and TMDs is unknown. The synovial tissue of the temporomandibular joint (TMJ) is made up of connective tissue with an extracellular matrix (ECM) composed of collagen and proteoglycan. One proteoglycan family, comprised of small leucine-rich repeat proteoglycans (SLRPs), was found to be involved in collagen fibril formation and interaction. In recent years, the participation of SLRPs such as lumican and fibromodulin in the internal derangement of TMJ has been suggested. Although these SLRPs may contribute to the restoration of the synovium, their effect is still unclear. The purpose of this study was to investigate the effect of DHEA, a sex hormone, on the expression of lumican and fibromodulin in human temporomandibular specimens and in cultured human TMJ fibroblast-like synovial cells in the presence or absence of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). In the in vivo study, both normal and osteoarthritic (OA) human temporomandibular synovial tissues were immunohistochemically examined. In the in vitro study, five fibroblast-like synoviocyte (FLS) cell lines were established from human TMJ synovial tissue of patients with osteoarthritis. The subcultured cells were then incubated for 3, 6, 12 or 24 h with/without IL-1beta (1 ng/mL) in the presence or absence of DHEA (10 μM). The gene expression of lumican and fibromodulin was examined using the real-time polymerase chain reaction (PCR) and their protein expression was examined using immunofluorescent staining. We demonstrated that the expression of lumican differs from that of fibromodulin in synovial tissue and furthermore, that IL-1beta induced a significant increase in lumican mRNA and immunofluorescent staining in FLS compared to cells without IL-1beta. DHEA plus IL-1beta induced a significant increase in fibromodulin, but not in lumican mRNA, compared to DHEA alone, IL-1beta alone and in the absence of DHEA and IL-1beta. In immunofluorescent staining, weaker fibromodulin staining of FLS cells was observed in cells cultured in the absence of both DHEA and IL-1beta compared to fibromodulin staining of cells cultured with DHEA alone, with DHEA plus IL-1beta, or with IL-1beta alone. These results indicate that DHEA may have a protective effect on synovial tissue in TMJ by enhancing fibromodulin formation after IL-1beta induced inflammation. DHEA enhancement of fibromodulin expression may also exert a protective effect against the hyperplasia of fibrous tissue that TGF-beta1 induces. In addition lumican and fibromodulin are differentially expressed under different cell stimulation conditions and lumican and fibromodulin may promote regeneration of the TMJ after degeneration and deformation induced by IL-1beta.
doi:10.4081/ejh.2015.2440
PMCID: PMC4378210  PMID: 25820556
Temporomandibular joint; dehydroepiandrosterone; lumican; fibromodulin; small leucine rich repeat proteoglycan
13.  Capacity to Delay Reward Differentiates Obsessive Compulsive Disorder and Obsessive Compulsive Personality Disorder 
Biological psychiatry  2013;75(8):653-659.
Background
Although the relationship between obsessive compulsive disorder (OCD) and obsessive compulsive personality disorder (OCPD) has long been debated, clinical samples of OCD (without OCPD) and OCPD (without OCD) have never been systematically compared. We studied whether individuals with OCD, OCPD, or both conditions differ on symptomatology, functioning, and a measure of self-control: the capacity to delay reward.
Methods
25 OCD, 25 OCPD, 25 comorbid OCD+OCPD, and 25 healthy controls (HC) completed clinical assessments and a validated intertemporal choice task that measures capacity to forego small immediate rewards for larger delayed rewards.
Results
OCD and OCPD subjects both showed impairment in psychosocial functioning and quality of life, as well as compulsive behavior, but only subjects with OCD reported obsessions. Individuals with OCPD, with or without comorbid OCD, discounted the value of delayed monetary rewards significantly less than OCD and HC. This excessive capacity to delay reward discriminates OCPD from OCD, and is associated with perfectionism and rigidity.
Conclusions
OCD and OCPD are both impairing disorders marked by compulsive behaviors, but they can be differentiated by the presence of obsessions in OCD and by excessive capacity to delay reward in OCPD. That individuals with OCPD show less temporal discounting (suggestive of excessive self-control) whereas prior studies have shown that individuals with substance use disorders show greater discounting (suggestive of impulsivity) supports the premise that this component of self-control lies on a continuum in which both extremes (impulsivity and overcontrol) contribute to psychopathology.
doi:10.1016/j.biopsych.2013.09.007
PMCID: PMC3969772  PMID: 24199665
obsessive compulsive disorder; obsessive compulsive personality disorder; delay discounting; temporal discounting; self-control; impulsivity
14.  In Vivo and In Vitro Evidences of Dehydroepiandrosterone Protective Role on the Cardiovascular System 
Context:
Dehydroepiandrosterone (DHEA) and its sulfate ester, Dehydroepiandrosterone Sulfate (DHEA-S) have been considered as putative anti-aging hormones for many years. Indeed, while DHEAS is the most abundant circulating hormone, its concentration is markedly decreased upon aging and early epidemiologic trials have revealed a strong inverse correlation between the hormone concentrations and the occurrence of several dysfunctions frequently encountered in the elderly. Naturally, hormonal supplementation has been rapidly suggested to prevent DHEA (S) deficiency and therefore, age-related development of these pathologies, using the same strategy as estrogen replacement therapy proposed in postmenopausal women.
Evidence Acquisition:
All references were searched using PubMed and the following strategy: our initial selection included all articles in English and we sorted them with the following keywords: “DHEA or DHEA-S” and “heart or vascular or endothelium or cardiovascular disease”. The search was limited to neither the publication date nor specific journals. The final selection was made according to the relevance of the article content with the aims of the review. According to these criteria, fewer than 10% of the articles retrieved at the first step were discarded.
Results:
In this short review, we have focused on the cardiovascular action of DHEA. We started by analyzing evidences in favor of a strong inverse association between DHEA (S) levels and the cardiovascular risk as demonstrated in multiple observational epidemiologic studies for several decades. Then we discussed the different trials aimed at supplementing DHEA (S), both in animals and human, for preventing cardiovascular diseases and we analyzed the possible reasons for the discrepancy observed among the results of some studies. Finally, we presented putative molecular mechanisms of action for DHEA (S), demonstrated in vitro in different models of vascular and cardiac cells, highlighting the complexity of the involved signaling pathways.
Conclusions:
The identification of the beneficial cardiovascular effects of DHEA (S) and a better understanding of the involved mechanisms should be helpful to develop new strategies or pharmacologic approaches for many lethal diseases in Western countries.
doi:10.5812/ijem.24660
PMCID: PMC4389253  PMID: 25926854
Dehydroepiandrosterone; Endothelium; Myocytes, Cardiac; Cardiovascular System; Disease; Steroids
15.  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
16.  Effect of dehydroepiandrosterone supplementation on bone mineral density, bone markers, and body composition in older adults 
Summary
We present results of a randomized, placebo-controlled trial to examine the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density (BMD), bone metabolism and body composition in 225 healthy adults aged 55 to 85 years.
Introduction
Dehydroepiandrosterone (DHEA) levels decline dramatically with age, concurrent with the onset of osteoporosis, suggesting a role for DHEA supplementation in preventing age-related bone loss.
Methods
We conducted a randomized, placebo-controlled trial to examine the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density (BMD), bone metabolism and body composition in 225 healthy adults aged 55 to 85 years.
Results
DHEA treatment increased serum DHEA and DHEA sulfate levels to concentrations seen in young adults. Testosterone, estradiol and insulin-like growth factor (IGF-1) levels increased in women (all p<0.001), but not men, receiving DHEA. Serum C-terminal telopeptide of type-1 collagen levels decreased in women (p=0.03), but not men, whereas bone-specific alkaline phosphatase levels were not significantly altered in either sex. After 12 months, there was a positive effect of DHEA on lumbar spine BMD in women (p=0.03), but no effect was observed for hip, femoral neck or total body BMD, and no significant changes were observed at any site among men. Body composition was not affected by DHEA treatment in either sex.
Conclusion
Among older healthy adults, daily administration of 50 mg of DHEA has a modest and selective beneficial effect on BMD and bone resorption in women, but provides no bone benefit for men.
doi:10.1007/s00198-007-0520-z
PMCID: PMC2435090  PMID: 18084691
Body composition; Bone metabolism; Bone mineral density (BMD); Dehydroepiandrosterone (DHEA) levels; Placebo-controlled trial; Testosterone
17.  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
18.  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
19.  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
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.  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
22.  Cardiovascular Disease Is Associated with Greater Incident Dehydroepiandrosterone Sulfate Decline in the Oldest Old: The Cardiovascular Health Study All Stars Study 
OBJECTIVES
To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age.
DESIGN
Longitudinal cohort study.
SETTING
Pittsburgh, Pennsylvania.
PARTICIPANTS
Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N =989, mean age 85.2, 63.5% women, 16.5% African American).
MEASUREMENTS
Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change.
RESULTS
Mean ± standard deviation DHEAS was 0.555 ± 0.414 μg/mL in 1996/97 and 0.482 ± 0.449 μg/mL in 2005/06 for women and 0.845 ± 0.520 μg/mL in 1996/97 and 0.658 ± 0.516 μg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (− 0.200 μg/mL) than in women (− 0.078 μg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 μg/mL (P =.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (β = − 0.04 μg/mL, P =.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio =1.46, 95% confidence interval =1.03–2.05).
CONCLUSION
DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline.
doi:10.1111/j.1532-5415.2010.02724.x
PMCID: PMC2880808  PMID: 20163485
dehydroepiandrosterone sulfate; cardiovascular disease; gender; aging
23.  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
24.  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
25.  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

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