High DHEAS in girls and metabolic features throughout pubertal maturation.

CONTEXT: An association between premature adrenarche and metabolic syndrome at presentation has been described. Our aim was to assess whether the presence of high dehydroepiandrosterone sulphate (DHEAS [HD]) at the adrenarche determines the risk of metabolic syndrome during puberty, taking into account body mass index (BMI) and birth weight. DESIGN: Prospective observational. PATIENTS: Five hundred four girls from the Growth and Obesity Chilean Cohort Study were followed from birth through puberty. At age ~7, subjects were classified by DHEAS concentrations into the HD (>75th percentile) or normal DHEAS (ND, ≤75th percentile) subgroups. MEASUREMENTS: Anthropometrics, semiannual clinical pubertal staging and hormonal and metabolic levels. The relationships among DHEAS at age ~7, metabolic syndrome, and each of its components independently, were analyzed by linear and logistic regression models during puberty and 1-year postmenarche, adjusted by confounders. RESULTS: Girls with HD at 7 years exhibited higher BMI, more central fat and higher serum androgen and insulin like growth factor (IGF)-I levels throughout puberty. Also, girls with HD had a greater prevalence of hyperglycemia at B2 and B4 breast stages, and of low HDL at B4. At 1 year after menarche, HD girls had a higher prevalence of metabolic syndrome, and those with BMI > 1 SD score had a higher metabolic score and insulin levels than ND girls with similar BMI. CONCLUSIONS: Our observations suggest that girls with HD at the age of adrenarche may be at greater risk for metabolic syndrome at adolescence, especially in those who are overweight or obese. Our results emphasize the importance of lifestyle interventions for childhood overweight and obesity among girls with HD.

GABAergic system's Injuries Induced by Sodium Sulfite in Caenorhabditis elegans Were Prevented by the Anti-Oxidative Properties of Dehydroepiandrosterone Sulfate.

Several pathophysiological processes involve Hypoxia conditions, where the nervous system is affected as well. We postulate that the GABAergic system is especially sensitive. Furthermore, drugs improving the resistance to hypoxia have been investigated, such as the neurosteroid dehydroepiandrosterone sulfate (DHEAS) which has shown beneficial effects in hypoxic processes in mammals; however, at the cellular level, its exact mechanism of action has yet to be fully elucidated. Here, we used a chemical hypoxia model through sodium sulfite (SS) exposure in Caenorhabditis elegans (C. elegans), a nematode whose response to hypoxia involves pathways and cellular processes conserved in mammals, and that allows study the direct effect of DHEAS without its conversion to sex hormones. This work aimed to determine the effect of DHEAS on damage to the GABAergic system associated with SS exposure in C. elegans. Worms were subjected to nose touch response (Not Assay) and observed in epifluorescence microscopy. DHEAS decreased the shrinkage response of Not Assay and the level of damage in GABAergic neurons on SS-exposed worms. Also, the enhanced nuclear localization of DAF-16 and consequently the overexpression of chaperone HSP-16.2 by hypoxia were significantly reduced in SS + DHEAS exposed worms. As well, DHEAS increased the survival rate of worms exposed to hydrogen peroxide. These results suggest that hypoxia-caused damage over the GABAergic system was prevented at least partially by DHEAS, probably through non-genomic mechanisms that involve its antioxidant properties related to its chemical structure.

Label-free impedimetric immunosensor based on arginine-functionalized gold nanoparticles for detection of DHEAS, a biomarker of pediatric adrenocortical carcinoma.

Pediatric adrenocortical carcinoma (pACC) is a rare and aggressive malignancy of high occurrence in Southern Brazil. pACC is characterized by the usual overproduction of dehydroepiandrosterone sulfate (DHEAS), whose detection in serum or plasma can be effective to the early diagnosis of the disease. Therefore, the present paper reports, for the first time, the construction and application of a label-free impedimetric immunosensor to detect DHEAS, which was based on the modification of an oxidized glassy carbon electrode with arginine-functionalized gold nanoparticles (AuNPs-ARG) and anti-DHEA IgM antibodies (ox-GCE/AuNPs-ARG/IgM). AuNPs-ARG was synthesized by a green route, and characterized by UV-VIS spectroscopy, FTIR, TEM, DLS, and XRD. The construction of ox-GCE/AuNPs-ARG/IgM was optimized through factorial design and response surface methodology. Cyclic voltammetry and electrochemical impedance spectroscopy measurements were employed to characterize the optimized immunosensor. The DHEAS detection principle was based on the variation of charge transfer resistance (∆Rct) relative to the Fe(CN)64-/3- electrochemical probe after immunoassays in the presence of the biomarker. A linear relationship between ∆Rct and DHEAS concentration was verified in the range from 10.0 to 110.0 µg dL-1, with a LOD of 7.4 µg dL-1. Besides the good sensitivity, the immunosensor displayed accuracy, stability, and specificity to detect DHEAS. The promising analytical performance of ox-GCE/AuNPs-ARG/IgM was confirmed by quantifying DHEAS in real patient plasma samples, with results that were comparable to the reference chemiluminescence assay. Our results suggest that the presented immunosensor can find clinical applications in the early diagnosis of pACC and to monitor DHEAS levels in other adrenal pathologies.

Low levels of dehydroepiandrosterone sulfate are associated with the risk of developing cardiac autonomic dysfunction in elderly subjects

ABSTRACT Objective: To assess the relationships between serum dehydroepiandrosterone sulfate (DHEA-S) levels and heart rate variability (HRV) among different age groups. Subjects and methods: Forty-five healthy men were divided into 3 groups: young age (YA; 20-39 yrs; n = 15), middle age (MA; 40-59 yrs; n = 15) and old age (OA; ≥ 60 yrs; n = 15). Hemodynamic parameters, linear analyses of HRV and concentrations of cortisol and DHEA-S were measured at rest. Results: The OA group presented a higher resting heart rate (84.3 ± 4.6 bpm) than the YA group (72.0 ± 4.4 bpm; p < 0.05). The YA group showed an attenuated variance of HRV (2235.1 ± 417.9 ms2) compared to the MA (1014.3 ± 265.2 ms2; p < 0.05) and OA (896.3 ± 274.1 ms2; p < 0.05) groups, respectively. The parasympathetic modulation of HRV was lower in both the MA (244.2 ± 58.0 ms2) and OA (172.8 ± 37.9 ms2) groups in comparison with the YA group (996.0 ± 255.4 ms2; p < 0.05), while serum DHEA-S levels were significantly lower in both the MA (91.2 ± 19.6 mg/dL) and OA (54.2 ± 17.7 mg/dL) groups compared to the YA group (240.0 ± 50.8 mg/dL; p < 0.05). A positive correlation between lower serum concentrations of DHEA-S and attenuated variance of HRV (r = 0.47, p = 0.031), as well as lower serum concentrations of DHEA-S and decreased parasympathetic modulation of HRV (r = 0.54, p = 0.010), were found. Conclusion: The present study demonstrated that the decline of plasma DHEA-S is associated with reduced cardiac autonomic modulation during the aging process.

High DHEAS Level in Girls Is Associated with Earlier Pubertal Maturation and Mild Increase in Androgens throughout Puberty without Affecting Postmenarche Ovarian Morphology.

OBJECTIVE: To assess whether the presence of high DHEAS (HD) at 7 years determines different timing, sequence, and rate of pubertal events, and whether it is associated with adrenal and/or ovarian hyperandrogenism and changes in ovarian morphology throughout puberty. METHODS: In a longitudinal study of 504 girls, clinical evaluation was performed every 6 months after 7 years of age to detect Tanner stages; hormonal and anthropometric measurements were conducted at thelarche (B2), breast Tanner 4 (B4), and 1 year after menarche; ultrasonographic evaluation was also performed after menarche. The girls were classified as HD if their DHEAS level was >42.1 µg/dL (>75th percentile) around 7 years. RESULTS: HD around 7 years is associated with a younger age at thelarche, pubarche, and menarche. Girls with HD had higher androstenedione and total testosterone levels, and a higher free androgen index (FAI), and lower levels of antimüllerian hormone (AMH) at B2, and higher levels of androstenedione and FAI at B4 and after menarche. All these results were significant even after adjusting for body mass index, age at first DHEAS determination, and birth weight. One year after menarche, polycystic ovarian morphology was detected in 7.6 and 7.3% of the HD and the normal DHEAS group, respectively. Ovarian volume was correlated with AMH, testosterone, androstenedione, and LH but not with DHEAS around 7 years. CONCLUSION: Prepubertal HD in normal girls was associated with earlier thelarche, pubarche, and menarche, and a mild androgen increase throughout puberty. We believe continuous follow-up of this cohort is important to prospectively address the interrelationships between biochemical adrenarche and early growth as determinants of ovarian function.

Assessing endocrine and immune parameters in human immunodeficiency virus-infected patients before and after the immune reconstitution inflammatory syndrome

ABSTRACT Objective The present study compares immune and endocrine parameters between HIV-infected patients who underwent the Immune Reconstitution Inflammatory Syndrome (IRIS-P) during antiretroviral therapy (ART) and HIV-patients who did not undergo the syndrome (non-IRIS-P). Materials and methods Blood samples were obtained from 31 HIV-infected patients (15 IRIS-P and 16 non-IRIS-P) before ART (BT) and 48 ± 2 weeks after treatment initiation (AT). Plasma Interleukin-6 (IL-6) and Interleukin-18 (IL-18) were determined by ELISA. Cortisol, dehydroepiandrosterone sulfate (DHEA-S) and thyroxin concentrations were measured using chemiluminescence immune methods. Results Concentrations of IL-6 (7.9 ± 1.9 pg/mL) and IL-18 (951.5 ± 233.0 pg/mL) were significantly higher (p < 0.05) in IRIS-P than in non-IRIS-P (3.9 ± 1.0 pg/mL and 461.0 ± 84.4 pg/mL, respectively) BT. Mean T4 plasma level significantly decreased in both groups of patients after treatment (p < 0.05). In both groups cortisol levels were similar before and after ART (p > 0.05). Levels of DHEA-S in IRIS-P decreased AT (1080.5 ± 124.2 vs. 782.5 ± 123.8 ng/mL, p < 0.05) and they were significantly lower than in non-IRIS-P (782.5 ± 123.8 vs. 1203.7 ± 144.0 ng/mL, p < 0.05). IRIS-P showed higher values of IL-6 and IL-18 BT and lower levels of DHEA-S AT than in non-IRIS-P. Conclusion These parameters could contribute to differentiate IRIS-P from non-IRIS-P. The significant decrease in DHEA-S levels in IRIS-P after ART might suggest a different adrenal response in these patients, which may reflect the severity of the disease.

Dehydroepiandrosterone, Its Sulfate and Cognitive Functions.

UNLABELLED: To present a review of cross-sectional and longitudinal studies that investigate the relationship between the hormones Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone sulfate (DHEA-S) and cognition. METHODS: The cognition items included in this review were global cognitive function, memory, attention, executive function, intelligence, perception and visuospatial ability. A systematic review was proceeded using three databases: PubMed, ISI Web of Science, and PsycINFO. RESULTS: Two thousand fifty five references about cognition and hormones were found; 772 duplicated references were excluded, resulting in 1.283 references to be evaluated. According to exclusion and inclusion criteria, 25 references were selected. A positive correlation between DHEA-S blood levels and global cognition was found in women and men. Other positive correlations between DHEA-S and working memory, attention and verbal fluency were found only in women. The DHEA effect on cognition is limited to one study conducted among young men with high-doses.

DHEA supplementation in ovariectomized rats reduces impaired glucose-stimulated insulin secretion induced by a high-fat diet.

Dehydroepiandrosterone (DHEA) and the dehydroepiandrosterone sulfate (DHEA-S) are steroids produced mainly by the adrenal cortex. There is evidence from both human and animal models suggesting beneficial effects of these steroids for obesity, diabetes mellitus, hypertension, and osteoporosis, conditions associated with the post-menopausal period. Accordingly, we hypothesized that DHEA supplementation in ovariectomized (OVX) female rats fed a high-fat diet would maintain glucose-induced insulin secretion (GSIS) and pancreatic islet function. OVX resulted in a 30% enlargement of the pancreatic islets area compared to the control rats, which was accompanied by a 50% reduction in the phosphorylation of AKT protein in the pancreatic islets. However, a short-term high-fat diet induced insulin resistance, accompanied by impaired GSIS in isolated pancreatic islets. These effects were reversed by DHEA treatment, with improved insulin sensitivity to levels similar to the control group, and with increased serine phosphorylation of the AKT protein. These data confirm the protective effect of DHEA on the endocrine pancreas in a situation of diet-induced overweight and low estrogen concentrations, a phenotype similar to that of the post-menopausal period.

Nongenomic bronchodilating action elicited by dehydroepiandrosterone (DHEA) in a guinea pig asthma model.

Primates secrete large amounts of the precursor steroid dehydroepiandrosterone (DHEA); in humans, its levels are low during childhood and start declining after the fourth decade. It has been postulated that the progressive decline in DHEA levels may be related with the severity of asthma associated with age. To determine whether DHEA may regulate the airway smooth muscle (ASM) activity, isolated tracheal rings with and without epithelium from male guinea pigs were isometrically recorded to characterize the response of ASM to DHEA at different concentrations on KCl- and carbachol (CCh)-induced contraction as well as on ovalbumin (OVA)-induced contraction in sensitized guinea pigs. Additionally, we used barometric plethysmography in sensitized guinea pigs in order to compare changes of the lung resistance increased by the antigen challenge to OVA in the absence and presence of different doses of DHEA. DHEA concentration-dependently abolished the contraction to KCl, CCh and OVA, and no differences were found in preparations with and without epithelium. DHEA-induced relaxation was not modified by the suppression of protein synthesis or transcription, pharmacological inhibition of nitric oxide (NO) synthase, nor by antagonist of ß2-adrenergic receptors or an inhibitor of the 3ß-HSD enzyme. Likewise, Ca(2+)-induced contraction in Ca(2+)-free depolarized tissues was antagonized by DHEA, and the contraction to the L-type voltage-dependent calcium channel activator (Bay K 8644) was inhibited by DHEA. Furthermore, DHEA prevented OVA-induced increases in lung resistance. These results indicate that DHEA-induced relaxation in ASM is a nongenomic (membrane) action and is not produced after its bioconversion. The data suggest that DHEA-induced relaxation is an epithelium- and NO-independent mechanism that involves a blockade of voltage-dependent calcium channels and possible non-selective cation channels.

A rational, non-radioactive strategy for the molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

CONTEXT: Molecular diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) has not been straightforward. OBJECTIVE: To conduct a comprehensive genetic analysis by Multiplex Ligation dependent Probe Amplification (MLPA) and evaluate its reliability for the molecular CAH-21OHD diagnosis. PATIENTS AND METHODS: We studied 99 patients from 90 families with salt-wasting (SW; n=32), simple-virilizing (SV; n=29), and non-classical (NC; n=29) CAH-21OHD. Molecular analysis was sequentially performed by detecting the most frequent point mutations by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), large rearrangements by MLPA, and rare mutations by direct sequencing. Parental segregation was evaluated. RESULTS: ASO-PCR detected microconversions in 164 alleles (91.1%). MLPA identified CYP21A1P large conversions to CYP21A2 in 7 of the remaining 16 (43.7%), 30-kb deletions including the 3'-end of CYP21A1P, C4B, and the 5'-end of CYP21A2 in 3 of the 16 (18.7%), and a complete CYP21A2 deletion in one (6.3%). Five alleles (2.7%) required direct sequencing; three mutations located in the CYP21A2 gene and two derived from CYP21A1P were found. No parental segregation was observed in patients with the c.329_336del and/or the CL6 cluster mutations. These cases were not diagnosed by ASO-PCR, but MLPA detected deletions in the promoter region of the CYP21A2 gene, explaining the genotype/phenotype dissociation. CONCLUSION: Using the proposed algorithm, all alleles were elucidated. False-positive results in MLPA occurred when mutations or polymorphisms were located close to the probe-binding regions. These difficulties were overcome by the association of MLPA with ASO-PCR and paternal segregation. Using these approaches, we can successfully use MLPA in a cost-effective laboratory routine for the molecular diagnosis of CAH-21OHD.