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Cirrhotic patients are susceptible to sepsis and critical illness-related corticosteroid insufficiency (CIRCI). Dehydroepiandrosterone sulfate (DHEAS) is a corticotropin-dependent adrenal androgen, which has immunostimulating and antiglucocorticoid effects. Considering the synchronized synthesis of cortisol and DHEAS and their opposing effects to each other, investigators have proposed measuring these two hormones as a ratio. Severe sepsis has been associated with low DHEAS, especially relative to high cortisol. Despite growing interest in the role of adrenal androgen replacement in critical illness, there have been no data about DHEAS and the DHEAS/cortisol ratio in patients with liver cirrhosis. We studied whether low concentrations of DHEAS and decreased DHEAS/cortisol ratio are associated with poor outcome in patients with liver cirrhosis and septic shock.
Background and Purpose: Previous studies found inconsistent results for the relationship between Alzheimer's disease and the levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate. This study performed a systematic review and meta-analysis to evaluate previous studies' results on this relationship. Method: Studies related to this outcome were obtained using a systematic search from the electronic databases of PubMed, Embase, Web of Science, and Psyc-ARTICLES in March 2018. The random-effects model was used to measure the strength of the association between Alzheimer's disease and the levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate, using the standardized mean difference. Results: Thirty-one eligible studies were included in the final analysis. There was no statistically significant association between the level of dehydroepiandrosterone and Alzheimer's disease (standardized mean difference: 0.51, 95% confidence interval: -0.44 to 1.45, Z = 1.06, p = 0.29). On the other hand, lower level dehydroepiandrosterone sulfate was observed in patients with Alzheimer's disease than in controls (standardized mean difference: -0.69, 95% confidence interval: -1.17 to -0.22, Z = -2.84, p < 0.01). Conclusion: Decreased dehydroepiandrosterone sulfate concentrations may be an important indicator for Alzheimer's disease, although whether dehydroepiandrosterone sulfate could be used as a diagnostic tool requires further research.
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.
Basal levels of monoamines and DHEA in four main limbic brain regions were measured in prepubertal Wistar Kyoto (WKY) rats (a putative animal model of childhood depression). Basal levels of "Brain-Derived Neurotrophic Factor (BDNF)" were also determined in two regions in the hippocampus, compared with Wistar strain controls. In the second phase, we examined the responsiveness of prepubertal WKY rats to different types of chronic antidepressant treatments: Fluoxetine, Desipramine, and dehydroepiandrosterone sulfate (DHEAS). WKY prepubertal rats exhibited different monoamine levels in the limbic system, reduced DHEA levels in the VTA and lower levels of BDNF in the hippocampus CA3 region compared to controls. In prepubertal WKY rats, only treatment with DHEAS produced a statistically significant decrease in immobility, compared to saline-administered controls in the forced swim test. Wistar controls were not affected by any antidepressant. The results imply that DHEA(S) and BDNF may be involved in the pathophysiology and pharmacotherapy of childhood depression.
Neuropsychiatric symptoms are important treatment targets in the management of dementia and can be present at very early clinical stages of neurodegenerative diseases. Increased cortisol has been reported in Alzheimer's disease (AD) and has been associated with faster cognitive decline. Elevated cortisol output has been observed in relation to perceived stress, depression, and anxiety. Dehydroepiandrosterone sulfate (DHEAS) has known anti-glucocorticoid effects and may counter the effects of cortisol.
Dehydroepiandrosterone sulfate (DHEAS) is the most abundant circulating steroid in human, with the highest concentrations between age 20 and 30, but displaying a significant decrease with age. Many beneficial functions are ascribed to DHEAS. Nevertheless, long-term studies are very scarce concerning the intake of DHEAS over several years, and molecular investigations on DHEAS action are missing so far. In this study, the role of DHEAS on the first and rate-limiting step of steroid hormone biosynthesis was analyzed in a reconstituted in vitro system, consisting of purified CYP11A1, adrenodoxin and adrenodoxin reductase. DHEAS enhances the conversion of cholesterol by 26%. Detailed analyses of the mechanism of DHEAS action revealed increased binding affinity of cholesterol to CYP11A1 and enforced interaction with the electron transfer partner, adrenodoxin. Difference spectroscopy showed K(d)-values of 40 ± 2.7 µM and 24.8 ± 0.5 µM for CYP11A1 and cholesterol without and with addition of DHEAS, respectively. To determine the K(d)-value for CYP11A1 and adrenodoxin, surface plasmon resonance measurements were performed, demonstrating a K(d)-value of 3.0 ± 0.35 nM (with cholesterol) and of 2.4 ± 0.05 nM when cholesterol and DHEAS were added. Kinetic experiments showed a lower Km and a higher kcat value for CYP11A1 in the presence of DHEAS leading to an increase of the catalytic efficiency by 75%. These findings indicate that DHEAS affects steroid hormone biosynthesis on a molecular level resulting in an increased formation of pregnenolone.
Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are the most abundant steroids in humans, and their serum concentrations progressively decrease with age. Although relationships between DHEA(-S) and many age-related illnesses have been postulated, the mechanisms for their effects remain unknown, and specific receptors for these molecules have not been identified. In this paper, to investigate the role of DHEA(-S) in atherogenesis, we studied the proliferation and migration of a rabbit vascular smooth muscle cell line, SM-3, in the presence of DHEA(-S). Cellular proliferation was inhibited by DHEA-S, and to a lesser extent by DHEA. Modified Boyden's chamber assays revealed that DHEA-S inhibited the migration of SM-3 cells toward PDGF-BB. In cell attachment assays, DHEA-S inhibited the attachment of SM3 cells to fibronectin. It was suggested that the inhibitory effect of DHEA-S for SM-3 proliferation and migration was due to the decreased interaction with fibronectin. Scatchard analysis revealed the presence of two populations of DHEA-S binding sites in the nuclear fraction, and a smaller number in the cytosolic fraction. Since the dissociation constant of the higher affinity site was similar to the serum DHEA-S concentration in humans (Kd = 5.8 microM), this binding site could be functional under physiologic conditions. These findings suggest that there may be receptor-mediated anti-atherogenic actions of DHEA-S.
Dehydroepiandrosterone sulfate (DHEAs), a prohormone secreted by the adrenal gland, plays a role in the synthesis of sex hormones, namely, androgen and estrogen. It has been found that the amount of DHEAs is correlated with age, although most studies have focused on the correlation of serum DHEAs levels with age and sex. Thus, this noninvasive, cross-sectional study aimed to investigate the correlation of urine DHEAs levels with age and sex in healthy Thai volunteers aged 20-80 years.
Human fetal cytochrome P450 3A7 (CYP3A7) is involved in both xenobiotic metabolism and the estriol biosynthetic pathway. Although much is understood about cytochrome P450 3A4 and its role in adult drug metabolism, CYP3A7 is poorly characterized in terms of its interactions with both categories of substrates. Herein, a crystallizable mutated form of CYP3A7 was saturated with its primary endogenous substrate dehydroepiandrosterone 3-sulfate (DHEA-S) to yield a 2.6 Å X-ray structure revealing the unexpected capacity to simultaneously bind four copies of DHEA-S. Two DHEA-S molecules are located in the active site proper, one in a ligand access channel, and one on the hydrophobic F'-G' surface normally embedded in the membrane. While neither DHEA-S binding nor metabolism exhibit cooperative kinetics, the current structure is consistent with cooperativity common to CYP3A enzymes. Overall, this information suggests that mechanism(s) of CYP3A7 interactions with steroidal substrates are complex.
Tight junctions (TJ) between brain endothelial cells are essential for formation and maintenance of the blood-brain barrier (BBB). Although loss of BBB integrity is associated with several neuropathological disorders, treatments that augment or stabilise the BBB are scarce. Here we show that physiological concentrations of dehydroepiandrosterone sulfate (DHEAS) stimulate the expression of the TJ proteins zonula occludens-1 (ZO-1) and claudin-3 in the brain-derived endothelial cell line bEnd.3 and promote TJ formation between neighbouring cells, demonstrated by augmented transendothelial resistance across cell monolayers. Silencing androgen receptor expression by siRNA does not prevent DHEAS-induced stimulation of ZO-1 expression, indicating that conversion of DHEAS into testosterone is not required for its actions. Suppression of Gnα11 expression by siRNA prevents DHEAS actions, pointing towards a G-protein-coupled receptor as being a mediator of the DHEAS effects. These results are consistent with the idea that DHEAS, acting as a hormone in its own right, supports the integrity of the BBB. The current findings might help in developing new strategies for the prevention or treatment of neurological disorders associated with BBB defects.
Low blood dehydroepiandrosterone sulfate (DHEAS) levels have strong positive associations with stroke and coronary heart disease. However, it is unclear whether DHEAS is independently associated with cardiovascular risk factors. Therefore, we examined the association between cardiovascular risk factors and DHEAS concentration among a high-risk population of Latinos (Puerto Ricans aged 45 to 75 years at baseline) in a cross-sectional analysis of the Boston Puerto Rican Health Study. Of eligible participants, 72% completed baseline interviews and provided blood samples. Complete data were available for 1355 participants. Associations between cardiovascular risk factors (age, sex, total cholesterol, high-density lipid cholesterol, triglycerides, and glucose) and log-transformed DHEAS (μg/dL) were assessed. In robust multivariable regression analyses, DHEAS was significantly inversely associated with age (β = -12.4; 95% CI: -15.2, -9.7; per 5 years), being female (vs. male) (β = -46; 95% CI: -55.3, -36.6), and plasma triglyceride concentration (β = -0.2; 95% CI: -0.3, -0.1; per 10 mg/dL) and was positively associated with total cholesterol and plasma glucose levels (β = 1.8; 95% CI: 0.6, 3 and β = 0.2; 95% CI: 0.04, 0.3, respectively, per 10 mg/dL) after adjustment for smoking, alcohol, and physical activity and for postmenopausal hormone use in women. Estimates were unchanged after adjustment for measures of chronic disease and inflammation. Women exhibited a stronger age-related decline in DHEAS and a positive association with glucose in contrast to findings among men (P interaction < 0.05). In conclusion, in this large study of Latinos with a heavy cardiovascular risk factor burden, we observed significant associations between cardiovascular disease (CVD) risk factors and DHEAS, with variations by sex. These findings improve our understanding of the role DHEAS may play in CVD etiology.
Introduction: An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are typical for adrenal tumors. Approximately 74% of DHEAS is hydrolyzed to DHEA by the steroid sulfatase (STS). The reverse reaction is DHEA sulfation. Besides these two enzyme reactions, the DHEAS transported through the cell membrane is important for its distribution and excretion. Case Presentation: We present a female adolescent with overweight and a very high DHEAS. The presence of a DHEAS-producing tumor was rejected using ultrasonography, Magnetic Resonance Tomography (MRT), and dexamethasone suppression. STS deficiency was suspected. Sequence analysis revealed a heterozygous nonsense mutation which predicts a truncation of the carboxyl region of the STS that is implicated in substrate binding. No partial gene deletion outside exon 5 was detected by multiplex ligation-dependent probe amplification. The bioassay revealed normal enzyme activity in the patient's leukocytes. A defect of transporter proteins was suggested. Both efflux [multidrug-resistance protein (MRP)2 and breast cancer-resistance protein (BCRP)] and uptake [organic anion-transporting polypeptide (OATP) and organic anion transporter (OAT) carriers] transporters were studied. Sequence analysis of exons revealed a heterozygous Q141K variant for BCRP. Conclusions: A novel heterozygous nonsense mutation in the STS gene and a known heterozygous missense variant in the BCRP gene were found. The heterozygous nonsense mutation in the STS gene is not supposed to be responsible for STS deficiency. The BCRP variant is associated with reduced efflux transport activity only in its homozygous state. The combination of the two heterozygous mutations could possibly explain the observed high levels of DHEAS and other sulfated steroids.
Employee problems arising from mental illnesses have steadily increased and become a serious social problem in recent years. Wood is a widely available plant material, and knowledge of the psychophysiological effects of inhalation of woody volatile compounds has grown considerably. In this study, we established an experimental method to evaluate the effects of Japanese cedar wood essential oil on subjects performing monotonous work. Two experiment conditions, one with and another without diffusion of the essential oil were prepared. Salivary stress markers were determined during and after a calculation task followed by distribution of questionnaires to achieve subjective odor assessment. We found that inhalation of air containing the volatile compounds of Japanese cedar wood essential oil increased the secretion of dehydroepiandrosterone sulfate (DHEA-s). Slight differences in the subjective assessment of the odor of the experiment rooms were observed. The results of the present study indicate that the volatile compounds of Japanese cedar wood essential oil affect the endocrine regulatory mechanism to facilitate stress responses. Thus, we suggest that this essential oil can improve employees' mental health.
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