PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (944495)

Clipboard (0)
None

Related Articles

1.  A SULT2A1 genetic variant identified by GWAS as associated with low serum DHEAS does not impact on the actual DHEA/DHEAS ratio 
DHEA is the major precursor of human sex steroid synthesis and is inactivated via sulfonation to DHEAS. A previous genome-wide association study related the single nucleotide polymorphism (SNP) rs2637125, located near the coding region of DHEA sulfotransferase, SULT2A1, to serum DHEAS concentrations. However, the functional relevance of this SNP with regard to DHEA sulfonation is unknown. Using data from 3300 participants of the population-based cohort Study of Health in Pomerania, we identified 43 individuals being homozygote for the minor allele of the SNP rs2637125 (AA) and selected two sex- and age-matched individuals with AG and GG genotype (n=172) respectively. Steroid analysis including measurement of serum DHEA and DHEAS was carried out by liquid chromatography/mass spectrometry, employing steroid oxime analysis for enhancing the sensitivity of DHEA detection. We applied quantile regression models to compare median hormone levels across SULT2A1 genotypes. Median comparisons by SULT2A1 genotype (AA vs AG and GG genotypes respectively) showed no differences in the considered hormones including DHEAS, DHEA, androstenedione, as well as cortisol and cortisone concentrations. SULT2A1 genotype also had no effect on the DHEA/DHEAS ratio. Sex-stratified analyses, as well as alternative use of the SULT2A1 SNP rs182420, yielded similar negative results. Genetic variants of SULT2A1 do not appear to have an effect on individual DHEA and DHEAS concentrations or the DHEA/DHEAS ratio as a marker of DHEA sulfonation capacity.
doi:10.1530/JME-12-0185
PMCID: PMC3535724  PMID: 23132913
DHEAS; steroids; genome-wide association study; genetics; epidemiology
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.  Differences in androgens of HIV positive patients with and without Kaposi sarcoma. 
Journal of Clinical Pathology  1995;48(6):513-518.
AIM--Since most forms of Kaposi sarcoma are much more common in men than in women, the aim of this study was to examine serum concentrations of sex steroids in HIV positive men with and without Kaposi sarcoma. METHODS--Blood samples from 34 HIV positive men without Kaposi sarcoma (KS-) and 28 with Kaposi sarcoma (KS+) and from 35 HIV negative men (controls) were analysed for adrenal and gonadal steroids. Further analysis was done in subgroups classified by CD4 lymphocyte counts. RESULTS--KS+ patients had significantly higher serum dehydroepiandrosterone (DHEA) and testosterone concentrations than the KS- patients, and their DHEA, DHEA sulphate, testosterone, and androstenedione values were higher than in the controls. The KS+ patients with more than 500 CD4 lymphocytes per mm3 had significantly higher serum DHEA, DHEA sulphate, and testosterone than the KS- patients with the same CD4 counts; those with 500-200 CD4 cells/mm3 had higher serum DHEA and testosterone than the equivalent KS- men; and those with < 200 CD4 cells/mm3 had raised DHEA only compared with KS- men. Both KS+ and KS- men had higher serum progesterone and oestradiol than the controls. Glucocorticoids were not significantly altered. CONCLUSIONS--The high androgen levels in KS+ patients, particularly in the early stages of the disease (> 500 CD4 cells/mm3), may affect the immune system by inducing an abnormal cytokine profile, or by increasing T8 proliferation and activation, or both. This raises the question of the relationship between androgens and Kaposi sarcoma.
PMCID: PMC502679  PMID: 7665693
4.  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
5.  Lack of substrate inhibition in a monomeric form of human cytosolic SULT2A1 
Mammalian cytosolic sulfotransferases (SULTs) frequently show substrate inhibition during the sulfation of increasing concentrations of substrates. SULT2A1, a major human liver isoform responsible for the conjugation of hydroxysteroids, bile acids and aliphatic hydroxyl groups in drugs and xenobiotics, is a homodimer and displays substrate inhibition during the conjugation of dehydroepiandrosterone (DHEA). Maltose binding protein (MBP)-SULT2A1 fusion protein, produced as an intermediate step in the purification of the SULT2A1 homodimer, elutes during size exclusion chromatography as a monomer. The initial-rate parameters (Km and Vmax) of the monomer (MBP-SULT2A1) and native SULT2A1 dimer for DHEA sulfation are extremely similar; however, the monomer is not inhibited by DHEA. Intrinsic fluorescence studies show that two DHEA molecules bind each SULT2A1 subunit, one in the catalytic site and one in an apparent allosteric site. Lack of dimerization in the MBP-SULT2A1 fusion protein decreased the Kd for binding of DHEA at the allosteric site. These results suggest that formation of the homodimer is associated with structural rearrangements leading to increased DHEA binding at an allosteric site that is associated with substrate inhibition.
PMCID: PMC3150496  PMID: 21822453
dehydroepiandrosterone; dimerization; maltose binding protein; substrate inhibition; sulfation; sulfotransferase; SULT2A1
6.  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
7.  Associations between polymorphisms in glucuronidation and sulfation enzymes and sex steroid concentrations in premenopausal women in the United States 
Glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGT) and sulfation, catalyzed by sulfotransferases (SULT), are pathways through which sex steroids are metabolized to less active compounds. These enzymes are highly polymorphic and genetic variants frequently result in higher or lower activity. The phenotypic effects of these polymorphisms on circulating sex steroids in premenopausal women have not yet been investigated. One hundred and seventy women ages 40-45 years had a blood sample drawn during the follicular phase of the menstrual cycle for sex steroid measures and to obtain genomic DNA. Urine was collected for 2-hydroxy (OH) estrone (E1) and 16α-OH E1 measures. Generalized linear regression models were used to assess associations between sex steroids and polymorphisms in the UGT1A and UGT2B families, SULT1A1, and SULT1E1. Women with the UGT1A1(TA7/TA7) genotype had 25% lower mean estradiol (E2) concentrations compared to the wildtype (TA6/TA6) (p = 0.02). Similar associations were observed between SULT1A1(R213/H213) and E1 (13% lower mean E1 concentration vs. wildtype; p-value = 0.02) and UGT2B4(E458/E458) and dehydroepiandrosterone (DHEA) (20% lower mean DHEA vs. wildtype; p-value = 0.03). The SULT1E1(A/C) and the UGT1A1(TA7)-UGT1A3(R11) haplotypes were associated with reduced estrogen concentrations. Further study of UGT and SULT polymorphisms and circulating sex steroid measures in larger populations of premenopausal women is warranted.
doi:10.1016/j.jsbmb.2010.12.014
PMCID: PMC3065887  PMID: 21193038
Uridine diphosphoglucuronosyltransferases; sulfotransferases; estrogens; androgens; premenopausal women
8.  Activation of peroxisome proliferator-activated receptors by chlorinated hydrocarbons and endogenous steroids. 
Environmental Health Perspectives  1998;106(Suppl 4):983-988.
Trichloroethylene (TCE) and related hydrocarbons constitute an important class of environmental pollutants whose adverse effects on liver, kidney, and other tissues may, in part, be mediated by peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors belonging to the steroid receptor superfamily. Activation of PPAR induces a dramatic proliferation of peroxisomes in rodent hepatocytes and ultimately leads to hepatocellular carcinoma. To elucidate the role of PPAR in the pathophysiologic effects of TCE and its metabolites, it is important to understand the mechanisms whereby PPAR is activated both by TCE and endogenous peroxisome proliferators. The investigations summarized in this article a) help clarify the mechanism by which TCE and its metabolites induce peroxisome proliferation and b) explore the potential role of the adrenal steroid and anticarcinogen dehydroepiandrosterone 3beta-sulfate (DHEA-S) as an endogenous PPAR activator. Transient transfection studies have demonstrated that the TCE metabolites trichloroacetate and dichloroacetate both activate PPAR alpha, a major liver-expressed receptor isoform. TCE itself was inactive when tested over the same concentration range, suggesting that its acidic metabolites mediate the peroxisome proliferative potential of TCE. Although DHEA-S is an active peroxisome proliferator in vivo, this steroid does not stimulate trans-activation of PPAR alpha or of two other PPAR isoforms, gamma and delta/Nuc1, when evaluated in COS-1 cell transfection studies. To test whether PPAR alpha mediates peroxisomal gene induction by DHEA-S in intact animals, DHEA-S has been administered to mice lacking a functional PPAR alpha gene. DHEA-S was thus shown to markedly increase hepatic expression of two microsomal P4504A proteins associated with the peroxisomal proliferative response in wild-type mice. In contrast, DHEA-S did not induce these hepatic proteins in PPAR alpha-deficient mice. Thus, despite its unresponsiveness to steroidal peroxisome proliferators in transfection assays, PPAR alpha is an obligatory mediator of DHEA-S-stimulated hepatic peroxisomal gene induction. DHEA-S, or one of its metabolites, may thus serve as an important endogenous regulator of liver peroxisomal enzyme expression.
Images
PMCID: PMC1533341  PMID: 9703482
9.  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
10.  Dehydroepiandrosterone and age-related cognitive decline 
Age  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
11.  Dehydroepiandrosterone and age-related cognitive decline 
Age (Dordrecht, Netherlands)  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
12.  DHEAS Levels and Mortality in Disabled Older Women: The Women’s Health and Aging Study I 
Background
Dehydroepiandrosterone sulfate (DHEAS) is an endogenously produced sex steroid that has been hypothesized to have anti-aging effects. Low DHEAS levels are associated with mortality in older men, but the relationship between DHEAS levels and mortality in women is not clearly defined.
Methods
The relationship between serum DHEAS level and 5-year mortality was analyzed in a cohort of 539 disabled women aged 65–100 years enrolled in the Women’s Health and Aging Study I (WHAS I). Using Cox proportional hazard models, we calculated multivariate-adjusted mortality risks by DHEAS quartiles and by DHEAS continuously, allowing for a nonlinear relationship. We also examined cause-specific mortality.
Results
We found a U-shaped relationship between DHEAS level and mortality. After adjusting for multiple covariates, women in the top and bottom DHEAS quartiles had a more than 2-fold higher 5-year mortality than did those in the middle quartiles (hazard ratio, 2.15; 95% confidence interval [CI], 1.17–3.98 for the top quartile and 2.05; 95% CI, 1.27–3.32 for the bottom quartile, each compared to the third quartile). Women with higher DHEAS levels tended to have greater cancer mortality, whereas those with lower DHEAS tended to have greater cardiovascular mortality.
Conclusion
Disabled older women with either low or high levels of DHEAS are at greater risk for death than are those with intermediate levels. More research is needed to determine if targeted dehydroepiandrosterone supplementation would provide clinical benefit to disabled older women.
PMCID: PMC2645634  PMID: 16960027
13.  Ethnic Differences in DNA Methyltransferases Expression in Patients with Systemic Lupus Erythematosus 
Journal of Clinical Immunology  2012;33(2):342-348.
Purpose
Systemic lupus erythematous (SLE) is a systemic autoimmune inflammatory disease with both genetic and epigenetic etiologies. Evidence suggests that deregulation of specific genes through epigenetic mechanisms may be a contributing factor to SLE pathology. There is increasing evidence that DNA methyltransferase activity may be involved. This study demonstrated modulation in expression of DNA methyltransferases (DNMTs) according to ethnicity in patients diagnosed with SLE. Furthermore, differential expression in one of the DNMTs was found in a subset of lupus patients on dehydroepiandrosterone (DHEA) therapy.
Methods
Real-time PCR analyses of DNMT1, DNMT3A and DNMT3B in peripheral blood mononuclear cells from a cohort of African American and European American lupus and non-lupus women were conducted. Also, global DNA methylation was assessed using the MethylFlashTM methylated quantification colorimetric assay.
Results
Significant increase in DNMT3A (p < 0.001) was shown in lupus patients when compared to age-matched healthy controls. This increase was associated with a higher SLEDI index. More striking was that expression levels for African American (AA) women were higher than European American women in the lupus populations. A subset of AA women on DHEA therapy showed a significant decrease (p < 0.05) in DNMT3A expression in comparison to lupus patients not on the therapy. DHEA is an androgenic steroid found in low levels in the serum of lupus patients. Supplementation of this hormone has been shown to be beneficial to some lupus patients. DHEA was not shown to effect DNMT1 or DNMT3B expression. Increased expression was also noted in DNMT3B (p < 0.05) in lupus patients compared to age-matched healthy controls. However, no significant difference was noted in DNMT1 (p = 0.2148) expression between lupus patients and healthy controls. Although increases were detected in de novo methyltransferases, a global decrease (p < 0.001) in 5-methycytosine was observed in lupus patients when compared to age-matched healthy controls.
Conclusion
These findings suggest that epigenetic changes may play a critical role in the manifestations of the disease observed among ethnic groups, particularly African American women who often have a higher incidence of lupus. DHEA therapy effects on DNMT3A expression in AA women warrant further investigation in a larger population.
doi:10.1007/s10875-012-9803-z
PMCID: PMC3573322  PMID: 23054340
Lupus; DNA methyltransferases; DHEA; DNMT3A; DNMT3B; DNMT1
14.  Substrate inhibition in human hydroxysteroid sulfotransferase SULT2A1: studies on the formation of catalytically non-productive enzyme complexes 
The cytosolic sulfotransferase hSULT2A1 is the major hydroxysteroid (alcohol) sulfotransferase in human liver, and it catalyzes the 3′-phosphoadenosine-5′-phosphosulfate (PAPS)-dependent sulfation of various endogenous hydroxysteroids as well as many xenobiotics that contain alcohol and phenol functional groups. The hSULT2A1 often displays substrate inhibition, and we have hypothesized that a key element in this response to increasing substrate concentration is the formation of non-productive ternary dead-end enzyme complexes involving the nucleotide product, adenosine 3′,5′-diphosphate (PAP). One of these substrates for hSULT2A1 is dehydroepiandrosterone (DHEA), a major circulating steroid hormone in humans that serves as precursor to both androgens and estrogens. We have utilized DHEA in both initial velocity studies and equilibrium binding experiments in order to evaluate the potential role of ternary complexes in substrate inhibition of the enzyme. Our results indicate that hSULT2A1 forms non-productive ternary complexes that involve either DHEA or dehydroepiandrosterone sulfate, and the formation of these ternary complexes displays negative cooperativity in the binding of DHEA.
doi:10.1016/j.abb.2010.12.027
PMCID: PMC3058861  PMID: 21187059
sulfotransferase; hydroxysteroid; hSULT2A1; substrate inhibition; negative cooperativity; non-productive enzyme complexes
15.  ACE inhibitor use was associated with lower serum dehydroepiandrosterone concentrations in older men 
Context
Angiotensin converting enzyme (ACE) activity may influence the production of adrenal androgen precursors and testosterone. Use of ACE inhibitors may therefore have an influence on serum sex hormone concentrations in older men.
Design and Methods
1486 out of 2,000 community-dwelling Chinese men aged 65 years who participated in a cohort study were randomly selected to have archived fasting morning serum analyzed for androgen precursors and sex hormones. DNA was extracted from whole blood and analyzed for ACE gene I/D polymorphism.
Results
Subjects with the ACE gene D allele (higher ACE activity) had higher serum dehydroepiandrosterone (DHEA) sulphate and DHEA than those with I/I genotype (P=0.014 and 0.018 respectively, Mann Whitney test). These differences were not significant after Bonferroni correction. Among those with history of hypertension, but without diabetes mellitus or cardiac failure, users of ACE inhibitors had significantly lower serum DHEA (median 1.78 versus 1.49 ng/ml in non-users, P =0.0074, Mann Whitney test) and also tended to have lower serum androstenedione and androst-5-ene-3β,17β-diol (0.68 versus 0.72 ng/ml in non-users; 552.4 versus 624.1 pg/ml respectively, both P values <0.05). Serum testosterone and estradiol were not significantly changed.
Conclusions
ACE inhibitor use was associated with lower serum DHEA in older men.
doi:10.1016/j.cca.2010.04.011
PMCID: PMC2883618  PMID: 20403346
androgen; dehydroepiandrosterone; angiotensin converting enzyme; angiotensin converting enzyme inhibitor; gene polymorphism
16.  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
17.  Androstenediol Complements Estrogenic Bioactivity during the Menopausal Transition 
Menopause (New York, N.y.)  2012;19(6):650-657.
Objective
The perimenopausal increase in circulating dehydroepiandrosterone sulfate (DHEAS) levels during the menopausal transition (MT) is accompanied by other adrenal steroids that have the potential to alter the estrogen/androgen balance and explain the wide inter-woman range of estrogen-related symptoms experienced during the MT.
Methods
Annual serum samples from the Study of Women’s Health Across the Nation (SWAN), which had previously been analyzed for immunoreactive estradiol (E2), testosterone (T), DHEAS and sex hormone binding globulin (SHBG), were selected based on DHEAS concentration and analyzed for immunoreactive and bioactive estrogens and androgens, including immunoreactive androstenedione (Adione), dehydroepiandrosterone (DHEA) and 5-androstene-3β,17β-diol (androstenediol, Adiol).
Results
A two-fold increase in circulating Adione and T was found to rise in parallel with the rise in circulating DHEAS, while DHEA and Adiol concentrations rose seven to eightfold. Circulating Adiol, which has both androgenic and estrogenic biological activity, was significantly associated (p<0.02) with circulating estrogen bioactivity only when E2 concentrations were low and Adiol levels were high.
Conclusions
The wide range of circulating levels of Adiol and its contribution to total circulating estrogenicity during the MT is consistent with the observed inter-woman difference in symptoms at this time. Therefore, we conclude that Adiol contributes to circulating estrogenicity when E2 production falls at menopause and may contribute significantly to the endocrine changes experienced by midlife women.
doi:10.1097/gme.0b013e31823df577
PMCID: PMC3366061  PMID: 22415563
Androstenediol; estrogenicity; menopause; adrenal
18.  Neurosteroid Dehydroepiandrosterone Interacts with Nerve Growth Factor (NGF) Receptors, Preventing Neuronal Apoptosis 
PLoS Biology  2011;9(4):e1001051.
The neurosteroid dehydroepiandrosterone (DHEA), produced by neurons and glia, affects multiple processes in the brain, including neuronal survival and neurogenesis during development and in aging. We provide evidence that DHEA interacts with pro-survival TrkA and pro-death p75NTR membrane receptors of neurotrophin nerve growth factor (NGF), acting as a neurotrophic factor: (1) the anti-apoptotic effects of DHEA were reversed by siRNA against TrkA or by a specific TrkA inhibitor; (2) [3H]-DHEA binding assays showed that it bound to membranes isolated from HEK293 cells transfected with the cDNAs of TrkA and p75NTR receptors (KD: 7.4±1.75 nM and 5.6±0.55 nM, respectively); (3) immobilized DHEA pulled down recombinant and naturally expressed TrkA and p75NTR receptors; (4) DHEA induced TrkA phosphorylation and NGF receptor-mediated signaling; Shc, Akt, and ERK1/2 kinases down-stream to TrkA receptors and TRAF6, RIP2, and RhoGDI interactors of p75NTR receptors; and (5) DHEA rescued from apoptosis TrkA receptor positive sensory neurons of dorsal root ganglia in NGF null embryos and compensated NGF in rescuing from apoptosis NGF receptor positive sympathetic neurons of embryonic superior cervical ganglia. Phylogenetic findings on the evolution of neurotrophins, their receptors, and CYP17, the enzyme responsible for DHEA biosynthesis, combined with our data support the hypothesis that DHEA served as a phylogenetically ancient neurotrophic factor.
Author Summary
Dehydroepiandrosterone (DHEA) and its sulphate ester are the most abundant steroid hormones in humans, and DHEA was described as the first neurosteroid produced in the brain. DHEA is known to participate in multiple events in the brain, including neuronal survival and neurogenesis. However, to date no specific cellular receptor has been described for this important neurosteroid. In this study, we provide evidence that DHEA exerts its neurotrophic effects by directly interacting with the TrkA and p75NTR membrane receptors of nerve growth factor (NGF), and efficiently activates their downstream signaling pathways. This activation prevents the apoptotic loss of NGF receptor positive sensory and sympathetic neurons. The interaction of DHEA with NGF receptors may also offer a mechanistic explanation for the multiple actions of DHEA in other peripheral biological systems expressing NGF receptors, such as the immune, reproductive, and cardiovascular systems.
doi:10.1371/journal.pbio.1001051
PMCID: PMC3082517  PMID: 21541365
19.  Low DHEAS levels are associated with depressive symptoms in elderly Chinese men: results from a large study 
Asian Journal of Andrology  2011;13(6):898-902.
This study investigated the association between depressive symptoms in elderly Chinese men and the total testosterone, dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), oestradiol and sex hormone-binding globulin (SHBG) levels, and the free androgen index. Cross-sectional data from 1147 community-dwelling elderly men, aged 65 and older, were used. Depressive symptoms were measured using the Chinese Geriatric Depression Scale (GDS). Total testosterone, free testosterone, DHEA, DHEAS, total oestradiol, the free androgen index and SHBG levels were assessed. DHEA was significantly associated with GDS score, and there was a trend towards DHEAS association, but this was not significant (β=−0.110, P=0.015; β=−0.074, P=0.055). However, no association was seen between depressive symptoms and total testosterone levels, free testosterone levels, oestradiol levels or SHBG levels. In terms of the presence of clinically relevant depressive symptoms, there were no statistically significant differences between patients in the lowest quartile of sex steroid hormone levels and those in other quartiles of sex steroid hormone levels. Similarly to Western studies, our study shows that DHEA and DHEAS levels are associated with depressive symptoms.
doi:10.1038/aja.2011.116
PMCID: PMC3739563  PMID: 21874029
Chinese; dehydroepiandrosterone; depression; elderly men; testosterone
20.  Dehydroepiandrosterone-dependent induction of peroxisomal proliferation can be reduced by aspartyl esterification without attenuation of inhibitory bone loss in ovariectomy animal model. 
Journal of Korean Medical Science  2000;15(5):533-541.
The purpose of this study was to determine whether esterification of dehydroepiandrosterone with aspartate (DHEA-aspartate) could reduce peroxisomal proliferation induced by DHEA itself, without loss of antiosteoporotic activity. Female Sprague-Dawley rats were ovariectomized, then DHEA or DHEA-aspartate was administered intraperitoneally at 0.34 mmol/kg BW 3 times a week for 8 weeks. DHEA-aspartate treatment in ovariectomized rats significantly increased trabeculae area in tibia as much as DHEA treatment. Urinary Ca excretion was not significantly increased by DHEA or DHEA-aspartate treatment in ovariectomized rats, while it was significantly increased by ovariectomy. Osteocalcin concentration and alkaline phosphatase activity in serum and cross linked N-telopeptide type I collagen level in urine were not significantly different between DHEA-aspartate and DHEA treated groups. DHEA-aspartate treatment significantly reduced liver weight and hepatic palmitoyl-coA oxidase activity compared to DHEA treatment. DHEA-aspartate treatment maintained a nearly normal morphology of peroxisomes, while DHEA treatment increased the number and size of peroxisomes in the liver. According to these results, it is concluded that DHEA-aspartate ester has an inhibitory effect on bone loss in ovariectomized rats with a marked reduction of hepatomegaly and peroxisomal proliferation compared to DHEA.
PMCID: PMC3054677  PMID: 11068990
21.  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
22.  Dehydroepiandrosterone Restoration of Growth Hormone Gene Expression in Aging Female Rats, in Vivo and in Vitro: Evidence for Actions via Estrogen Receptors 
Endocrinology  2005;146(12):5176-5187.
A decline in dehydroepiandrosterone (DHEA) and GH levels with aging may be associated with frailty and morbidity. Little is known about the direct effects of DHEA on somatotropes. We recently reported that 17β-estradiol (E2), a DHEA metabolite, stimulates the expression of GH in vitro in young female rats. To test the hypothesis that DHEA restores function in aging somatotropes, dispersed anterior pituitary (AP) cells from middle-aged (12–14 months) or young (3–4 months) female rats were cultured in vitro with or without DHEA or E2 and fixed for immunolabeling or in situ hybridization. E2 increased the percentage of AP cells with GH protein or mRNA in the aged rats to young levels. DHEA increased the percentages of somatotropes (detected by GH protein or mRNA) from 14–16 ± 2% to 29–31 ± 3% (P ≤0.05) and of GH mRNA (detected by quantitative RT-PCR) only in aging rats. To test DHEA’s in vivo effects, 18-month-old female rats were injected with DHEA or vehicle for 2.5 d, followed by a bolus of GHRH 1 h before death. DHEA treatment increased serum GH 1.8-fold (7 ± 0.5 to 12 ± 1.3 ng/ml; P = 0.02, by RIA) along with a similar increase (P = 0.02) in GH immunolabel. GHRH target cells also increased from 11 ± 1% to 19 ± 2% (P = 0.03). Neither GH nor GHRH receptor mRNAs levels were changed. To test the mechanisms behind DHEA’s actions, AP cells from aging rats were treated with DHEA with or without inhibitors of DHEA metabolism. Trilostane, aminogluthemide, or ICI 182,780 completely blocked the stimulatory effects of DHEA, suggesting that DHEA metabolites may stimulate aging somatotropes via estrogen receptors.
doi:10.1210/en.2005-0811
PMCID: PMC1868401  PMID: 16150906
AP, Anterior pituitary; DHEA, dehydroepiandrosterone; E2, 17β-estradiol; ER, estrogen receptor; GHRH R, GHRH receptor; HPRT, hypoxanthine guanine phosphoribosyltransferase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; IOD, integrated optical density; ITS, insulin, transferrin, sodium selenite, and BSA; QRT-PCR, quantitative RT-PCR
23.  SULT2A1 Gene Copy Number Variation is Associated with Urinary Excretion Rate of Steroid Sulfates 
Human cytosolic sulfotransferases (SULT) 2A1 is the main enzyme involved in the sulfate conjugation of dehydroepiandrosterone, a weak androgen, and the main androgen precursor, whereas estrogens are mainly conjugated by SULT1A1. Here we have identified a copy number variation (CNV) polymorphism in the SULT2A1 gene in a Swedish population including healthy men (N = 30). Moreover, the CNV of SULT1A1 and SULT2A1 was further characterized in relation to urinary levels of androgen sulfate metabolites before and after an intramuscular dose of 500 mg testosterone enanthate. Individuals expressing two or more CNVs excrete 80 and 40% higher levels of DHEAS (p = 0.02) and androsteroneS (p = 0.01), respectively as compared to individuals with one gene copy. The mean area under the urine concentration time-curve from time 0 (prior to the administration of 500 mg testosterone) to 15 days post dose values were 80% higher for DHEAS (p = 0.046) and testosteroneS (p = 0.019) in individuals with two and three SULT2A1 gene copies as compared to individuals with one gene copy. The SULT1A1 CNV on the other hand did not affect the sulfation activity toward the androgens. In conclusion our results indicate that functional CNV polymorphisms in SULT2A1 and SULT1A1 are common in a Swedish population and that SULT2A1 CNV is associated with the urinary concentrations of androgen sulfate metabolites.
doi:10.3389/fendo.2013.00088
PMCID: PMC3709130  PMID: 23874324
SULT2A1; SULT1A1; copy number variation; DHEAS; androgens; testosterone
24.  Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake 
Glucocorticoids increase adipocyte proliferation and differentiation, a process underpinned by the local reactivation of inactive cortisone to active cortisol within adipocytes catalyzed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The adrenal sex steroid precursor dehydroepiandrosterone (DHEA) has been shown to inhibit 11β-HSD1 in murine adipocytes; however, rodent adrenals do not produce DHEA physiologically. Here, we aimed to determine the effects and underlying mechanisms of the potential antiglucocorticoid action of DHEA and its sulfate ester DHEAS in human preadipocytes. Utilizing a human subcutaneous preadipocyte cell line, Chub-S7, we examined the metabolism and effects of DHEA in human adipocytes, including adipocyte proliferation, differentiation, 11β-HSD1 expression, and activity and glucose uptake. DHEA, but not DHEAS, significantly inhibited preadipocyte proliferation via cell cycle arrest in the G1 phase independent of sex steroid and glucocorticoid receptor activation. 11β-HSD1 oxoreductase activity in differentiated adipocytes was inhibited by DHEA. DHEA coincubated with cortisone significantly inhibited preadipocyte differentiation, which was assessed by the expression of markers of early (LPL) and terminal (G3PDH) adipocyte differentiation. Coincubation with cortisol, negating the requirement for 11β-HSD1 oxoreductase activity, diminished the inhibitory effect of DHEA. Further consistent with glucocorticoid-opposing effects of DHEA, insulin-independent glucose uptake was significantly enhanced by DHEA treatment. DHEA increases basal glucose uptake and inhibits human preadipocyte proliferation and differentiation, thereby exerting an antiglucocorticoid action. DHEA inhibition of the amplification of glucocorticoid action mediated by 11β-HSD1 contributes to the inhibitory effect of DHEA on human preadipocyte differentiation.
doi:10.1152/ajpendo.00314.2012
PMCID: PMC3840204  PMID: 24022868
dehydroepiandrosterone; human adipogenesis; 11β-hydroxysteroid dehydrogenase type 1; insulin sensitivity
25.  Salivary Cortisol and DHEA Levels in the Korean Population: Age-Related Differences, Diurnal Rhythm, and Correlations with Serum Levels  
Yonsei Medical Journal  2007;48(3):379-388.
Purpose
The primary objective of this study was to examine the changes of basal cortisol and DHEA levels present in saliva and serum with age, and to determine the correlation coefficients of steroid concentrations between saliva and serum. The secondary objective was to obtain a standard diurnal rhythm of salivary cortisol and DHEA in the Korean population.
Materials and Methods
For the first objective, saliva and blood samples were collected between 10 and 11 AM from 359 volunteers ranging from 21 to 69 years old (167 men and 192 women). For the second objective, four saliva samples (post-awakening, 11AM, 4PM, and bedtime) were collected throughout a day from 78 volunteers (42 women and 36 men) ranging from 20 to 40 years old. Cortisol and DHEA levels were measured using a radioimmunoassay (RIA).
Results
The morning cortisol and DHEA levels, and the age-related steroid decline patterns were similar in both genders. Serum cortisol levels significantly decreased around forty years of age (p < 0.001, when compared with people in their 20s), and linear regression analysis with age showed a significant declining pattern (slope = -2.29, t = -4.297, p < 0.001). However, salivary cortisol levels did not change significantly with age, but showed a tendency towards decline (slope = -0.0078, t = -0.389, p = 0.697). The relative cortisol ratio of serum to saliva was 3.4-4.5% and the ratio increased with age (slope = 0.051, t = 3.61, p < 0.001). DHEA levels also declined with age in saliva (slope = -0.007, t = -3.76, p < 0.001) and serum (slope = -0.197 t = -4.88, p < 0.001). In particular, DHEA levels in saliva and serum did not start to significantly decrease until ages in the 40s, but then decreased significantly further at ages in the 50s (p < 0.001, when compared with the 40s age group) and 60s (p < 0.001, when compared with the 50 age group). The relative DHEA ratio of serum to saliva was similar throughout the ages examined (slop = 0.0016, t = 0.344, p = 0.73). On the other hand, cortisol and DHEA levels in saliva reflected well those in serum (r = 0.59 and 0.86, respectively, p < 0.001). The highest salivary cortisol levels appeared just after awakening (about two fold higher than the 11 AM level), decreased throughout the day, and reached the lowest levels at bedtime (p < 0.001, when compared with PM cortisol levels). The highest salivary DHEA levels also appeared after awakening (about 1.5 fold higher than the 11AM level) and decreased by 11AM (p < 0.001). DHEA levels did not decrease further until bedtime (p = 0.11, when compared with PM DHEA levels).
Conclusion
This study showed that cortisol and DHEA levels change with age and that the negative slope of DHEA was steeper than that of cortisol in saliva and serum. As the cortisol and DHEA levels in saliva reflected those in serum, the measurement of steroid levels in saliva provide a useful and practical tool to evaluate adrenal functions, which are essential for clinical diagnosis.
doi:10.3349/ymj.2007.48.3.379
PMCID: PMC2628086  PMID: 17594144
Saliva cortisol; saliva DHEA; correlation; age-related changes; diurnal rhythm

Results 1-25 (944495)