Plasma Levels Of Dehydroepiandrosterone Research Articles

High Pretreatment DHEA Is Associated with Inferior Immunotherapy Response in Metastatic Non-Small Cell Lung Cancer.

Background: Sex difference in the immune response may influence patients' response to immune checkpoint inhibitors (ICIs). We conducted a prospective observation study to determine the correlation between pretreatment sex hormone levels and response to ICIs in metastatic non-small cell lung cancer (NSCLC). Method: Pretreatment plasma samples from 61 patients with newly diagnosed NSCLC prior to ICI therapy were collected. Six sex hormone levels [pyrazole triol, 17 β-estradiol, 5-androstenediol, 3β-androstenediol, dehydroepiandrosterone (DHEA), and S-equol] were measured using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Overall survival (OS) and progression-free survival (PFS) were compared between the high- and low-level groups in the whole cohort. Result: Among the six sex hormones measured, DHEA levels were significantly higher among patients without clinical benefits in the discovery cohort; the remaining sex hormones did not differ significantly. In the whole cohort, median PFS was 22 months for patients with low DHEA levels vs. 3.8 months for those with high DHEA [hazard ratio, 14.23 (95% CI, 4.7-43); p < 0.001]. A significant association was also observed for OS [hazard ratio, 8.2 (95% CI, 2.89-23.35); p < 0.0001]. Conclusions: High pretreatment plasma DHEA levels were associated with poor clinical outcomes for patients with metastatic NSCLC treated with ICIs.

Changes in plasma levels of endocrine hormones in lepromatous leprosy patients

BackgroundLeprosy affects various endocrine glands and causes disorders in internal organs in addition to the skin and peripheral nerves. These disorders are often silent and remain undiagnosed or underreported. In particular, patterns of hormone changes during leprosy, especially in lepromatous leprosy (LL) patients, are often associated with dysregulation of different endocrine and sex hormones. The aim of this study was to assess changes in four endocrine hormones — namely cortisol, dehydroepiandrosterone (DHEA), growth hormone (GH), and leptin — among LL patients compared with apparently healthy controls. MethodIn total, 80 plasma samples were systematically retrieved from a biorepository at the Armauer Hansen Research Institute (AHRI), based on quality, adequacy of sample volume, and appropriateness of linked clinical and sociodemographic data. Forty of the samples were obtained from LL patients (cases) and the remaining 40 from apparently healthy controls. Enzyme-linked immunosorbant assay (ELISA) was used to quantify levels of DHEA, cortisol, GH, and leptin hormones in the plasma samples. Data were analyzed using non-parametric statistics and the Mann–Whitney U-test (GraphPad Prism version 7.01). A p-value < 0.05 was considered statistically significant. ResultsPlasma levels of cortisol concentration were significantly higher in LL cases (median = 111.4 ng/ml, range = 20.54–525.7) compared with healthy controls (median = 51.98 ng/ml, range = 3.805–328.4) (p = 0.003). Levels of GH and leptin were significantly lower in LL cases compared with healthy controls (median values for GH = 1.01 µIU/ml, range = 0.4625–86.82 and 2 µIU/ml, range = 0.5838–63.36, respectively (p = 0.022); median values for leptin = 891 pg/ml, range = 728.4–21816 and 5147 pg/ml, range = 730.4–52747, respectively (p < 0.0001)). There was an apparent reduction in the plasma levels of DHEA among LL cases compared with healthy controls (p = 0.297), although this difference was not statistically significant. ConclusionAlterations in levels of endocrine hormones seen in LL patients reflect clinical and immunological conditions during lepromatous leprosy. However, large-scale studies are warranted to determine how leprosy causes such alterations in hormones and the interplay between endocrine hormones and the immune system during leprosy disease.

Early Signs of Microvascular Endothelial Dysfunction in Adolescents with Newly Diagnosed Essential Hypertension.

Endothelial dysfunction represents one of the key pathomechanisms in many diseases, including hypertension. Peripheral arterial tonometry (PAT) evaluates the functional status of microvascular endothelium and offers a biomarker of early, potentially reversible, vascular damage. This study aimed to assess endothelial function using conventional and novel indices of PAT in pediatric hypertensives. As such, 100 adolescents with normal blood pressure, and essential and white-coat hypertension were examined using EndoPAT 2000. Conventional reactive hyperemia index (RHI) and novel indices of hyperemic response, including the area under the curve of hyperemic response (AUC), were evaluated. AUC was the only parameter sensitive to the effect of hypertension, with significantly lower values in essential hypertensives compared to normotensives and white-coat hypertensives (p = 0.024, p = 0.032, respectively). AUC was the only parameter significantly correlating with mean ambulatory monitored blood pressure (r = −0.231, p = 0.021). AUC showed a significant negative association with age (p = 0.039), but a significant positive association with pubertal status indexed by plasma levels of dehydroepiandrosterone (p = 0.027). This is the first study reporting early signs of microvascular endothelial dysfunction evaluated using PAT in adolescents with newly diagnosed essential hypertension. Detailed analysis of hyperemic response using overall magnitude indexed by AUC provided a more robust method compared to the conventional evaluation of RHI.

Effect of alpine grazing on plasma and hair cortisol, serotonin, and DHEA in dairy cows and its welfare impact

Through the analysis of blood and hair samples, this study evaluated the effects of grazing in alpine areas on welfare indices and indicators of stress in dairy cows. Twenty-one Holstein dairy cows (body weight: 637 ± 21.5 kg; days in milk: 133 ± 17.7, and second parity) were randomly assigned to 3 groups: control (nongrazing), 12 h of alpine grazing (12 hG), and 24 h of alpine grazing (24 hG). Blood samples for plasma collection were taken for 3 consecutive days at the end of the experiment. Hair samples were collected at the beginning and end of the experiment. Hormone measurements included cortisol, serotonin, and dehydroepiandrosterone (DHEA) in both plasma and hair samples. Plasma cortisol and DHEA levels did not differ among the 3 groups, whereas the plasma serotonin level was higher in the 24 hG group than that in the other groups. The plasma cortisol to DHEA ratio was lower in the 24 hG group than that in the control and 12 hG group. The hair samples taken at the end of the experiment showed that the cortisol level was significantly higher in the control group than that in both of the grazing groups and also higher in the 12 hG than that in the 24 hG group. Hair DHEA and serotonin levels were highest in the 24 hG group. The hair cortisol to DHEA ratio was significantly higher in the control group than that in the 12 hG and 24 hG groups and in the 12 hG group than that in the 24 hG group. Our study showed that grazing dairy cows in alpine areas for 24 h improved their welfare, as indicated by increased serotonin levels in hair and plasma, increased hair DHEA level, and decreased stress indicators, including the hair cortisol level and cortisol to DHEA ratio. Farm facilities should allocate optimal grazing time for optimal welfare of dairy cows.

Dehydroepiandrosterone on metabolism and the cardiovascular system in the postmenopausal period.

Dehydroepiandrosterone (DHEA), mostly present as its sulfated ester (DHEA-S), is an anabolic hormone that naturally declines with age. Furthermore, it is the most abundant androgen and estrogen precursor in humans. Low plasma levels of DHEA have been strongly associated with obesity, insulin resistance, dyslipidemia, and high blood pressure, increasing the risk of cardiovascular disease. In this respect, DHEA could be regarded as a promising agent against metabolic syndrome (MetS) in postmenopausal women, since several age-related metabolic diseases are reported during aging. There are plenty of experimental evidences showing beneficial effects after DHEA therapy on carbohydrate and lipid metabolism, as well as cardiovascular health. However, its potential as a therapeutic agent appears to attract controversy, due to the lack of effects on some symptoms related to MetS. In this review, we examine the available literature regarding the impact of DHEA therapy on adiposity, glucose metabolism, and the cardiovascular system in the postmenopausal period. Both clinical studies and in vitro and in vivo experimental models were selected, and where possible, the main cellular mechanisms involved in DHEA therapy were discussed. Schematic representation showing some of the general effects observed after administration DHEA therapy on target tissues of energy metabolism and the cardiovascular system. ↑ represents an increase, ↓ represents a decrease, - represents a worsening and ↔ represents no change after DHEA therapy.

&lt;p&gt;Can Low SHBG Serum Concentration Be A Good Early Marker Of Male Hypogonadism In Metabolic Syndrome?&lt;/p&gt;

IntroductionIn men suffering from metabolic syndrome, accompanying insulin resistance may result in a lowering of sex hormone–binding globulin (SHBG) plasma levels and cause changes in their androgenic status.AimThe objective of the research was to assess selected androgens and SHBG plasma levels in males meeting diagnostic criteria for MS compared to healthy males.Patients and methodsThe group consisted of 65 men aged between 40 and 70 years old fitting IDF metabolic syndrome criteria and 84 controls. Dehydroepiandrosterone (DHEA) and its sulphate (DHEA–S), total and free testosterone and SHBG serum levels were evaluated. Calculated free and bioavailable testosterone were estimated using an algorithm proposed by the International Society for the Study of the Aging Male.ResultsMen diagnosed with MS showed a statistically significant decrease in plasma levels of DHEA in comparison to healthy ones: 11.579 (8.39–15.56) vs 14.014 (9.611–17.125) ng/mL; p = 0.0350, SHBG: 47.46 (35.78–62.83) vs 71.965 (54.45–91.56) nM/L; p<0.0001 and total testosterone: 5.2 (3.8–6.5) vs 6.3 (5.4–8.25) ng/mL; p = 0.0001 (values presented as a median with Q1–Q3).ConclusionThe results suggest that SHBG is a good early marker for metabolic dysregulation in MS, considering its strength of association and significance is comparable to, or better than, those of MS criteria.

Prechemotherapy Levels of Plasma Dehydroepiandrosterone and Its Sulfated Form as Predictors of Cancer-Related Cognitive Impairment in Patients with Breast Cancer Receiving Chemotherapy.

Study ObjectiveDehydroepiandrosterone (DHEA) and its sulfated form (DHEAS)—jointly referred to as DHEA(S)—are neurosteroids known to regulate brain development and function that have been found to be positively correlated with cognitive function. It is unknown whether prechemotherapy plasma DHEA(S) levels are associated with the onset of cancer‐related cognitive impairment (CRCI). The objective of this study was to evaluate whether an association exists between prechemotherapy plasma DHEA(S) levels and onset of CRCI in patients with breast cancer receiving chemotherapy.DesignMulticenter, prospective cohort study.SettingTwo specialized cancer centers in Singapore.PatientsEighty‐one patients with early‐stage breast cancer (stages I–III) who had no prior exposure to chemotherapy and/or radiotherapy and were scheduled to receive anthracycline‐based or taxane‐based chemotherapy treatment with curative intent.Measurements and Main ResultsPatients completed assessments for self‐perceived and objective cognitive function at three time points: prechemotherapy (T1), during chemotherapy (T2), and after chemotherapy (T3). Plasma samples were collected prior to chemotherapy, and DHEA(S) levels were quantified by using ultra–high‐performance liquid chromatography–tandem mass spectrometry. Multivariable logistic regression was used to adjust for clinically important factors and to evaluate the association between prechemotherapy plasma DHEA(S) levels and CRCI. Mean ± SD age was 48.9 ± 9.3 years, with 27.8% of patients experiencing clinically significant cognitive impairment based on global Functional Assessment of Cancer Therapy–Cognitive Function scores. The mean ± SD prechemotherapy plasma DHEAS and DHEA levels were 1.61 ± 0.91 μmol/L and 19.21 ± 13.13 nmol/L, respectively. Prechemotherapy DHEAS levels were found to be associated with impairment in the self‐perceived cognitive domains of verbal fluency (adjusted odds ratio [OR] 0.27, 95% confidence interval [CI] 0.08–0.96) and mental acuity (adjusted OR 0.25, 95% CI 0.08–0.74). Conversely, DHEA levels were not associated with impairment in any cognitive subdomains.ConclusionOur findings suggest that patients with higher prechemotherapy DHEAS levels had lower odds of developing self‐perceived cognitive impairment. Future studies are required to further investigate the effect of DHEA(S) on specific cognitive domains and to validate our findings in independent cohorts.

The Effect of Statins on Levels of Dehydroepiandrosterone (DHEA) in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

BackgroundCurrently, statins are used to treat polycystic ovary syndrome (PCOS). This systematic review and meta-analysis aimed to investigate the effect of statins on serum or plasma levels of dehydroepiandrosterone (DHEA) in women with PCOS.Material/MethodsDatabases that were searched included PubMed, Embase, and the Cochrane Library from their inception to August of 2018. Published randomized controlled trials (RCTs) were identified that evaluated the impact of statins on plasma DHEA levels in women with PCOS. The Cochrane risk of bias tool was used to assess the quality of the included RCTs. A random-effects model was used to analyze the pooled results.ResultsMeta-analysis was performed on data from ten published studies that included 735 patients and showed that statin treatment could significantly reduce plasma DHEA levels when compared with controls (SMD, −0.43; 95% CI, −0.81–0.06; p=0.02; I2=82%). Statins were significantly more effective than placebo in reducing the levels of DHEAs. Subgroup analysis based on statin type showed that atorvastatin significantly reduced DHEA levels (SMD, −0.63; 95% CI, −1.20 – −0.05; p=0.03; I2=38%) but simvastatin did not significantly reduce DHEA levels (SMD: −0.14; 95% CI, −0.49–0.28; p=0.43; I2=77%). Subgroup analysis based on duration of treatment showed no significant difference between 12 weeks of statin treatment (SMD, −0.61; 95% CI, −1.23–0.02; p=0.06; I2=85%) and 24 weeks (SMD, −0.34; 95% CI −0.95–0.28; p=0.29; I2=83%).ConclusionsMeta-analysis showed that statins significantly reduced the levels of DHEA when compared with placebo in patients with PCOS.

Determination of dehydroepiandrosterone and its biologically active oxygenated metabolites in human plasma evinces a hormonal imbalance during HIV-TB coinfection

An estimated one third of the world’s population is affected by latent tuberculosis (TB), which once active represents a leading cause of death among infectious diseases. Human immunodeficiency virus (HIV) infection is a main predisposing factor to TB reactivation. Individuals HIV-TB co-infected develop a chronic state of inflammation associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This results in a hormonal imbalance, disturbing the physiological levels of cortisol and dehydroepiandrosterone (DHEA). DHEA and its oxygenated metabolites androstenediol (AED), androstenetriol (AET) and 7-oxo-DHEA are immunomodulatory compounds that may regulate physiopathology in HIV-TB co-infection. In order to study possible changes in plasma levels of these hormones, we developed an approach based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). To our knowledge, this represents the first report of their simultaneous measurement in HIV-TB individuals and the comparison with healthy donors, obtaining statistically higher plasma levels of DHEA, AET and 7-oxo-DHEA in patients. Moreover, we found that concentrations of 7-oxo-DHEA positively correlated with absolute CD4+ T cell counts, nadir CD4+ T cell values and with individuals who presented TB restricted to the lungs. This research contributes to understanding the role of these hormones in HIV-TB and emphasizes the importance of deepening their study in this context.

DHEA Administration Activates Transcription of Muscular Lipid Metabolic Enzymes via PPARα and PPARδ in Obese Rats.

Administration of dehydroepiandrosterone (DHEA), a precursor of sex steroid hormones, reduces total and visceral fat mass and elevates adipocytic adiponectin gene expression. The aim of this study is to investigate whether levels of peroxisome proliferator-activated receptors (PPARs) in muscle and transcription of PPAR target genes are affected by long-term DHEA administration or exercise training, and whether altered PPAR levels are associated with circulating adiponectin level in obese rats. After 14 weeks on a high-sucrose diet, obese male Wistar rats were assigned randomly to one of 3 groups: control, DHEA administration (1 mg/kg body weight), or exercise training (treadmill running for 1 h, 25 m/min, 5 days/week) for 6 weeks (n=7 for each group). Plasma DHEA and total adiponectin levels in the DHEA-treated and exercise-training groups were significantly higher than those in the obese control group. Additionally, DHEA administration and exercise training significantly increased muscular PPARα and PPARδ protein levels, with a concomitant increase in mRNA expression of 3β-hydroxyacyl-CoA dehydrogenase and cytochrome c oxidase IV, which are target genes of PPARα and PPARδ respectively. Moreover, DHEA administration increased these protein and mRNA levels to the same degree as exercise training. Circulating adiponectin level was positively correlated with plasma DHEA and with muscle levels of PPARα and PPARδ. These results suggest that in obese rats, secretion of adiponectin due to chronic DHEA administration and exercise training may contribute to an increase in the transcription of genes encoding lipid metabolic enzymes, mediated via elevated expression of PPARα and PPARδ in muscle.

HIV-TB coinfection impairs CD8(+) T-cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses.

Tuberculosis (TB) is the leading cause of death among HIV-positive patients. The decreasing frequencies of terminal effector (TTE ) CD8(+) T cells may increase reactivation risk in persons latently infected with Mycobacterium tuberculosis (Mtb). We have previously shown that dehydroepiandrosterone (DHEA) increases the protective antitubercular immune responses in HIV-TB patients. Here, we aimed to study Mtb-specific cytotoxicity, IFN-γ secretion, memory status of CD8(+) T cells, and their modulation by DHEA during HIV-TB coinfection. CD8(+) T cells from HIV-TB patients showed a more differentiated phenotype with diminished naïve and higher effector memory and TTE T-cell frequencies compared to healthy donors both in total and Mtb-specific CD8(+) T cells. Notably, CD8(+) T cells from HIV-TB patients displayed higher Terminal Effector (TTE ) CD45RA(dim) proportions with lower CD45RA expression levels, suggesting a not fully differentiated phenotype. Also, PD-1 expression levels on CD8(+) T cells from HIV-TB patients increased although restricted to the CD27(+) population. Interestingly, DHEA plasma levels positively correlated with TTE in CD8(+) T cells and in vitro DHEA treatment enhanced Mtb-specific cytotoxic responses and terminal differentiation in CD8(+) T cells from HIV-TB patients. Our data suggest that HIV-TB coinfection promotes a deficient CD8(+) T-cell differentiation, whereas DHEA may contribute to improving antitubercular immunity by enhancing CD8(+) T-cell functions during HIV-TB coinfection.

P.1.e.001 Have sex hormones a role in the pathogenesis of psychotic symptoms in major psychoses?

Purpose of the Study: Sex hormones act as modulators of neurotransmitters in the brain and appear to be implicated in the pathogenesis and prognosis of mood disorders and schizophrenia. Preliminary data would indicate high levels of progesterone to be protective against psychotic symptoms [1,2], while, with regard to dehydroepiandrosterone (DHEA), results are discordant. If in one study DHEA appeared to protect bipolar patients against paranoid delusions, in another this hormone was found to be higher in schizophrenia patients compared with healthy controls [2,3]. Aim of this study is to compare the levels of progesterone and DHEA between patients with different diagnosis and in relation to the presence of psychotic symptoms. Methods: Fifty-five male patients, consecutively hospitalized in our patients’ clinic, were included into the study. Inclusion criteria consisted of: (1) a diagnosis of a mood or psychotic disorder and (2) lack of clinical conditions affecting hormonal plasma concentrations. Progesterone and DHEA plasma dosages were always measured at the admission in the morning and patients had to be drug free for at least two weeks Two analyses of variance (ANOVAs) were performed: in the first one plasma progesterone and DHEA plasma levels were compared according to diagnostic subgroups (schizophrenia, mood disorders, substance induced psychosis); in the second one the plasma levels of the two hormones were compared according to the presence of psychotic symptoms. Finally a binary logistic regression was performed to find if clinical variables were associated with abnormal plasma levels of DHEA or progesterone. In particular, age at onset, duration of illness, duration of untreated illness, BPRS mean total score, BPRS (unusual thought content) mean score, BPRS (hallucinations) mean score and the sum of mean scores of the two BPRS items were considered as independent variables, while the presence of abnormal DHEA/progesterone plasma levels as the dependent variable. Results: 20% of total sample (N= 55) presented abnormal values of DHEA and 32.7% of progesterone. Higher plasma levels of DHEA were found in patients with a history of psychotic symptoms (F = 8.454, p = 0.005), and plasma levels of progesterone showed only a trend (F = 3.772, p = 0.058). In contrast no significant differences of the plasma levels of the two hormones emerged between diagnostic groups (F = 0.859, p = 0.43). A longer duration of untreated illness was found to be positively associated with abnormal plasma levels of DHEA (OR= 1.193, p = 0.032), while a significant negative association was found between BPRS (unusual thought content) scores and abnormal plasma levels of DHEA (OR= 0.544, p = 0.04). Conclusions: Higher plasma levels of DHEA appear to be associated with the occurrence of psychotic symptoms, but less prominent delusional symptoms in acute phase. These results could indicate that high plasma levels of DHEA would be an index of chronicity independently from the diagnosis, but they could be protective against the acute psychotic exacerbation. Previous conflicting data can be explained on the basis of these findings.

Simultaneous measurement of testosterone, androstenedione and dehydroepiandrosterone (DHEA) in serum and plasma using Isotope-Dilution 2-Dimension Ultra High Performance Liquid-Chromatography Tandem Mass Spectrometry (ID-LC–MS/MS)

The adrenal and gonadal androgens, testosterone, androstenedione and dehydroepiandrosterone (DHEA) play an important role in sexual development as well as in other processes. We developed a method for simultaneous quantitative analysis of serum and plasma testosterone, androstenedione and DHEA levels using Isotope-Dilution Liquid-Chromatography Tandem Mass Spectrometry (ID-LC–MS/MS). Samples underwent liquid–liquid extraction and were analyzed on an Acquity 2D-UPLC-System and a Xevo TQ-S tandem mass spectrometer (Waters).The intra-assay and inter-assay coefficients of variation were <4.0%, <6.3% and <7.0% and <6.0%, <8.1% and <7.7% for testosterone, androstenedione and DHEA, respectively. Inter-assay CVs at the lower limit were 10.6%, 16.9% and 9.0% for testosterone (0.10nmol/L), androstenedione (0.10nmol/L) and DHEA (1.0nmol/L), respectively. Recoveries of spiked analytes were 93–107%.The present testosterone method compared well (y=1.00x−0.04; r=0.998) to a published ID-LC–MS/MS method for testosterone in our lab. The latter method being concordant with a published reference method (Bui et al., 2013). The present method compared well to a published ID-LC–MS/MS method (Kushnir et al., 2010) (y=1.06x−0.06; r=0.996 for testosterone; y=1.04x−0.04; r=0.995 for androstenedione and y=1.03x+0.01; r=0.991 for DHEA).In conclusion, we developed a sensitive and accurate ID-LC–MS/MS method to simultaneously measure serum testosterone, androstenedione and DHEA in serum and plasma.

Spondyloepimetaphyseal dysplasia Pakistani type: Expansion of the phenotype

Spondyloepimetaphyseal dysplasia (SEMD), Pakistani type, is a skeletal dysplasia characterized by platyspondyly, delayed epiphyseal ossification, mild metaphyseal abnormalities, short stature, and short and bowed legs, and is caused by mutations in PAPSS2. In a single Turkish patient also hyperandrogenism was reported. We describe five patients from a Turkish family with SEMD Pakistani type with homozygosity for a nonsense mutation (p.R329X) leading to a stop codon in PAPSS2. Plasma levels of dehydroepiandrosterone (DHEA) and androstenedione were normal, but DHEA sulfate levels were low in four of the patients. Two patients and a mother had history of pubertal hyperandrogenism. Testosterone level was mildly elevated in one of the female patients, and insulin resistance was not detected in any of the patients. The patients also had precocious costal calcification, small iliac bones, short femoral necks, coxa vara, short halluces and fused vertebral bodies, none of which has been reported previously in this entity.

Dehydroepiandrosterone has strong antifibrotic effects and is decreased in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an ageing-related lung disorder characterised by expansion of the myofibroblast population and aberrant lung remodelling. Dehydroepiandrosterone (DHEA), a steroid pro-hormone, decreases with age but an exaggerated decline has been associated with chronic degenerative diseases. We quantified the plasma levels of DHEA and its sulfated form (DHEA-S) in 137 IPF patients and 58 controls and examined the effects of DHEA on human lung fibroblasts. Plasma DHEA/DHEA-S was significantly decreased in male IPF patients (median (range) DHEA: 4.4 (0.2-29.2) versus 6.7 (2.1-15.2) ng · mL(-1), p<0.01; DHEA-S: 47 (15.0-211) versus 85.2 (37.6-247.0) μg · dL(-1), p<0.001), while in females only DHEA-S was significantly decreased (32.6 (15.0-303.0) versus 68.3 (16.4-171) μg · dL(-1), p<0.001). DHEA caused a decrease in fibroblast proliferation and an approximately two-fold increase in fibroblast apoptosis, probably through the intrinsic pathway with activation of caspase-9. This effect was accompanied by upregulation of several pro-apoptotic proteins (Bax and cyclin-dependent kinase-inhibitor CDNK1A) and downregulation of anti-apoptotic proteins, such as cellular inhibitor of apoptosis (c-IAP)1 and c-IAP2. DHEA also caused a significant decrease of transforming growth factor-β1-induced collagen production and fibroblast to myofibroblast differentiation, and inhibited platelet-derived growth factor-induced fibroblast migration. These findings demonstrate a disproportionate decrease of DHEA/DHEA-S in IPF patients and indicate that this molecule has multiple antifibrotic properties.

Year-round territorial aggression is independent of plasma DHEA in the European nuthatch Sitta europaea

Plasma testosterone can play an important role in promoting aggressive behaviors relating to territory defense in breeding male birds. Some birds defend territories also during the non-breeding phase, when testosterone circulates at basal levels. In such species, plasma levels of the pro-hormone dehydroepiandrosterone (DHEA) may support non-breeding territoriality by acting as a local substrate for sex steroids. To test this possible role of plasma DHEA, we examined the seasonal DHEA profile of male (and female) European nuthatches Sitta europaea: a male and female nuthatch pair will defend an all-purpose territory throughout the year. We hypothesized that plasma DHEA would be detectable in wintering nuthatches with a territory. However, only ca. half of the territorial wintering males (and females) displayed detectable DHEA levels, suggesting that plasma DHEA is not a major sex steroid precursor during non-breeding. Further, among hatching-year birds, plasma DHEA was significantly lower in territorial birds than in “floaters”, i.e., subordinate birds without a territory. To experimentally examine the role of DHEA in non-breeding territoriality, we treated adult wintering males with DHEA and measured effects on aggressive responses to conspecific challenge. DHEA treatment elevated plasma levels of DHEA (and testosterone), but did not enhance territorial behaviors or their persistence. Taken together, our data suggest that DHEA (and, indeed, sex steroids per se) do not regulate non-breeding territoriality in the nuthatch. Given that territorial aggression in nuthatches is expressed year-round, a hormone for its activation may be redundant.

Stress in the wild: Chronic predator pressure and acute restraint affect plasma DHEA and corticosterone levels in a songbird

The effects of chronic stressors on glucocorticoid levels are well described in laboratory rodents, but far less is known about the effects of chronic stressors on wild animals or on dehydroepiandrosterone (DHEA) levels. DHEA can be produced by the adrenal cortex and has prominent antiglucocorticoid properties. Here, we examined wild songbirds to elucidate the relationship between chronic predator pressure and plasma DHEA and corticosterone levels. We measured circulating steroid levels at baseline and after acute restraint in the breeding and nonbreeding seasons. During the breeding season, males in low predator pressure (LPP) environments had higher baseline DHEA levels than males in high predator pressure (HPP) environments. Also, acute restraint decreased DHEA levels in LPP males only but increased corticosterone levels in HPP and LPP males similarly. During the nonbreeding season, DHEA and corticosterone levels were lower than during the breeding season, and acute restraint decreased DHEA levels in both HPP and LPP males. Unlike males, breeding females showed no effect of predator pressure on baseline DHEA or corticosterone levels. These data suggest that naturalistic chronic and acute stressors affect circulating DHEA and corticosterone levels in wild animals and highlight the importance of using multiple endpoints when studying the physiological effects of chronic stress.

Correlation of circulating dehydroepiandrosterone with activated protein C generation and carotid intima-media thickness in male patients with Type 2 diabetes

Dehydroepiandrosterone exerts a protective effect against cardiovascular diseases. However, the relationship of dehydroepiandrosterone with the anticoagulant factor activated protein C, generated by the thrombin-thrombomodulin complex on vascular endothelial cells, remains unknown. This study aimed at studying the relationship between dehydroepiandrosterone and activated protein C generation in patients with Type 2 diabetes. Sixty-two male patients with Type 2 diabetes were enrolled in this study. Data obtained from 40 healthy male subjects were used as controls. The plasma levels of dehydroepiandrosterone, the activated protein C-protein C inhibitor complex, high-sensitivity C-reactive protein and monocyte chemoattractant protein-1 were measured by enzyme immunoassays. Carotid intima-media thickness was measured by ultrasonography. The plasma levels of dehydroepiandrosterone (5.15 ± 2.81 vs. 3.76 ± 2.16 ng/ml; P < 0.005) and the activated protein C-protein C inhibitor complex (1.90 ± 1.07 vs. 1.02 ± 0.51 ng/ml; P < 0.001) were significantly lower in patients with diabetes than in normal subjects. Univariate analysis showed a significant correlation of the plasma level of dehydroepiandrosterone with that of the activated protein C-protein C inhibitor complex (r = 0.48, P < 0.001), high-sensitivity C-reactive protein (r = -0.30, P < 0.05) and with the mean intima-media thickness (r = -0.28, P < 0.05) in patients with diabetes. Stepwise multiple regression analysis showed that the plasma level of dehydroepiandrosterone is significantly correlated with the plasma levels of the activated protein C-protein C inhibitor complex (F = 18.06) and high-sensitivity C-reactive protein (F = 4.94). There was no correlation between the plasma levels of dehydroepiandrosterone and monocyte chemoattractant protein-1. These results suggest that lower circulating levels of dehydroepiandrosterone are associated with decreased activated protein C generation and higher intima-media thickness in patients with Type 2 diabetes.

Homozygous CYP17A1 mutation (H373L) identified in a 46,XX female with combined 17α-hydroxylase/17,20-lyase deficiency

Background: Defects in cytochrome P450c17 are uncommon forms of congenital adrenal hyperplasia caused by CYP17A1 mutations. An H373L mutation in the CYP17A1 gene has been identified in Japanese and Chinese patients. This mutation impairs 17α-hydroxylase and 17,20-lyase activity. Case: A 23-year-old Korean female (46,XX) presented with absent spontaneous puberty and hypertension. Hormonal findings were consistent with combined 17α-hydroxylase/17,20-lyase deficiency. Very high levels of progesterone and 11-deoxycorticosterone were detected, coincident with normal 17-hydroxysteroid levels. Plasma levels of dehydroepiandrosterone, androstenedione and testosterone were extremely low. Mutation analysis of the CYP17A1 gene identified a homozygous missense mutation changing His (CAC) to Leu (CTC) at codon 373. This mutation is known to completely abolish both 17α-hydroxylase and 17,20-lyase activity. The patient’s nonconsanguineous parents were heterozygous for this mutation. Of note, her serum steroid levels indicated decreased, but still present, 17α-hydroxylase activity in vivo. Conclusion: We detected a homozygous H373L mutation in a patient with combined 17α-hydroxylase/17,20-lyase deficiency. Our findings demonstrate minimally preserved 17α-hydroxylase activity in vivo and contribute to our knowledge of the regional prevalence of this mutation in Northeast Asia.

Age-Related Changes in Plasma Dehydroepiandrosterone Levels in Adults with Down’s Syndrome and the Risk of Dementia

People with Down's syndrome (DS) are at high risk of developing early onset dementia. Recent studies suggest a link between age-related decreases in dehydroepiandrosterone (DHEA) concentrations and dementia in the general population. The present study investigates the relationship between DHEA serum levels and age and the risk of dementia in adults with DS. The DHEA plasma concentrations of 67 adults with DS and 65 age-matched controls were determined. Participants with DS were assessed for the presence of dementia using the CAMDEX informant interview. The DHEA plasma concentrations decreased with age in subjects with DS as well as in controls. Age significantly predicted DHEA levels in both groups (B = -0.06, t = -4.536, P < 0.001 in the DS group and B = -0.04, t = -2.928, P < 0.005 in control participants). The mean ± SD DHEA level was 3.47 ± 1.41 μmol/l in controls and 2.79 ± 1.24 μmol/l in participants with DS. This difference was significant (t = -2.981, P < 0.01). Within the DS population, ancova revealed a significant relationship between DHEA concentrations and dementia (F(1,65) = 4.348, P < 0.05). We found that DHEA levels declined significantly with age in people with DS and controls and were lower, in comparison to age-matched controls, in people with DS across all ages studied. Those with DS and evidence of dementia have lower DHEA concentrations than those with DS (controlling for age) but without dementia.