The associates of anxiety among lung cancer patients: Dehydroepiandrosterone (DHEA) as a potential biomarker.

OBJECTIVE: Anxiety is a prevalent comorbidity in lung cancer (LC) patients associated with a decline in quality of life. Dehydroepiandrosterone (DHEA), a neuroactive steroid, levels rise in response to stress. Prior research on the association between DHEA and anxiety has yielded contradictory results and no study has investigated this association in LC patients. METHODS: A total of 213 patients with LC were recruited from a general hospital. Data on demographic and cancer-related variables were collected. Using the Chinese version of the Hospital Anxiety and Depression Scale (HADS), the degree of anxiety was determined. Cortisol, DHEA, and Dehydroepiandrosterone sulfate (DHEA-S) levels in saliva were measured. Adjusting for confounding variables, a multivariate regression analysis was conducted. RESULTS: 147 men and 66 women comprised our group with an average age of 63.75 years. After accounting for demographic and treatment-related factors, anxiety levels were significantly correlated with, post-traumatic stress symptoms (PTSSs) (ß = 0.332, p < 0.001) and fatigue (ß = 0.247, p = 0.02). Association between anxiety and three factors, including DHEA, PTSSs, and fatigue, was observed in patients with advanced cancer stages (III and IV) (DHEA ß = 0.319, p = 0.004; PTSS ß = 0.396, p = 0.001; fatigue ß = 0.289, p = 0.027) and those undergoing chemotherapy (DHEA ß = 0.346, p = 0.001; PTSS ß = 0.407, p = 0.001; fatigue ß = 0.326, p = 0.011). CONCLUSIONS: The association between anxiety and DHEA remained positive in advanced cancer stages and chemotherapy patients. Further study is necessary to determine whether DHEA is a potential biomarker of anxiety in LC patients.

Associations of schizophrenia with the activities of the HPA and HPG axes and their interactions characterized by hair-based biomarkers.

BACKGROUND: Past studies on schizophrenia (SCZ) and the stress-sensitive neuroendocrine systems have mostly focused on a single system and traditionally utilized acute biomarkers (e.g., biomarkers from blood, urine and saliva) that poorly match the chronic course of schizophrenia in time span. Using eight biomarkers in hair, this study aimed to explore the functional characteristics of SCZ patients in the hypothalamic-pituitary-adrenocortical (HPA) and hypothalamic-pituitary-gonadal (HPG) axes and the interaction between the two axes. METHODS: Hair samples were taken from 137 SCZ patients and 73 controls. The SCZ patients were diagnosed by their attending physician according to the Diagnostic and Statistical Manual of Mental Disorders IV and were clinically stable after treatment. Gender, age, BMI, frequency of hair washing, marital status, education level, family history of mental illness and clozapine dosage were concurrently collected as covariates. The 10-item perceived stress scale (PSS-10) and the social readjustment rating scale were used to assess chronic stress status in SCZ patients. Eight hair biomarkers, cortisol, cortisone, dehydroepiandrosterone (DHEA), testosterone, progesterone, cortisol/cortisone, cortisol/DHEA and cortisol/testosterone, were measured by high performance liquid chromatography tandem mass spectrometer. Among them, cortisol, cortisone, DHEA and cortisol/DHEA reflected the functional activity of the HPA axis, and testosterone and progesterone reflected the functional activity of the HPG axis, and cortisol/cortisone reflected the activity of 11ß-hydroxysteroid dehydrogenase types 2 (11ß-HSD 2), and cortisol/testosterone reflected the HPA-HPG interaction. RESULTS: SCZ patients showed significantly higher cortisone and cortisol/testosterone than controls (p<0.001, η²p=0.180 and p=0.015, η²p=0.031), lower testosterone (p=0.009, η²p=0.034), progesterone (p<0.001, η²p=0.069) and cortisol/cortisone (p=0.001, η²p=0.054). There were significant intergroup differences in male and female progesterone (p=0.003, η²p=0.088 and p=0.030, η²p=0.049) and female testosterone (p=0.028, η²p=0.051). In SCZ patients, cortisol, cortisol/cortisone, cortisol/DHEA and cortisol/testosterone were positively associated with PSS-10 score (ps<0.05, 0.212

Hair levels of steroid, endocannabinoid, and the ratio biomarkers predict viral suppression among people living with HIV/AIDS in China.

BACKGROUND: Predicting viral suppression early is crucial to improving treatment outcomes among people living with HIV/AIDS (PLWH) in clinics. Viral suppression is affected by stress, making stress indicators a potential predictive factor. Most of previous studies used the self-report questionnaire as stress indicators, but there were great drawbacks due to its subjective. In contrast, end products of neuroendocrine systems such as hypothalamic-pituitaryadrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes and endogenous cannabinoid system (ECS) that involved in regulating stress as objective stress indicators are urgently needed to predict viral suppression. Therefore, this study aimed to investigate whether neuroendocrine indictors can strongly predict viral suppression among PLWH in China. METHODS: This cross-sectional study recruited 1198 PLWH on antiretroviral therapy (ART) in Guangxi, China. The concentrations of steroids (i.e., cortisol, cortisone, dehydroepiandrosterone, testosterone and progesterone) and endocannabinoids (i.e., N-arachidonoyl-ethanolamine and 1-arachidonyl glycerol) in hair were quantitated using the LC-APCI+-MS/MS method. To screen biomarkers that were used to predict viral suppression, association between hair biomarkers and viral suppression was examined by Mann-Whitney U test and partial correlation analyses. Receiver operating characteristic (ROC) curves and binary logistic regression based on the optimal classification threshold determined with ROC curves were used to estimate the prediction effects of the screened biomarkers on viral suppression (HIV-1 RNA < 200 copies/mL). RESULTS: Hair levels of dehydroepiandrosterone (DHEA), and N-arachidonoyl-ethanolamine (AEA), and the cortisol to DHEA ratio exhibited significant intergroup differences (ps < 0.05) and were correlated with HIV viral load (ps < 0.05). Hair DHEA concentrations strongly predicted viral suppression, showing good classification performance (area under the ROC curve = 0.651, p < 0.01) and strong predictive utility (adjusted odd ratio = 2.324, 95 % confidence interval = 1.211-4.899, p < 0.05) with an optimal threshold of 10.5 pg/mg. A hair AEA concentration of 2.4 pg/mg was the optimal threshold for predicting viral suppression based on good classification performance (area under the ROC curve = 0.598, p < 0.05) and predictive power (adjusted odd ratio = 2.124, 95 % confidence interval = 1.045-4.244, p < 0.05). In hair levels of cortisol to DHEA, viral suppression was observed to be highly predictive, with a threshold of 10.5 pg/mg being optimal for classification (area under the ROC curve = 0.624, p < 0.05) and prediction (adjusted odd ratio = 0.421, 95 % confidence interval = 0.201-0.785, p < 0.05). CONCLUSION: Hair levels of DHEA, and AEA and the cortisol to DHEA ratio were screened and verified to have significant predictive power with optimal thresholds for predicting viral suppression in a large-scale cohort. The data may provide new insights into predictors of successful virological outcomes and inform public health intervention and clinical practice to assist PLWH in achieving and sustaining viral suppression.

Cortisol/DHEA ratio in morbidly obese patients before and after bariatric surgery: Relation to metabolic parameters and cardiovascular performance.

INTRODUCTION: Bariatric surgery (BS) is the most effective therapy for morbid obesity. Cortisol and DHEA are steroid hormones with opposing effects, thus using Cortisol/DHEA ratio (C/D) rather than the use of either hormone alone has been found to predict health outcomes more reliably. It was interesting to study C/D as an indicator of favorable metabolic and cardiovascular outcomes after BS. OBJECTIVE: To assess C/D in morbidly obese patients before and after BS in relation to metabolic parameters and cardiovascular performance. PATIENTS AND METHODS: Forty morbidly obese patients were followed prospectively for 1 year after BS. Fasting blood glucose (FBG), fasting insulin (FI), C/D, lipid profile, high-sensitive CRP (hs-CRP), and echocardiography were done before BS and at 3 months and 1 year post BS. RESULTS: A total of 40 morbidly obese patients undergone sleeve gastrectomy. Blood pressure, FBG, FI, hs-CRP, C/D were significantly decreased after BS (p < 0.001). At 1 year post BS; significant reduction in left ventricular posterior wall thickness (LVPW) (p < 0.001), left ventricular mass (LVM) (p = 0.003), relative wall thickness (RWT) (p < 0.001) with a significant improvement in early diastolic velocity (E) (p < 0.001), early diastolic velocity/late diastolic velocity (E/A) (p = 0.01). After BS; C/D significantly positively correlated with FBG (p = 0.019), hs-CRP (p = 0.008), interventricular septum thickness (IVS) (p = 0.028), LVPW (p = 0.028), relative wall thickness (RWT) (p = 0.022), early diastolic velocity /early diastolic velocity (E') measured by pulsed tissue Doppler imaging (E/E') (p = 0.001), and significantly negatively correlated with E' (p = 0.032). C/D was the single significant independent variable affecting E' and E/E' post BS. CONCLUSION: C/D can be used as a surrogate marker of the improved FBG and the resolution of inflammation post BS. C/D is an independent predictor of diastolic function improvement post BS.

Noninvasive detection of human dehydroepiandrosterone, progesterone and testosterone using LC-MS/MS revealed effects of birth control pills/devices and body weight on ovulatory prediction.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been increasingly used to measure steroids in human saliva. We studied the performance of a conventional LC-MS/MS for measuring dehydroepiandrosterone (DHEA), testosterone and progesterone in human saliva. These three steroids were co-extracted by liquid-liquid extraction and derivatized. Derivatives were resolved on a C18 column and quantified using an LC-MS/MS (AB Sciex API 2000) instrument. The assay's limits of quantification were 0.03 ng/mL for all three steroids. Inter-assay coefficients of variation were 16.6-18.8% (DHEA), 12.0-15.8% (testosterone), and 12.7-19.3% (progesterone). Assay linearity analysis showed R2 of 0.9926, 0.9750 and 0.9949 for DHEA, testosterone and progesterone, respectively. No carry-over between samplings was observed. An ion-enhancement effect of 11.6% for DHEA determination and ion-suppression effects of 13.9% and 20.7% for analysis of progesterone and testosterone, respectively, were determined. No interferences by 9 steroid analogs were detected. Spiked recoveries were 85.5% (DHEA), 86.5% (testosterone), and 92.6% (progesterone). Comparison with laboratory developed test (LDT)-LC-MS/MS methods by other New York State Department of Health certified laboratories revealed R2 = 0.9425 (DHEA, LC-MS/MS = 1.0267 LDT + 21.989), R2 = 0.9849 (testosterone, LC-MS/MS = 0.9447 LDT + 9.8037), and R2 = 0.9736 (progesterone, LC-MS/MS = 1.1196 LDT + 0.0985). Reference intervals for the 3 steroids in saliva for young males and females were estimated. Results of intra-individual salivary progesterone analysis indicated that caution should be exercised when using progesterone concentrations in predicting ovulation for females who are under treatment with birth control pills/devices or has body a weight of > 90 kg.

Organ- and Age-Specific Differences of Dioscorea polystachya Compounds Measured by UPLC-QTOF/MS.

Dioscorea polystachya, named Chinese yam, is widely cultivated as a functional food and natural medicine in China. There is currently little information about the chemical characteristics of Dioscorea polystachya in different organs (tuber cortex and tuber flesh) and at various ages. In this study, an ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) was used to profile chemical compounds in Dioscorea polystachya. As a result, thirty-eight compounds were detected in yam tuber cortex and tuber flesh. More compounds were detected in yam tuber cortex than in tuber flesh. Compounds such as dehydroepiandrosterone, allantoin and flavonoids were selected as biomarker candidates. Dehydroepiandrosterone was found more abundant in tuber flesh, while allantoin and flavonoids showed higher levels in tuber cortex. Furthermore, the levels of dioscin, malvalic acid and sucrose differed significantly among age groups and were highest in the tubers at 2 years. While the levels of allantoin, adenosine and glutamine increased with the growing years and were highest at 4 years. Thus, 2-year old Dioscorea polystachya tubers could be harvested to prepare dioscin, malvalic acid and sucrose supplements. The 4-year-old Dioscorea polystachya tubers would be the best choice for obtaining a large amount of allantoin and adenosine in industrial production.

The influence of dehydroepiandrosterone on effector functions of neutrophils

Dehydroepiandrosterone (DHEA) is a steroid hormone secreted by the adrenal glands, gonads and brain. It is a precursor to sex hormones and also is known to have immune modulatory activity. However, little is known about the relationship between DHEA and neutrophils and thus our study evaluates the influence of DHEA in the effector functions of neutrophils. Human neutrophils were treated in vitro with DHEA and further infected with Salmonella enterica serovar Typhimurium. The treatment of neutrophils with 0.01 µM of DHEA increased the phagocytosis of Salmonella independent of TLR4 as the treatment did not modulate the TLR4 expression. Additionally, DHEA caused a decrease in ROS (reactive oxygen species) production and did not influence the formation of the neutrophil extracellular trap (NET). Steroid treated neutrophils, infected or stimulated with LPS (lipopolysaccharide), showed reduced production of IL-8, compared to untreated cells. Also, the protein levels of p-NFκB were decreased in neutrophils treated with DHEA, and this reduction could explain the reduced levels of IL-8. These results led us to conclude that the steroid hormone DHEA has important modulatory functions in neutrophils

Increased dehydroepiandrosterone (DHEA) is associated with anxiety in adolescent girls.

The pubertal period is a time of rapid increase in the incidence of anxiety disorders, and thus, pubertal hormones may play a role in the precipitation of anxious psychopathology. DHEA, a steroid hormone that surges in adolescence, has been previously linked to anxiety, although the direction of this effect has been mixed. Using a cross-sectional design in a sample of 286 adolescent girls, the present study examined associations between salivary DHEA concentrations and self-report and interview-based measures of anxiety while controlling for pubertal status, menarche status, assessment time of day, and other hormones including testosterone, estradiol, and progesterone. Increased salivary DHEA concentrations were associated with more self-reported anxiety symptoms, increased anxiety symptom counts based on clinical interview, and increased probability of an anxiety disorder. Out of all anxiety symptom domains examined, generalized anxiety disorder symptoms were the best predictor of salivary DHEA concentrations after controlling for pubertal development. Collectively, our findings suggest relevance for DHEA in the development of anxiety in the pubertal period, as well as a robust relationship between DHEA and emerging symptoms of pathological worry during adolescence. The present study underscores the importance of examining associations between DHEA concentrations and anxiety in longitudinal designs.

Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study.

Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics. Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels. Results: PDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample. Conclusions: Sociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

Rapid and structure-specific cellular uptake of selected steroids.

Steroid hormones and their respective nuclear receptors are essential mediators in numerous physiologic and pathophysiologic processes, ranging from regulation of metabolism, immune function, and reproductive processes to the development of hormone-dependent cancers such as those of the breast and prostate. Because steroids must enter cells before activating nuclear receptors, understanding the mechanisms by which cellular uptake occurs is critical, yet a clear understanding of these mechanisms has been elusive. It is generally assumed that diffusion-driven uptake is similar across various steroids whereas an elevated cellular concentration is thought to reflect active uptake, but these assumptions have not been directly tested. Here we show that intact cells rapidly accumulate free steroids to markedly elevated concentrations. This effect varies widely depending on steroid structure; more lipophilic steroids reach more elevated concentrations. Strong preferences exist for 3ß-OH, Δ5-steroids vs. 3-keto, Δ4-structural features and for progestogens vs. androgens. Surprisingly, steroid-structure-specific preferences do not require cell viability, implying a passive mechanism, and occur across cells derived from multiple tissue types. Physiologic relevance is suggested by structure-specific preferences in human prostate tissue compared with serum. On the other hand, the presence of serum proteins in vitro blocks much, but not all, of the passive accumulation, while still permitting a substantial amount of active accumulation for certain steroids. Our findings suggest that both passive and active uptake mechanisms make important contributions to the cellular steroid uptake process. The role of passive, lipophilicity-driven accumulation has previously been largely unappreciated, and its existence provides important context to studies on steroid transport and action both in vitro and in vivo.

Do dehydroepiandrosterone, progesterone, and testosterone influence women's depression and anxiety levels? Evidence from hair-based hormonal measures of 2105 rural Indian women.

Depressive and anxiety disorders substantially contribute to the global burden of disease, particularly in poor countries. Higher prevalence rates for both disorders among women indicate sex hormones may be integrated in the pathophysiology of these disorders. The Kshetriya Gramin Financial Services study surveyed a random sample of 4160 households across 876 villages in rural Tamil Nadu, India. An interviewer-administered questionnaire was conducted to quantify depressive (K6-D) and anxiety (K6-A) symptoms. Alongside, hair samples for sex hormone profiling were collected from a subsample of 2105 women aged 18-85 years. Importantly, 5.9%, 14.8%, and 46.3% of samples contained non-detectable hormone levels for dehydroepiandrosterone, progesterone, and testosterone, respectively. Our primary analysis imputes values for the non-detectable sample and we check robustness of results when non-detectable values are dropped. In this cohort of women from rural India, higher depressive symptomatology is associated with lower levels of dehydroepiandrosterone and higher depressive and anxiety symptoms are associated with higher levels of testosterone. Progesterone shows no clear association with either depressive or anxiety symptoms. These results support a potential protective effect of higher endogenous dehydroepiandrosterone levels. An important caveat on the potential negative effect of hair testosterone levels on women's mental health is that the testosterone analysis is sensitive to how non-detectable values are treated.

Chronotype, social jetlag and sleep loss in relation to sex steroids.

Chronotype describes preferences for functioning at different times of the day. At the onset of puberty, a sharp shift towards eveningness starts, reaching its peak at the end of adolescence, followed by a steady shift towards morningness as the ageing process occurs. Puberty is also the time when sex differences appear, with men being more inclined to eveningness than women, which diminishes around menopause; the described pattern of changes in chronotype leads to the hypothesis that reproductive hormones may be the driving factor behind this conversion. In the present study, we aimed to verify this hypothesis by analysing participants' testosterone, progesterone and dehydroepiandrosterone (DHEA) levels in the three months, as indicated by assays in 3-cm hair strands from the scalp. Participants (n = 239) of both sexes also completed the Munich Chronotype Questionnaire. The results showed that in men higher testosterone levels were related to eveningness and less sleep loss, whereas greater sleep loss was associated with lower levels of DHEA. In women, no associations between chronotype and levels of the analysed hormones were found. The results support the hypothesis that testosterone levels play a role in shaping eveningness. We further hypothesised that a possible cause of the higher secretion level of testosterone in men with the evening chronotype is a mechanism to offset the negative consequences of sleep loss.

Prenatal salivary sex hormone levels and birth-weight-for-gestational age.

OBJECTIVE: To determine whether prenatal sex hormones from maternal saliva are associated with birth-weight-for-gestational age. STUDY DESIGN: We measured salivary progesterone, testosterone, estradiol, dehydroepiandrosterone (DHEA), and cortisone in 504 pregnant women in a Mexico City cohort. We performed linear and modified Poisson regression to examine associations of log-transformed hormones with birth-weight-for-gestational age z-scores and the risk of small-for-gestational age (SGA) and large-for-gestational age (LGA) adjusting for maternal age, sex, BMI, parity, smoking, education, and socioeconomic status. RESULTS: In total, 15% of infants were SGA and 2% were LGA. Each interquartile range increment in testosterone/estradiol ratio was associated with a 0.12 decrement in birth-weight-for-gestational age z-score (95% CI: -0.27 to -0.02) and a 50% higher risk of SGA versus appropriate-for-gestational age (AGA) (95% CI: 1.13-1.99). CONCLUSION: Higher salivary testosterone/estradiol ratios may affect fetal growth, and identifying the predictors of hormone levels may be important to optimizing fetal growth.

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

BACKGROUND Currently, 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 AND METHODS Databases 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. RESULTS Meta-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%). CONCLUSIONS Meta-analysis showed that statins significantly reduced the levels of DHEA when compared with placebo in patients with PCOS.

Biomolecular engineering of antidehydroepiandrosterone antibodies: a new perspective in cancer diagnosis and treatment using single-chain antibody variable fragment.

AIM: To develop a monoclonal antibody against dehydroepiandrosterone (DHEA) and miniaturize it, generating a single-chain antibody variable fragment (scFv) against DHEA as an adrenocortical carcinoma (ACC) marker. MATERIAL & METHODS: DHEA conjugated to keyhole limpet hemocyanin was used as an immunogen to obtain anti-DHEA hybridomas. Variable fragments were cloned from hybridoma 5B7 total RNA, and used to detect DHEA in normal adrenal tissue and ACC cells. RESULTS: IgM monoclonal antibody was highly specific, and the recombinant scFv preserved parental antibody characteristics, allowing tissue localization of DHEA. CONCLUSION: Undefined small lesions are challenges for clinicians and impact clinical adrenocortical tumor management. Generating an anti-DHEA scFv facilitates development of imaging tests for early diagnosis of pediatric ACC.

Childhood urbanicity and hair steroid hormone levels in ten-year-old children.

BACKGROUND: Research suggests that it may be more stressful for children to grow up in an urban area than in a rural area. Urbanicity may affect physiological stress system functioning as well as the timing of sexual maturation. The purpose of the current study was to investigate whether moderate urbanicity (current and childhood, ranging from rural areas to small cities) was associated with indices of long-term hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axis functioning (cortisol, cortisone, dehydroepiandrosterone and progesterone levels) and whether sex moderated any associations. METHOD: Children (N = 92) were all 10 years old and from the Dutch general population. Hair samples were collected and single segments (the three cm most proximal to the scalp) were assayed for concentrations of steroid hormones (LCMS/MS method). Neighborhood-level urbanicity and socioeconomic status were measured from birth through age ten years. Analyses were controlled for neighborhood- and family socioeconomic status, body mass index and season of sampling. RESULTS: The results from multivariate analyses of variance showed no associations between current or childhood moderate urbanicity and hair steroid hormone concentrations. Interaction terms between moderate urbanicity and sex were not statistically significant. CONCLUSIONS: Associations between urbanicity and steroid hormone levels may only be detectable in highly urban areas and/or during later stages of adolescence. Alternatively, our findings may have been due to most children being from families with a higher socioeconomic status.

Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD.

Allopregnanolone and pregnanolone (together termed allo + pregnan) are neurosteroid metabolites of progesterone that equipotently facilitate the action of gamma-amino-butyric acid (GABA) at GABAA receptors. The adrenal steroid dehydroepiandrosterone (DHEA) allosterically antagonizes GABAA receptors and facilitates N-methyl-D-aspartate (NMDA) receptor function. In prior research, premenopausal women with posttraumatic stress disorder (PTSD) displayed low cerebrospinal fluid (CSF) levels of allo + pregnan [undifferentiated by the gas chromatography-mass spectrometry (GC-MS) method used] that correlated strongly and negatively with PTSD reexperiencing and negative mood symptoms. A PTSD-related decrease in the ratio of allo + pregnan to 5α-dihydroprogesterone (5α-DHP: immediate precursor for allopregnanolone) suggested a block in synthesis of these neurosteroids at 3α-hydroxysteroid dehydrogenase (3α-HSD). In the current study, CSF was collected from unmedicated, tobacco-free men with PTSD (n = 13) and trauma-exposed healthy controls (n = 17) after an overnight fast. Individual CSF steroids were quantified separately by GC-MS. In the men with PTSD, allo + pregnan correlated negatively with Clinician-Administered PTSD Scale (CAPS-IV) total (ρ=-0.74, p = 0.006) and CAPS-IV derived Simms dysphoria cluster (ρ=-0.71, p = 0.01) scores. The allo+pregnan to DHEA ratio also was negatively correlated with total CAPS (ρ=-0.74, p = 0.006) and dysphoria cluster (ρ=-0.79, p = 0.002) scores. A PTSD-related decrease in the 5α-DHP to progesterone ratio indicated a block in allopregnanolone synthesis at 5α-reductase. This study suggests that CSF allo + pregnan levels correlate negatively with PTSD and negative mood symptoms in both men and women, but that the enzyme blocks in synthesis of these neurosteroids may be sex-specific. Consideration of sex, PTSD severity, and function of 5α-reductase and 3α-HSD thus may enable better targeting of neurosteroid-based PTSD treatments.

Steroid profiles by liquid chromatography-mass spectrometry of matched serum and single dominant ovarian follicular fluid from women undergoing IVF.

RESEARCH QUESTION: Can IVF outcomes be predicted from the steroid profile generated by liquid chromatography-mass spectrometry (LC-MS/MS) from follicular fluid collected from a single dominant follicle and serum after ovarian stimulation. DESIGN: Prospective observational cohort study in which serum and follicular fluid were collected from women and used to generate steroid profiles by LC-MS/MS. A total of 93 consecutive women enrolled for IVF treatment were recruited at the Fertility Unit, Royal Prince Alfred Women and Babies Hospital, Sydney between September 2014 and July 2015. Baseline and serum levels at oocyte retrieval, as well as follicular fluid samples from the largest single antral follicle, were collected. All samples underwent steroid analysis within a single batch to measure progesterone (P4), oestradiol (E2), oestrone (E1), dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), dihydrotestosterone (DHT), and 3 α, 5α androstanediol (3α-diol) and 3ß, 5α androstanediol (3ß-diol). RESULTS: P4, E2, E1, A4, T, DHEA and A4 were detectable in all baseline serum levels, at oocyte retrieval and in follicular fluid samples, whereas DHT, 3α-diol and 3ß-diol were only detectable in a minority of samples. The most consistent predictor of pre-transfer (number of follicles >14mm in diameter, oocytes retrieved or fertilized, day-5 blastocysts) outcomes was baseline serum anti-Müllerian hormone. In follicular fluid, E2 was a negative predictor of the number of oocytes retrieved and the number of day-5 blastocysts but no follicular fluid steroids predicted pregnancy outcome. CONCLUSIONS: None of the nine steroids measured in follicular fluid predicted pregnancy outcome in women undergoing IVF.

Salivary Pubertal Hormones, Sleep Disturbance, and an Evening Circadian Preference in Adolescents: Risk Across Health Domains.

PURPOSE: Puberty influences biological and psychological development during adolescence. This includes a shift toward an evening circadian preference, which is characterized by greater physical and mental activity at night compared to the morning. This study examines how pubertal hormones are related to risk across key health domains among adolescents with an evening circadian preference. METHODS: Participants were adolescents with an evening circadian preference (n = 165, 96 female and 69 male, mean age = 14.8) from an NICHD-funded study. Hormones included testosterone, dehydroepiandrosterone (DHEA), and estradiol (females only). Sleep measures included weeknight total sleep time and weeknight bedtime. Circadian preference was assessed with the Children's Morningness-Eveningness Preferences Scale. Health domains included emotional, cognitive, behavioral, social, and physical health. RESULTS: For female adolescents, estradiol was related to higher risk in the emotional domain. Among female adolescents with later bedtimes, higher estradiol was associated with higher behavioral domain risk (specifically alcohol and substance use). For male adolescents with a more extreme evening circadian preference, higher DHEA and testosterone were associated with higher behavioral domain risk, specifically greater alcohol and substance use or sensation seeking (DHEA only). Among female adolescents with a more extreme evening circadian preference, higher DHEA was associated with greater physical health risk. CONCLUSIONS: Pubertal hormones may be associated with heightened risk across select health domains. Specifically, higher levels of hormones may contribute to increased risk for alcohol and substance use as well as sensation seeking in the context of an evening circadian preference.

A relationship in adrenal androgen levels between mothers and their children from a dioxin-exposed region in Vietnam.

Over the past decades, southern Vietnam has been burdened by dioxins from contaminated herbicides sprayed during the Vietnam War. In a previous study, we found that dioxin exposure decreased levels of salivary dehydroepiandrosterone (DHEA), an adrenal androgen, in 3-year-old children. In present study, to assess the relationship between adrenal hormones disruption in lactating mothers and in children, we compared mother-child pairs from dioxin- and nondioxin-contaminated regions. In 2010 and 2011, mother-child pairs from a dioxin hotspot region (n=37) and a non-contaminated region (n=47) were recruited and donated breast milk and serum samples for dioxin and steroid hormones determination. Mothers were 20-30years old and had given birth to their first child between 4 and 16weeks previously. One year later, saliva samples were collected from the children. Dioxin levels in breast milk were determined by gas chromatography/high-resolution mass spectrometry. Salivary DHEA, cortisol in children and androstenedione (A-dione), estradiol, cortisol, and DHEA in maternal serum were analyzed by liquid chromatography/tandem mass spectrometry. Concentrations of dioxin congeners in the hotspot region were 2- to 5-fold higher than in samples from the non-contaminated region. Salivary DHEA levels in children and serum A-dione levels in mothers were significantly higher in the hotspot region; no difference was found in the levels of other hormones. Moreover, there was a significant positive correlation between the elevated hormone levels in mothers and children (r=0.62, p<0.001). Several dioxin congeners exhibited strong significant dose-response relationships with salivary DHEA and serum A-dione levels. Our findings suggest that dioxin disrupts adrenal androgens in mothers and breastfeeding children through the same mechanism.