Human cytochrome P450 3A7 binding four copies of its native substrate dehydroepiandrosterone 3-sulfate.

Human fetal cytochrome P450 3A7 (CYP3A7) is involved in both xenobiotic metabolism and the estriol biosynthetic pathway. Although much is understood about cytochrome P450 3A4 and its role in adult drug metabolism, CYP3A7 is poorly characterized in terms of its interactions with both categories of substrates. Herein, a crystallizable mutated form of CYP3A7 was saturated with its primary endogenous substrate dehydroepiandrosterone 3-sulfate (DHEA-S) to yield a 2.6 Å X-ray structure revealing the unexpected capacity to simultaneously bind four copies of DHEA-S. Two DHEA-S molecules are located in the active site proper, one in a ligand access channel, and one on the hydrophobic F'-G' surface normally embedded in the membrane. While neither DHEA-S binding nor metabolism exhibit cooperative kinetics, the current structure is consistent with cooperativity common to CYP3A enzymes. Overall, this information suggests that mechanism(s) of CYP3A7 interactions with steroidal substrates are complex.

Early-life matters: The role of fetal adrenal steroids in the relationship between cytokines within the placental circulation and cognitive development among infants in the Philippines.

Prenatal exposure to inflammation is related to the risk for cognitive impairment in offspring. However, mechanisms underlying the link between inflammatory cytokines at the maternal-fetal interface and human cognitive development are largely unknown. This study addressed this research gap by examining whether i) cytokines within the placenta are associated with different domains of neurocognitive development during infancy, and ii) if DHEA-S in cord blood mediates these associations. We also explored the role of early-life socioeconomic status (SES) in moderating the effect of fetal adrenal steroids on cognitive development in low- and middle-income country contexts. A cohort of 242 mother-infant dyads in Leyte, the Philippines participated in the study and all of them were followed from early pregnancy until 12-months. Concentrations of pro- and anti-inflammatory cytokines in the placenta, and DHEA-S in cord blood collected at delivery were evaluated. The multifactorial aspects of the infant's cognitive functioning were assessed based on the Bayley Scales of Infant Development, third edition (BSID-III). We used Structural Equation Modelling (SEM) with an orthogonal rotation to examine associated paths among latent variables of pro- and anti-inflammatory cytokines in the placenta, fetal neuroendocrine factors, and cognitive development. Pathway analyses showed that both pro- and anti-inflammatory cytokines in the placenta were indirectly related to cognitive (p < 0.05) and language developmental outcomes (p < 0.1) via DHEA-S in cord blood among the low SES group. Yet, we found no statistically significant indirect effect of pro- or anti-inflammatory cytokines on neurocognitive development among the high SES sub-sample. This study extends our understanding of how early-life socioeconomic conditions modify biological pathways underlying the relationship between prenatal factors and postpartum cognitive development.

DHEA-S production capacity in relation to perceived prolonged stress.

We and other research groups have previously described that levels of the anabolic hormone dehydroepiandrosterone sulfate (DHEA-S) are lowered in individuals who report prolonged stress. We have also shown that the DHEA-S production capacity during acute stress is attenuated in individuals reporting high prolonged stress. This study aimed to further investigate the DHEA and DHEA-S production capacity in relation to prolonged stress. Eighty-one healthy participants in the age 20-50 years old were included in the study and divided into a low stress (n = 45) and a high stress group (n = 36) according their response to a single question regarding perceived stress during the preceding month. They underwent the Trier Social Stress Test while blood samples were drawn before, during and after the stress test. The concentration of DHEA, DHEA-S, cortisol and ACTH was measured. The results showed that the high stress group exhibited a significantly lower response of DHEA-S (40% lower) than the low stress group, while DHEA, cortisol and ACTH responses did not differ between the groups. Reduced DHEA-S production may constitute one of the links between stress and poor health.

Sulphated dehydroepiandrosterone serum levels are reduced in women with alcohol use disorder and correlate negatively with craving: A sex-separated cross-sectional and longitudinal study.

Previous studies have established a role of sex hormones in alcohol use disorder (AUD).Only few clinical investigations with low numbers of patients with AUD have focused on the sulphated form of dehydroepiandrosterone (DHEA-S), despite its function as a neuromodulating sex steroid on receptors in the central nervous system (γ-aminobutyric acid type A, N-methyl-D-aspartate, sigma-1 receptors). DHEA-S serum levels were compared between 200 inpatients with AUD (44% women) admitted for withdrawal treatment and 240 healthy controls (45% women) and analysed longitudinally in patients from early abstinence (baseline) to a median of 5 days later. We also correlated DHEA-S levels with craving, liver enzyme activities, and prospective alcohol-related readmissions during a 24-month follow-up. DHEA-S concentrations were lower in female patients than in female healthy controls during baseline (70%) and decreased from baseline to follow-up in the female and male patients groups (down to: women, 92%; men, 76%). Baseline DHEA-S concentrations correlated with the total and obsessive subscales of the Obsessive-Compulsive Drinking Scale and with maximum visual analogue scale craving scores in female patients (Rho ≤ -0.240) and gamma-glutamyl transferase activity in female (Rho = -0.292) and male (Rho = -0.391) patients. DHEA-S did not significantly predict outcome. We found interactions with smoking behaviour and age. This is the first study based on large cohorts of inpatients with AUD undergoing a qualified detoxification treatment to provide sex-separated evidence for associations of DHEA-S serum concentrations with AUD and related phenotypes. The results stimulate further investigations whether DHEA-S directly influences alcohol craving building a basis to develop sex-sensitive prevention and treatment strategies.

Comparative profiling of prenatal cortisol and DHEA-S among pregnant women with poor birth outcome and pregnant women with normal birth outcome.

CONTEXT: Cortisol and dehydroepiandrosterone-sulfate (DHEA-S) are indispensable hormones for normal pregnancy. It is unclear if these hormones, specifically DHEA-S can offer value for predicting poor birth outcome. OBJECTIVE: To compare prenatal cortisol and DHEA-S levels among pregnant women with normal or poor birth outcome. METHODS: Plasma and saliva were collected prospectively from women in second-third trimester of pregnancy. Women with normal birth outcome (NBO) (n = 501) included live birth, no pregnancy complications and ≥2.5 kg infant birth weight. Women with poor birth outcome included adverse birth outcome (ABO) (n = 50) or low birth weight outcome (LBW) (n = 147). Enzyme-linked immunosorbent assay was performed to measure hormone concentrations in plasma and saliva. RESULTS: Circulatory-DHEA-S levels in pregnant women with ABO were higher than women with NBO (p = .043). Among ABO, only stillbirth cases demonstrated significant increase in circulatory-DHEA-S levels (p = .006). Circulatory and salivary cortisol/DHEA-S ratio was lower among women with stillbirth (p = .004) and ABO outcome (p = .043) respectively compared with women with NBO. Consistently, increased odds of ABO were observed in pregnant women with highest circulatory-DHEA-S levels (odds ratio quartile score 1 vs. 4, 2.79, p = .027) and lowest salivary cortisol/DHEA-S ratio (score 4 vs. 2, 2.83, p = .025). Increased odds of stillbirth outcome were observed in pregnant women with highest circulatory-DHEA-S levels (odds ratio quartile score 1 vs. 4, 8.47, p = .046) and lowest circulatory cortisol/DHEA-S ratio (score 4 vs. 1, 4.803, p = .048). Associations remained significant after adjusting for confounders. Women with LBW did not demonstrate significant changes in cortisol or DHEA-S levels. CONCLUSION: Prenatal measurement of DHEA-S or cortisol/DHEA-S ratio may offer significant value for predicting adverse birth, specifically stillbirth outcome.

Blood Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate as Pathophysiological Correlates of Chronic Pain: Analyses Using a National Sample of Midlife Adults in the United States.

OBJECTIVE: Identifying biomarkers is a priority in translational chronic pain research. Dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S, are adrenocortical steroids in the blood with neuroprotective properties that also produce sex hormones. They may capture key sex-specific neuroendocrine mechanisms of chronic pain. DESIGN: Cross-sectional study. METHODS: Using data from 1,216 community-dwelling adults aged 34-84 from the Midlife in the United States (MIDUS) cohort, we examined blood DHEA and DHEA-S levels in association with chronic pain in men and women, adjusting for demographics, chronic diseases, medications including opioids, and psychosocial factors. If an association was found, we further explored dose-response relationships by the number of pain locations and the degree of pain interference. RESULTS: In women, chronic pain was associated with 0.072 lower (95% confidence interval [CI], -0.127 to -0.017) log10 DHEA-S µg/dL, with pain in one to two locations associated with 0.068 lower (95% CI, -0.131 to -0.006) and in three or more locations 0.071 lower (95% CI, -0.148 to 0.007) log10 DHEA-S (P for trend = 0.074). Furthermore for women, low-interference pain was associated with 0.062 lower (95% CI, -0.125 to -0.000), whereas high-interference pain was associated with 0.138 lower (95% CI, -0.233 to -0.043) log10 DHEA-S (P for trend = 0.004). Chronic pain was not associated with DHEA or DHEA-S levels in men or DHEA levels in women. CONCLUSIONS: Chronic pain and its functional interference correspond to lower blood DHEA-S levels in women.

Diagnostic value of standard deviation score of log-transformed serum dehydroepiandrosterone sulfate in patients with hypothalamic-pituitary-adrenal axis insufficiency.

Serum dehydroepiandrosterone sulfate (DHEA-S) levels reflect the state of adrenocorticotropic hormone (ACTH) secretion. However, it is difficult to use serum DHEA-S to diagnose hypothalamic-pituitary-adrenal (HPA) axis insufficiency due to its non-normal and highly skewed distribution. In this study, we focused on HPA insufficiency caused by hypothalamic and/or pituitary dysfunction and evaluated the usefulness of the standard deviation score of log-transformed DHEA-S (ln DHEA-S SD score), which was calculated from the established age- and sex-specific reference values. We retrospectively reviewed the medical records of 94 patients suspected of having HPA insufficiency, in whom serum DHEA-S measurement and the rapid ACTH stimulation test were performed, and included 65 patients who met our criteria in this study. The ln DHEA-S SD scores were distributed more normally than measured DHEA-S levels and were significantly higher in patients with a peak cortisol level ≥18 µg/dL than in those below this value, suggesting that this score is a legitimate and strong indicator of adrenocortical function. The optimal cut-off value for impaired HPA function was -0.853, with a sensitivity of 70.3% and a specificity of 100%. Among the 37 patients whose peak cortisol levels were below 18 µg/dL, 11 patients with ln DHEA-S scores ≥-0.853 exhibited significantly higher basal ACTH and basal and peak cortisol levels than the 26 patients with scores <-0.853. Thus, this score plays a supportive role in evaluating HPA axis function, particularly in patients with borderline cortisol responses to ACTH.

Possible Adrenal Involvement in Long COVID Syndrome.

Background: A significant number of patients with COVID-19 experience prolonged symptoms, known as Long COVID. The most frequent symptoms are fatigue and cognitive dysfunction. We describe a patient suffering from Long COVID in whom adrenal involvement was highlighted. Methods: The patient described Long COVID symptoms that persist 3 months after the negativization of the molecular swab test. The main symptoms were weakness, brain fog, dizziness, and muscular and joint pain. All routine lab panels for inflammation, anemia, and thyroid and liver function were conducted. Moreover, salivary cortisol and DHEA-S determinations were used to compute the adrenal stress index (ASI). Results: All tests were negative, except the ASI that showed very low levels of free cortisol. The patient started hydrocortisone acetate supplementation. Conclusion: Long COVID symptoms could be explained by an adrenal involvement, due to a COVID-19 action on adrenal glands and by a iatrogenic side effect of high glucocorticoid therapy during the COVID-19 infection. Salivary cortisol determination is effective for establishing a correct recovery plan.

Reproducibility of saliva progesterone measured by immunoassay compared to liquid chromatography mass spectrometry.

Immunoassay overestimates progesterone in blood, but no studies have tested whether this occurs in saliva. We measured progesterone in saliva using immunoassay and mass spectrometry. We tested the immunoassay for cross reactivity with dehydroepiandrosterone sulfate (DHEA-S) and 17α-hydroxyprogesterone (17α-OHP). Progesterone was significantly higher in immunoassay compared to mass spectrometry. Immunoassay progesterone levels increased in when incremental levels of 17α-OHP standard was added. This effect was not observed with the addition of DHEA-S. Research using salivary progesterone immunoassay techniques should be wary, particularly with individuals taking steroid supplementation or with high levels of progesterone metabolites.

Cortisol and DHEA-S levels in pregnant women with severe anxiety.

BACKGROUND: A complex interaction between cortisol and dehydroepiandrosterone-sulphate (DHEA-S) is crucial in the stress system balance; several studies have reported increased cortisol levels during chronic stress and a weak counter-regulation by DHEA-S. During pregnancy, scarce information about this system is available, although cortisol and DHEA-S play an important role in the initiation and acceleration of labor. We conducted the present study in order to determine both cortisol and DHEA-S levels during the last trimester of pregnancy in patients exhibiting severe anxiety. METHODS: Pregnant women during the 3rd trimester of pregnancy were evaluated by using the self-reported version of the Hamilton Anxiety Rating Scale (HARS). According to the scores obtained from the psychometric scale, participants were divided into two groups: 1) patients exhibiting a cutoff score > 15 were considered with severe anxiety (ANX) (n = 101), and control pregnant subjects (CTRL) (n = 44) with a cutoff score < 5. Morning cortisol, DHEA-S and Cortisol/DHEA-S index were measured in all participants. Comparisons between groups were performed; additionally, correlations between clinical variables, biochemical data and HARS were calculated. RESULTS: Cortisol levels were significantly higher in the ANX group (p < 0.001), whereas those of DHEA-S were significantly lower in the same group (p < 0.01) when compared to healthy pregnant subjects. An increased cortisol/DHEA-S index was observed in the ANX group (p < 0.05). A significant association between cortisol and HARS scores (p = 0.03), was observed even after adjusting by gestational weeks (p = 0.004). CONCLUSIONS: Our data support that the cortisol/DHEA-S index is higher in pregnant women with high anxiety levels as compared with healthy pregnant women.

Low serum albumin, aspartate aminotransferase, and body mass are risk factors for frailty in elderly people with diabetes-a cross-sectional study.

BACKGROUND: Frailty is broadly characterized by vulnerability and decline in physical, mental and social activities and is more common in elderly patients with type 2 diabetes mellitus (T2DM). Frailty is closely associated with nutrition, muscle strength, inflammation, and hormones etc. In hormones, dehydroepiandrosterone sulfate (DHEA-S) and cortisol are suggested to be such candidates affecting frailty. Little investigation has been performed using a wider range of measures of frailty to clarify risk factors for frailty including the above two hormones. METHODS: We performed a cross-sectional study to investigate the risk factors for frailty in elderly T2DM patients (n = 148; ≥65 years), using a broad assessment, the clinical frailty scale. We compared parameters between the non-frail and frail groups using the unpaired t and Mann-Whitney U tests. The Jonckheere-Therpstra test was used to identify relationships with the severity of frailty, and risk factors were identified using binary regression analysis. RESULTS: Simple regression analysis identified a number of significant risk factors for frailty, including DHEAS < 70 µg/dL and cortisol/DHEA-S ratio ≥ 0.2. Multiple regression analysis showed that low albumin (< 4.0 g/dl) (odds ratio [OR] = 5.79, p < 0.001), low aspartate aminotransferase (AST) activity (< 25 IU/L) (OR = 4.34, p = 0.009), and low body mass (BM) (< 53 kg) (OR = 3.85, p = 0.012) were independent risk factors for frailty. A significant decrease in DHEA-S and a significant increase in the cortisol/DHEA-S ratio occurred alongside increases in the severity of frailty. DHEA-S concentration positively correlated with both serum albumin and BM. CONCLUSIONS: Hypoalbuminemia, low AST, and low BM are independent risk factors for frailty in elderly T2DM patients, strongly implying relative malnutrition in these frail patients. DHEA-S may be important for the maintenance of liver function and BM. A decrease in DHEA-S and an increase in the cortisol/DHEAS ratio may be involved in the mechanism of the effect of malnutrition in elderly T2DM patients.

The effects of cortisol and adrenal androgen on bone mass in Asians with and without subclinical hypercortisolism.

Analyses using the largest Korean cohort of adrenal incidentaloma (AI) revealed that subtle cortisol excess in premenopausal women and reduced dehydroepiandrosterone-sulfate (DHEA-S) in postmenopausal women and men are associated with bone mineral density (BMD) reduction in Asian patients with subclinical hypercortisolism (SH). INTRODUCTION: Few studies evaluated bone metabolism in Asians with SH. We investigated associations of cortisol and DHEA-S, an adrenal androgen, with BMD in Asians with AI, with or without SH. METHODS: We used cross-sectional data of a prospective multicenter study from Korea. We measured BMD, bone turnover markers, cortisol levels after 1-mg dexamethasone suppression test (1-mg DST), DHEA-S, and baseline cortisol to DHEA-S ratio (cort/DHEA-S) in 109 AI patients with SH (18 premenopausal, 38 postmenopausal women, and 53 men) and 686 with non-functional AI (NFAI; 59 premenopausal, 199 postmenopausal women, and 428 men). RESULTS: Pre- and postmenopausal women, but not men, with SH had lower BMDs at lumbar spine (LS) than those with NFAI (P = 0.008~0.016). Premenopausal women with SH also had lower BMDs at the hip than those with NFAI (P = 0.009~0.012). After adjusting for confounders, cortisol levels after 1-mg DST demonstrated inverse associations with BMDs at all skeletal sites only in premenopausal women (ß = - 0.042~- 0.033, P = 0.019~0.040). DHEA-S had positive associations with LS BMD in postmenopausal women (ß = 0.096, P = 0.001) and men (ß = 0.029, P = 0.038). The cort/DHEA-S had inverse associations with LS BMD in postmenopausal women (ß = - 0.081, P = 0.004) and men (ß = - 0.029, P = 0.011). These inverse associations of cort/DHEA-S remained significant after adjusting for cortisol levels after 1-mg DST (ß = - 0.079~- 0.026, P = 0.006~0.029). In postmenopausal women, the odds ratios of lower BMD by DHEA-S and cort/DHEA-S was 0.26 (95% CI, 0.08-0.82) and 3.40 (95% CI, 1.12-10.33), respectively. CONCLUSION: Subtle cortisol excess in premenopausal women and reduced DHEA-S in postmenopausal women and men may contribute to BMD reduction in Asians with SH.

Noninvasive determination of human cortisol and dehydroepiandrosterone sulfate using liquid chromatography-tandem mass spectrometry.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) for measurements of steroids in human saliva has garnered increased interest in the area of clinical psychoneuroendocrinological research. However, performance characteristics of LC-MS/MS methods for the analysis of steroids in saliva are limited. Human saliva samples were collected via passive drool. Cortisol and dehydroepiandrosterone sulfate (DHEA-S) in the samples were extracted together, resolved on a C18-A column, and analyzed using tandem mass spectrometry. The LC-MS/MS method had limits of quantitation of 0.03 and 0.06 ng/mL for DHEA-S and cortisol, respectively. Method evaluations showed coefficient variation (%CV) of inter-assay ranging 4.6-17.9% for DHEA-S and cortisol, recoveries of 102.4-109.5% for DHEA-S and 94.6-98.3% for cortisol, and assay linearity with R2 = 0.9964 for DHEA-S (1.0-25.0 ng/mL) and R2 = 0.997 (1.0-25.0 ng/mL) for cortisol. No cross contamination among samples was observed. Human saliva showed 20% and 18% ion enhancement effect for DHEA-S and cortisol assay, respectively. No interference by ten common steroids was detected. Regression analysis of method comparisons with laboratory-developed test (LDT) method revealed R2 = 0.9688 (LC-MS/MS = 0.9665 LDT-LC-MS/MS - 0.7355) for cortisol, and R2 = 0.9039 (LC-MS/MS = 1.0173 LDT-LC-MS/MS + 3.6797) for DHEA-S. Reference ranges for young adults were determined to be 0.3-5.9 ng/mL for females and 0.1-5.6 ng/mL for males for salivary cortisol, and 0.6-7.4 ng/mL for females and 0.6-10.1 ng/mL for males for salivary DHEA-S. An LC-MS/MS method for quantifying cortisol and DHEA-S in human saliva was developed and validated for clinical and psychoneuroendocrinological research that require noninvasive means of measuring these hormones.

Increased androgen secretion in patients with prolactinomas: the impact of altered HPA function.

BACKGROUND AND OBJECTIVES: Earlier studies suggested that hyperprolactinemia was associated with elevated serum DHEA-S levels. The importance of DHEA-S measurements in the diagnosis of adrenal insufficiency prompted us to assess adrenal androgen levels in hyperprolactinemic subjects with normal or impaired function. METHODS: Prospective study including 122 medically treated and 26 surgically patients with prolactinomas. Serum PRL, DHEA and DHEA-S levels were measured before and repeatedly after cabergoline therapy and also in the perioperative period of surgically treated patients. RESULTS: Serum PRL levels decreased (P < 0.001) in all 101 medically treated patients with normal HPA function from 728.3 ± 1507 reaching 29.1 ± 39 and 14.9 ± 24.4 µg/L at 3 and 12 months, respectively. Concurrently serum DHEA-S levels decreased (P < 0.001) from 245.9 ± 196 to 216.2 ± 203.3 and to 169.7 ± 121.1 µg/dl at 3 and 12 months, respectively. These effects were reversed in 19 patients who discontinued treatment and were re-demonstrated after therapy resumption. Among the 22 surgically treated patients with normal HPA, peri-operative PRL levels decreased rapidly (P < 0.001) with a parallel decline in serum DHEA-S levels (P = 0.03). Strong correlations were noted between PRL and DHEA-S decrements observed with medical or surgical therapy. Medically (n = 21) and surgically (n = 4) patients with impaired HPA function had very low DHEA-S values that were unchanged despite marked reductions in PRL secretion. CONCLUSION: Hyperprolactinemia is associated with a reproducible and reversible increase in serum DHEA-S that was observed in medically- and surgically-treated patients with normal HPA function. Thus, a normal age- and gender-adjusted serum DHEA-S level continues to imply normal HPA function even among hyperprolactinemic subjects.

Association between locomotive syndrome and blood parameters in Japanese middle-aged and elderly individuals: a cross-sectional study.

BACKGROUND: Locomotive syndrome (LS) is associated with weakness and loss of function in the musculoskeletal organs. We aimed to determine the association between LS components and blood parameters in middle-aged and elderly individuals. METHODS: We included 223 middle-aged and elderly individuals in this study (104 men and 119 women; age: 40-85 years). All participants were asked to fast for at least 3 h before the venous blood samples were obtained and the hemoglobin, total protein, glycated hemoglobin (HbA1c), growth hormone, albumin and lipid profile were measured. Three functional tests, the stand-up test, the two-step test, and the 25-question geriatric locomotive function scale (GLFS) were used to assess the risk of LS. Walking speed was assessed by the 10-m walking test. Maximal isometric muscle strengths of the knee extensors were examined, and the weight bearing index (knee extension strength/body weight) was calculated. To assess an independent association between blood parameters and LS, the area under the receiver operating characteristic curve analysis (area under the curve, sensitivity, and specificity) and a binary logistic regression analysis were performed with adjustment for age. RESULTS: Of the 223 subjects, 119 (53.3%) fulfilled the diagnostic criteria for LS (including a two-step test score < 1.3, difficulty with one-leg standing from 40 cm in the stand-up test, and a 25-question GLFS score ≥ 7). Increased levels of HbA1c were significant risk factors for LS with an OR of 2.62 (OR95%CI = 1.43-4.80), as determined by a logistic regression analysis. Additionally, dehydroepiandrosterone-sulfate (DHEA-S) levels were significant only in the male subjects (OR = 0.992 [OR95%CI = 0.986-0.998]), at a threshold of 88 (AUC; 0.70, sensitivity; 79.6%, specificity; 49.1%). Moreover, 101 of 223 participants (41 men, 60 women) were analyzed for serum albumin levels, with a prevalence of LS at 55.4%, indicating that low levels of albumin were significant risk factors for LS (OR = 0.148 [OR95%CI = 0.023-0.954], p = 0.0445). CONCLUSIONS: These results suggest that higher HbA1c and lower albumin are associated with the prevalence of LS in Japanese middle-aged and elderly individuals. Furthermore, low DHEA-S levels may be useful screening tools for LS in men.

Association Between Cortisol to DHEA-s Ratio and Sickness Absence in Japanese Male Workers.

PURPOSE: This study aimed to investigate the association between serum levels of cortisol and dehydroepiandrosterone sulfate (DHEA-s) and sickness absence over 2 years in Japanese male workers. METHOD: A baseline survey including questions about health behavior, along with blood sampling for cortisol and DHEA-s, was conducted in 2009. In total, 429 men (mean ± SD age, 52.9 ± 8.6 years) from whom blood samples were collected at baseline were followed until December 31, 2011. The hazard ratios (HR) and 95% confidence intervals (CI) for sickness absence were calculated using a Cox proportional hazard model, adjusted for potential confounders. RESULTS: Among 35 workers who took sickness absences, 31 had physical illness. A high cortisol to DHEA-s ratio increased the risk of sickness absence (crude HR = 2.68, 95% CI 1.12-6.41; adjusted HR = 3.33, 95% CI 1.35-8.20). The cortisol to DHEA-s ratio was linearly associated with an increased risk of sickness absence (p for trend < .050). Single effects of cortisol and DHEA-s levels were not associated with sickness absences. This trend did not change when limited to absences resulting from physical illness. CONCLUSION: Hormonal conditions related to the hypothalamus-pituitary-adrenocortical axis and adrenal function should be considered when predicting sickness absence. The cortisol to DHEA-s ratio may be more informative than single effects of cortisol and DHEA-s levels.

Walking training and cortisol to DHEA-S ratio in postmenopause: An intervention study.

The literature indicates that the plasma cortisol-to-dehydroepiandrosterone-sulfate (DHEA-S) ratio is a marker of health status after menopause, when a decline in both estrogen and DHEA-S and an increase in cortisol occur. An increase in the cortisol-to-DHEA-S ratio has been positively correlated with metabolic syndrome, all-cause mortality, cancer, and other diseases. The aim of this study was to investigate the effects of a walking program on the plasma cortisol-to-DHEA-S ratio in postmenopausal women. Fifty-one postmenopausal women participated in a 13-week supervised walking program, in the metropolitan area of Pescara (Italy), from June to September 2013. Participants were evaluated in April-May and September-October of the same year. The linear mixed model showed that the variation of the log10Cortisol-to-log10DHEA-S ratio was associated with the volume of exercise (p = .03). Participants having lower adherence to the walking program did not have a significantly modified log10Cortisol or log10DHEA-S, while those having the highest adherence had a significant reduction in log10Cortisol (p = .016) and a nearly significant increase in log10DHEA-S (p = .084). Walking training appeared to reduce the plasma log10Cortisol-to-log10DHEA-S ratio, although a minimum level of training was necessary to achieve this significant reduction.

Circulating dehydroepiandrosterone-sulphate decreases even with a slight change in oestradiol.

The aim of this study was to determine the effect of hormone replacement therapy (HRT) on changes in circulating dehydroepiandrosterone-sulphate (DHEA-S) with focus on the relationship between oestrogen level and change in DHEA-S. Forty-two women were enrolled in this longitudinal study. Nineteen women received oral oestradiol and twenty-three women received transdermal oestradiol continuously. Twenty women received progesterone continuously except for women who had undergone hysterectomy. Circulating oestradiol, follicle-stimulating hormone, luteinising hormone and DHEA-S levels before and at 3 months after commencement of HRT were measured. Circulating DHEA-S level was significantly decreased at 3 months (p < .001). Oestradiol level at 3 months ranged from 6.5 pg/ml to 159 pg/ml. There was no significant correlation of ΔDHEA-S (DHEAS level at 3 months-DHEA-S level at baseline) with Δoestradiol (r = 0.114, p = .471). Circulating DHEA-S level was significantly decreased at 3 months in all the four quartiles and divided according to Δoestradiol, and ΔDHEA-S did not show significant differences. In conclusion, circulating DHEA-S decreases even with a slight increase in oestradiol level. Impact statement What is already known on this subject: A transient increase in DHEA-S in women during the menopausal transition may be involved in the occurrence of menopausal symptoms and/or unfavourable metabolic changes. Hormone replacement therapy decreases circulating DHEA-S level. However, dose dependency of the change in DHEA-S on oestrogen has not been reported. What the results of this study add: Circulating DHEA-S decreases even with a slight increase in oestradiol level. What the implications are of these findings for clinical practice and/or further research: Adrenal function may respond to a small change in oestrogen.

Dehydroepiandrosterone (DHEA) supplementation results in supraphysiologic DHEA-S serum levels and progesterone assay interference that may impact clinical management in IVF.

PURPOSE: Dehydroepiandrosterone (DHEA) is often prescribed for poor responders in IVF in an effort to improve response to ovarian stimulation. The effect of DHEA supplementation and resultant supraphysiologic DHEA-S serum levels on sex steroid assays has not been evaluated in this population. This study seeks to determine the relationship between DHEA supplementation and progesterone measurements to characterize the degree of interference with particular immunoassays. METHODS: Characterization was accomplished in two phases. First, DHEA-S standard control reagents with no progesterone present were assayed for both DHEA-S and progesterone levels. Second, serum pools from 60 unique IVF patients' serum were used to create six pooled serum samples: three from patients on DHEA supplementation and three from patients not on DHEA supplementation. The three pools were composed of patients whose serum fell into low, medium, and high progesterone ranges. Baseline DHEA-S and progesterone were measured, and the mean level of DHEA-S in the mid-range progesterone pool was used as the mid-point for addition of DHEA-S standard to the serum pools from patients without DHEA supplementation. Progesterone from these pools was then measured on three commercially available immunoassay systems. RESULTS: The first experiment revealed a linear increase in progesterone when analyzing the DHEA-S standard ranging from 0.5 µg/dL [corrected] in the blank control (no DHEA-S) to up to 2.0 µg/dL [corrected] in the high control (DHEA-S >700 µg/dL), [corrected] indicating that the DHEA-S cross-reacts with the progesterone assays. In the second experiment, patients' serum DHEA-S and progesterone were measured from pooled serum samples of those taking DHEA and those not taking DHEA. Adding DHEA-S to the pooled serum of those not taking DHEA resulted in a linear increase in progesterone levels on two of three commercially available immunoassays (p < 0.05). CONCLUSIONS: DHEA-S can interfere with standard progesterone immunoassays used in clinical ART programs, and thus serum progesterone levels in IVF patients on DHEA supplementation may not reflect truly bioactive progesterone.

Decreased dehydroepiandrosterone sulphate levels in adolescents with post-traumatic stress disorder after single sexual trauma.

BACKGROUND: Recent evidence shows that the hypothalamic-pituitary-adrenal (HPA) axis can be dysregulated in chronic sexual abuse victims with post-traumatic stress disorder (PTSD). We hypothesized that PTSD in adolescents exposed to a single sexual trauma may function as a chronic stressor leading to HPA-axis dysregulation. AIMS: The objective of this study was to assess dehydroepiandrosterone sulphate (DHEA-S) and cortisol levels in female adolescents |with single sexual trauma-related PTSD compared to healthy controls. METHOD: We assessed 20 female adolescent (age 12-18) single sexual trauma victims with PTSD from the Ondokuz Mayis University Department of Child and Adolescent Psychiatry between December 2013 and December 2014. PTSD symptoms were assessed using the Child Depression Inventory (CDI) and Child Posttraumatic Stress Reaction Index (CPSRI). Blood cortisol and DHEA-S were measured in 20 female adolescent sexual abuse victims with PTSD and 20 healthy adolescents after 12-h fasting using the chemiluminescence method. RESULTS: Compared to age-matched controls, female adolescent sexual abuse victims with PTSD had significantly lower DHEA-S levels (U = 70.00, Z = - 3.517, p = 0.01, r = 0.55). There was also a significant negative correlation between DHEA-S and CDI scores (Spearman r = - 0.522, p < 0.01). CONCLUSIONS: Decreased DHEA-S levels and correlation with depressive symptoms are evidence for a dysregulated HPA-axis in female adolescent single sexual trauma victims with PTSD. Further research is now recommended with large patient groups in order to maximize generalizations.