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Background: Few studies are available on the relationship of androstenedione with inflammation and obesity and the effect of androstenedione and inflammation on the association between testosterone and obesity. This study intended to examine the mediation effect of inflammatory markers on the association of testosterone with obesity and the moderation effect of androstenedione on the association of testosterone with inflammation and obesity in Chinese rural men. Materials and methods: This cross‐sectional research enrolled 2536 male rural inhabitants from the Henan Rural Cohort study. The serum concentrations of testosterone and androstenedione were determined by liquid chromatography–tandem mass spectrometry. Linear and logistic regression were used to examine the relationships between testosterone, inflammatory markers, and obesity. Mediation and moderation analyses were carried out to evaluate the potential effects of inflammatory markers on the relationship between testosterone and obesity, as well as androstenedione on the relationships of testosterone with inflammation and obesity. Results: After adjusting for confounding factors, the results showed that testosterone and androstenedione were negatively related to obesity, and inflammatory markers were positively associated with obesity. Besides, testosterone and androstenedione were negatively associated with inflammatory markers. Mediation analysis showed that white blood cell, neutrophil, monocyte, and high‐sensitivity C‐reactive protein had mediating effects on the association between testosterone and obesity. The most vital mediator was high‐sensitivity C‐reactive protein, and its proportion of the effect was 11.02% (defined by waist circumference), 11.15% (defined by waist‐to‐hip ratio), 12.92% (defined by waist‐to‐height ratio), and full mediating effect (defined by body mass index). Moreover, androstenedione played negative moderation effects on the associations of testosterone with inflammation and obesity. Conclusion: Inflammatory markers and androstenedione were first found to have modifying effects on the association of testosterone with obesity. Higher levels of testosterone and androstenedione could reduce the inflammation level and risk of obesity, indicating their potential roles in the prevention and treatment of chronic diseases. [ABSTRACT FROM AUTHOR]

Current liquid chromatography-tandem mass spectrometry (LC-MS/MS) applications for circulating androgen measurements are technically diverse. Previously, variable results have been reported for testosterone. Data are scarce for androstenedione and absent for dehydroepiandrosterone sulfate (DHEAS). We assessed the agreement of androstenedione, DHEAS and testosterone LC-MS/MS measurements among nine European centers and explored benefits of calibration system unification. Androgens were measured twice by laboratory-specific procedures in 78 patient samples and in EQA materials. Results were obtained by in-house and external calibration. Intra- and inter-laboratory performances were valued. Intra-laboratory CVs ranged between 4.2–13.2 % for androstenedione, 1.6–10.8 % for DHEAS, and 4.3–8.7 % and 2.6–7.1 % for female and male testosterone, respectively. Bias and trueness in EQA materials were within ±20 %. Median inter-laboratory CV with in-house vs. external calibration were 12.0 vs. 9.6 % for androstenedione (p<0.001), 7.2 vs. 4.9 % for DHEAS (p<0.001), 6.4 vs. 7.6 % for female testosterone (p<0.001) and 6.8 and 7.4 % for male testosterone (p=0.111). Median bias vs. all laboratory median with in-house and external calibration were −13.3 to 20.5 % and −4.9 to 18.7 % for androstenedione, −10.9 to 4.8 % and −3.4 to 3.5 % for DHEAS, −2.7 to 6.5 % and −11.3 to 6.6 % for testosterone in females, and −7.0 to 8.5 % and −7.5 to 11.8 % for testosterone in males, respectively. Methods showed high intra-laboratory precision but variable bias and trueness. Inter-laboratory agreement was remarkably good. Calibration system unification improved agreement in androstenedione and DHEAS, but not in testosterone measurements. Multiple components, such as commutability of calibrators and EQA materials and internal standard choices, likely contribute to inter-laboratory variability. [ABSTRACT FROM AUTHOR]

Background: Primary angle closure glaucoma (PACG) is the leading cause of irreversible blindness in Asia, and no reliable, effective diagnostic, and predictive biomarkers are used in clinical routines. A growing body of evidence shows metabolic alterations in patients with glaucoma. We aimed to develop and validate potential metabolite biomarkers to diagnose and predict the visual field progression of PACG. Methods: Here, we used a five-phase (discovery phase, validation phase 1, validation phase 2, supplementary phase, and cohort phase) multicenter (EENT hospital, Shanghai Xuhui Central Hospital), cross-sectional, prospective cohort study designed to perform widely targeted metabolomics and chemiluminescence immunoassay to determine candidate biomarkers. Five machine learning (random forest, support vector machine, lasso, K-nearest neighbor, and GaussianNaive Bayes [NB]) approaches were used to identify an optimal algorithm. The discrimination ability was evaluated using the area under the receiver operating characteristic curve (AUC). Calibration was assessed by Hosmer-Lemeshow tests and calibration plots. Results: Studied serum samples were collected from 616 participants, and 1464 metabolites were identified. Machine learning algorithm determines that androstenedione exhibited excellent discrimination and acceptable calibration in discriminating PACG across the discovery phase (discovery set 1, AUCs=1.0 [95% CI, 1.00-1.00]; discovery set 2, AUCs = 0.85 [95% CI, 0.80-0.90]) and validation phases (internal validation, AUCs = 0.86 [95% CI, 0.81-0.91]; external validation, AUCs = 0.87 [95% CI, 0.80-0.95]). Androstenedione also exhibited a higher AUC (0.92-0.98) to discriminate the severity of PACG. In the supplemental phase, serum androstenedione levels were consistent with those in aqueous humor (r=0.82, p=0.038) and significantly (p=0.021) decreased after treatment. Further, cohort phase demonstrates that higher baseline androstenedione levels (hazard ratio = 2.71 [95% CI: 1.199-6.104], p=0.017) were associated with faster visual field progression. Conclusions: Our study identifies serum androstenedione as a potential biomarker for diagnosing PACG and indicating visual field progression. [ABSTRACT FROM AUTHOR]

Estrogens play critical roles in embryonic development, gonadal sex differentiation, behavior, and reproduction in vertebrates and in several human cancers. Estrogens are synthesized from testosterone and androstenedione by the endoplasmic reticulum membrane-bound P450 aromatase/cytochrome P450 oxidoreductase complex (CYP19/CPR). Here, we report the characterization of novel mammalian CYP19 isoforms encoded by CYP19 gene copies. These CYP19 isoforms are all defined by a combination of mutations in the N-terminal transmembrane helix (E42K, D43N) and in helix C of the catalytic domain (P146T, F147Y). The mutant CYP19 isoforms show increased androgen conversion due to the KN transmembrane helix. In addition, the TY substitutions in helix C result in a substrate preference for androstenedione. Our structural models suggest that CYP19 mutants may interact differently with the membrane (affecting substrate uptake) and with CPR (affecting electron transfer), providing structural clues for the catalytic differences. [ABSTRACT FROM AUTHOR]

Background: Androgen deprivation therapy (ADT) is a mainstay of prostate cancer in both adjuvant and palliative settings. Since androgens are crucial for functional status and psychological functions, we evaluated whether blood testosterone, androstenedione, or DHEA concentrations were associated with functional status and psychological alterations in patients with localised (PCa) or metastatic prostate cancer (mPCa) receiving ADT with analogues of luteinising hormone-releasing hormone (LHRH). Methods: The five Fried criteria were considered to identify frailty syndrome. In addition, complementary evaluations were carried out to measure other variables of interest. Sleep quality was assessed using the Athens Insomnia Scale, cognitive functions were assessed using the Mini-Mental State Examination, and symptoms of depression were measured using the Yesavage Geriatric Depression Scale. Logistic regression analysis was performed to determine if the androgens level could be related to frailty syndrome, sleep impairment, depressive symptoms, and cognitive functions. Results: The results of the multivariate analyses show that high concentrations of androstenedione were significantly associated with frailty syndrome in both groups (p = 0.018; odds ratio = 4.66, 95% confidence interval [1.30–16.6]). There were significant relationships between frailty syndrome and the systemic concentration of androstenedione (p = 0.01), but not the concentration of testosterone (p = 0.60) or DHEA (p = 0.42). In addition, the results of the non-parametric tests show significant results between a decreased gait speed in the two groups (metastatic and localised) and the concentration of androstenedione (p = 0.015). High androstenedione levels were associated with a slow walking speed in the mCaP group (p = 0.016), while high testosterone levels were associated with a better walking speed in the localised CaP group (p = 0.03). For the concentration of androstenedione in plasma, the area under the curve was 0.72, with a 95% CI of 0.55–0.88 with acceptable values, and with a cut-off point of 4.51 pg/mL, a sensitivity of 82.9%, and specificity of 53.8%. No relationships between the concentration of androgens in plasma and sleep quality, cognitive functions, or symptoms of depression suggest that the changes were specific to frailty syndrome. Conclusions: Further research into the role of androstenedione should be evaluated in follow-up studies in order to recommend its use as a suitable biomarker of frailty syndrome in prostate cancer patients. [ABSTRACT FROM AUTHOR]

This cross-sectional study examines the Doi-Alshoumer PCOS clinical phenotype classification in relation to measured clinical and biochemical characteristics of women with polycystic ovary syndrome (PCOS). Two cohorts of women (Kuwait and Rotterdam) diagnosed with PCOS (FAI > 4.5%) were examined. These phenotypes were created using neuroendocrine dysfunction (IRMA LH/FSH ratio > 1 or LH > 6 IU/L) and menstrual cycle status (oligo/amenorrhea) to create three phenotypes: (A) neuroendocrine dysfunction and oligo/amenorrhea, (B) without neuroendocrine dysfunction but with oligo/amenorrhea, and (C) without neuroendocrine dysfunction and with regular cycles. These phenotypes were compared in terms of hormonal, biochemical, and anthropometric measures. The three suggested phenotypes (A, B, and C) were shown to be sufficiently distinct in terms of hormonal, biochemical, and anthropometric measures. Patients who were classified as phenotype A had neuroendocrine dysfunction, excess LH (and LH/FSH ratio), irregular cycles, excess A4, infertility, excess T, highest FAI and E2, and excess 17αOHPG when compared to the other phenotypes. Patients classified as phenotype B had irregular cycles, no neuroendocrine dysfunction, obesity, acanthosis nigricans, and insulin resistance. Lastly, patients classified as phenotype C had regular cycles, acne, hirsutism, excess P4, and the highest P4 to E2 molar ratio. The differences across phenotypes suggested distinct phenotypic expression of this syndrome, and the biochemical and clinical correlates of each phenotype are likely to be useful in the management of women with PCOS. These phenotypic criteria are distinct from criteria used for diagnosis. [ABSTRACT FROM AUTHOR]

This study aimed to validate an enzyme-linked immunosorbent assay (ELISA) and create a reference interval for androstenedione from captive Texas tortoises (Gopherus berlandieri). Reference interval creation for androstenedione could allow comparison of an individual's values to others of the species in an effort to evaluate excess or deficiency and/or provide the basis for diagnosis of reproductive health or capability. In other species, androstenedione is associated with puberty onset and specific reproductive diseases; however, values and function of this hormone remain poorly studied in reptiles. The 25 adult male tortoises sampled were maintained at Texas A&M University's Winnie Carter Wildlife and Exotic Animal Center. Serum was assayed via a validated androstenedione ELISA. Male Texas tortoise serum androstenedione concentrations were found to be 5.40 ± 5.16 ng/ml (mean ± SD), with establishment of a reference interval of 0.57–18.58 ng/ml. Relatively increased androstenedione values were associated with increased carapace length, carapace height, and tortoise weight but not gular horn length of male Texas tortoises. This information may benefit the care, management, and reproduction of captive tortoises. Extrapolation should be considered for evaluation of other species until their own intervals are established. Further research should include determination of baseline values of androstenedione for both healthy and reproductively challenged female tortoises. [ABSTRACT FROM AUTHOR]

Objective: The essential role of ACTH on the growth and function of the human foetal adrenal (HFA) has long been recognized. In addition, many studies have suggested a role of the pituitary hormone prolactin (PRL) in the regulation of the HFA, but the effects of this hormone on steroidogenesis and gene expression are still unknown. Our objective was to investigate the effect of ACTH and PRL on the steroidogenic capacities of the HFA. Design: In vitro/ex vivo experimental study. Methods: We used a hanging drop in vitro organ culture system. First trimester HFA samples were cultured for 14 days in basal conditions or treated with ACTH, PRL, or a combination of the 2 (3 to 11 replicates depending on the experiment). Steroids were measured by liquid chromatography/tandem mass spectrometry or immunoassay, gene expression by RT-qPCR, and protein expression by immunoblot. Results: ACTH significantly increased corticosterone, cortisol, and cortisone production, both by itself and when used together with PRL. PRL stimulation by itself had no effect. Combined stimulation with ACTH + PRL synergistically and selectively increased adrenal androgen (DHEAS and ?4-androstenedione) production and CYP17A1 expression in the HFA, while treatment with each single hormone had no significant effect on those steroids. Conclusions: These results have important implications for our understanding of the hormonal cues regulating adrenal steroidogenesis in the HFA during the first trimester in physiological and pathological conditions and warrant further studies to characterize the molecular mechanisms of converging ACTH and PRL signalling to regulate CYP17A1 expression. [ABSTRACT FROM AUTHOR]

This study was to assess the effects of androstenedione (AED) on intestinal cytokines interferon α (IFN-α), interleukin 1α (IL-1α), interleukin 1β (IL-1β), nuclear factor κB (NF-κB) and tumor necrosis factor α (TNF-α) in adult zebrafish (Danio rerio) when exposed to different concentrations of AED (0, 0.2, 2.3 and 23.7 μg·L–1) for 60 days. The results showed that AED at three treatment groups had no significant effects on the levels of IFN-α, IL-1α, NF-κB and TNF-α in the intestine of male zebrafish as compared with the solvent control (P>0.05), but 0.2 and 2.3 μg·L–1 of AED had a prominent inhibitory effect on the contents of IL-1β in the intestine (P<0.05). For female fish, AED significantly increased the contents of intestinal NF-κB, TNF-α, IFN-α and IL-1α at 2.3 and 23.7 μg·L–1 (P<0.05), but it did not have a noticeable impact on IL-1β level (P>0.05). In conclusion, the androgen AED had a potential interference effect on the immune system and inflammatory response in the intestine of zebrafish, and the effects of the androgen had gender differences in zebrafish, indicating female zebrafish were more sensitive to AED exposure. The results of this study provide a reference for the effects of AED on intestinal cytokines in fish, and help to assess the toxicity of AED on aquatic organisms. [ABSTRACT FROM AUTHOR]

The key steps of our synthesis were a Saegusa-Ito oxidation reaction, a direct C14 -hydroxylation, and a Stille cross-coupling. Keywords: cardiotonic steroids; digitoxigenin; androstenedione; Stille cross-coupling; hydroxylation; semi-synthesis EN cardiotonic steroids digitoxigenin androstenedione Stille cross-coupling hydroxylation semi-synthesis 2034 2036 3 10/09/23 20231024 NES 231024 Graph Cardenolides represent a unique family of natural products exhibiting positive inotropic activities. Reviewing the extensive literature, we found that no direct C14 -hydroxylation had been achieved; C14 hydroxylation has mainly been achieved through a Mukaiyama hydration reaction, which requires the construction of a C14-C15 unsaturated bond, resulting in multiple synthesis steps. Cardiotonic steroids, digitoxigenin, androstenedione, hydroxylation, semi-synthesis, Stille cross-coupling. [Extracted from the article]

Introduction: Immunoassays are the most common method in routine practice for measuring androgens in women. Study’s aim was to establish new population specific indirect reference intervals (RI) for dehydroepiandrostenedione sulphate (DHEAS) and for new androstenedione test available on automated Roche Cobas electrochemiluminescent immunoassay method. Materials and methods: From extracted laboratory records, testosterone, sex hormone binding globulin and follicle-stimulating hormone were used as reference tests to exclude possibly diseased women. After the data selection steps, the study included 3500 subjects for DHEAS and 520 for androstenedione aged 20-45 years. To evaluate the need for age partitioning, we calculated standard deviation ratio and bias ratio. For each hormone, 90% and 95% RIs were calculated with appropriate statistical method. Results: Total age group (20-45 years) 95% RIs were: 2.77-11.50 μmol/L for DHEAS and 2.48-8.89 nmol/L for androstenedione. Age-stratified 95% RIs for DHEAS were: 3.65-12.76 μmol/L (20-25 years); 2.97-11.50 μmol/L (25-35 years) and 2.30-9.83 μmol/L (35-45 years). Age-stratified 95% RIs for androstenedione were: 3.02-9.43 nmol/L (20-30 years) and 2.23-7.75 nmol/L (30-45 years). Conclusion: New RIs for DHEAS were slightly wider for age group 20-25 and 35-45, while the differences in the age group 25-35 years were more pronounced. Androstenedione RI showed significantly higher concentrations than the manufacturer’s. Age-related decrease of androgens should be considered when calculating RIs. We propose population specific, age-stratified RIs for DHEAS and androstenedione on electrochemiluminescent method, which should improve test interpretation in women of reproductive age. [ABSTRACT FROM AUTHOR]

Simple Summary: The quality of in vitro matured oocytes is usually lower than that of in vivo matured oocytes, possibly due to the absence of some important signal regulators in vitro. In this study, we found that progesterone and androstenedione were upregulated in FF during in vivo pig oocyte maturation. The supplementation of progesterone or androstenedione during in vitro maturation significantly improved the pig oocyte maturation rate or subsequent embryo developmental competence. Oocytes matured in vitro are useful for assisted human and farm animal reproduction. However, the quality of in vitro matured oocytes is usually lower than that of in vivo matured oocytes, possibly due to the absence of some important signal regulators in vitro. In this study, untargeted metabolomics was used to detect the changes in the metabolites in the follicular fluid (FF) during in vivo pig oocyte maturation and in the culture medium during in vitro maturation. Our results showed that the total metabolite changing profile of the in vivo FF was different from that of the in vitro maturation medium, but the levels of 23 differentially expressed metabolites (DEMs) changed by following the same trend during both in vivo and in vitro pig oocyte maturation. These 23 metabolites may be important regulators of porcine oocyte maturation. We found that progesterone and androstenedione, two factors in the ovarian steroidogenesis pathway enriched from the DEMs, were upregulated in the FF during in vivo pig oocyte maturation. The levels of these two factors were 31 and 20 fold, respectively, and they were higher in the FF than in the culture medium at the oocyte mature stage. The supplementation of progesterone and androstenedione during in vitro maturation significantly improved the pig oocyte maturation rate and subsequent embryo developmental competence. Our finding suggests that a metabolic abnormality during in vitro pig oocyte maturation affects the quality of the matured oocytes. This study identified some important metabolites that regulate oocyte maturation and their developmental potential, which will be helpful to improve assisted animal and human reproduction. [ABSTRACT FROM AUTHOR]

Primary culture of granulosa cells is a prerequisite for a complete study of the normal functioning of the ovary and its pathologies. In this work, we selected the optimal protocol for obtaining a primary culture of mouse granulosa cells in the most functionally active state and revealed the effects of androstenedione and serotonin on the expression of ovarian markers that reflect the functional status of granulosa cells. The morpho-functional analysis of the ovary after PMSG stimulation revealed that 48 hours after PMSG stimulation is the optimal time for obtaining granulosa cells in the most active functional state. Using the set of 14 ovarian functional state marker genes we reveal that androstenedione inhibits cumulus and immature granulosa markers but stimulates genes characteristic of the mature state of granulosa. At the same time, granulosa cells express serotonergic receptors and transporter SERT. The ovarian marker genes expression analysis revealed that serotonin affects the expression of genes characterizing the differentiation of granulosa cells towards cumulus cells. Summarizing, we can conclude that serotonin and androstenedione have an antagonistic effect on the functional state of mouse granulosa cells in primary culture in vitro. [ABSTRACT FROM AUTHOR]

Introduction: Some but not all women with polycystic ovary syndrome (PCOS) develop the metabolic syndrome (MS). The objective of this study was to determine if a subset of women with PCOS had higher androgen levels predisposing them to MS and whether routinely measured hormonal parameters impacted the metabolic syndrome score (siMS). Methods: We included data from a discovery (PCOS clinic data) and a replication cohort (Hull PCOS Biobank) and utilized eight routinely measured hormonal parameters in our clinics (free androgen index [FAI], sex hormone‐binding globulin, dehydroepiandrosterone sulphate (DHEAS), androstenedione, luteinizing hormone [LH], follicular stimulating hormone, anti‐Müllerian hormone and 17 hydroxyprogesterone [17‐OHP]) to perform a K‐means clustering (an unsupervised machine learning algorithm). We used NbClust Package in R to determine the best number of clusters. We estimated the siMS in each cluster and used regression analysis to evaluate the effect of hormonal parameters on SiMS. Results: The study consisted of 310 women with PCOS (discovery cohort: n = 199, replication cohort: n = 111). The cluster analysis identified two clusters in both the discovery and replication cohorts. The discovery cohort identified a larger cluster (n = 137) and a smaller cluster (n = 62), with 31% of the study participants. Similarly, the replication cohort identified a larger cluster (n = 74) and a smaller cluster (n = 37) with 33% of the study participants. The smaller cluster in the discovery cohort had significantly higher levels of LH (7.26 vs. 16.1 IU/L, p <.001), FAI (5.21 vs. 9.22, p <.001), androstenedione (3.93 vs. 7.56 nmol/L, p <.001) and 17‐OHP (1.59 vs. 3.12 nmol/L, p <.001). These findings were replicated in the replication cohort. The mean (±SD) siMS score was higher in the smaller cluster, 3.1 (±1.1) versus 2.8 (±0.8); however, this was not statistically significant (p =.20). In the regression analysis, higher FAI (β =.05, p =.003) and androstenedione (β =.03, p =.02) were independently associated with a higher risk of SiMS score, while higher DHEAS levels were associated with a lower siMS score (β = −.07, p =.03) Conclusion: We identified a subset of women in our PCOS cohort with significantly higher LH, FAI, and androstenedione levels. We show that higher levels of androstenedione and FAI are associated with a higher siMS, while higher DHEAS levels were associated with lower siMS. [ABSTRACT FROM AUTHOR]

Cytochrome P450 enzymes are promising biocatalysts for industrial use because they catalyze site-selective C–H oxidation and have diverse catalytic reactions and a broad substrate range. In this study, the 2α-hydroxylation activity of CYP154C2 from Streptomyces avermitilis MA-4680T toward androstenedione (ASD) was identified by an in vitro conversion assay. The testosterone (TES)-bound structure of CYP154C2 was solved at 1.42 Å, and this structure was used to design eight mutants, including single, double, and triple mutants, to improve the conversion efficiency. Mutants L88F/ M191F and M191F/V285L were found to enhance the conversion rates significantly (i.e., 8.9-fold and 7.4-fold for TES, 46.5-fold and 19.5-fold for ASD, respectively) compared with the wild-type (WT) enzyme while retaining high 2α-position selectivity. The substrate binding affinity of the L88F/M191F mutant toward TES and ASD was enhanced compared with that of WT CYP154C2, supporting the measured increase in the conversion efficiencies. Moreover, the total turnover number and kcat/Km of the L88F/M191F and M191F/V285L mutants increased significantly. Interestingly, all mutants containing L88F generated 16α-hydroxylation products, suggesting that L88 in CYP154C2 plays a vital role in substrate selectivity and that the amino acid corresponding to L88 in the 154C subfamily affects the orientation of steroid binding and substrate selectivity. IMPORTANCE Hydroxylated derivatives of steroids play essential roles in medicine. Cytochrome P450 enzymes selectively hydroxylate methyne groups on steroids, which can dramatically change their polarity, biological activity and toxicity. There is a paucity of reports on the 2α-hydroxylation of steroids, and documented 2α-hydroxylate P450s show extremely low conversion efficiency and/or low regio- and stereoselectivity. This study conducted crystal structure analysis and structure-guided rational engineering of CYP154C2 and efficiently enhanced the conversion efficiency of TES and ASD with high regio- and stereoselectivity. Our results provide an effective strategy and theoretical basis for the 2α-hydroxylation of steroids, and the structure-guided rational design of P450s should facilitate P450 applications in the biosynthesis of steroid drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: 17β-Hydroxysteroid dehydrogenase type1 (HSD17B1) is responsible for converting estrone, a weak estrogen, into the more potent estradiol in the ovaries of vertebrates ranging from teleosts to mammals. We evaluated its expression in the placentae of various eutherian species and demonstrated that it was only expressed in the human placenta. The ubiquitous transcription factor SP1-binding site was conserved in the promoter region of the HSD17B1/Hsd17b1 gene across the species. This region conferred the promoter activities both in human and ovine HSD17B1. However, in the ovine placenta, cytosine residues of this SP1 site in the HSD17B1 promoter region were completely methylated. Human HSD17B1 had high activity for testosterone production, similar to its homologs in other species. On the basis of this fact, the significance of placental HSD17B1 expression is discussed. During mammalian gestation, large amounts of progesterone are produced by the placenta and circulate for the maintenance of pregnancy. In contrast, primary plasma estrogens are different between species. To account for this difference, we compared the expression of ovarian and placental steroidogenic genes in various mammalian species (mouse, guinea pig, porcine, ovine, bovine, and human). Consistent with the ability to synthesize progesterone, CYP11A1/Cyp11a1, and bi-functional HSD3B/Hsd3b genes were expressed in all species. CYP17A1/Cyp17a1 was expressed in the placenta of all species, excluding humans. CYP19A/Cyp19a1 was expressed in all placental estrogen-producing species, whereas estradiol-producing HSD17B1 was only strongly expressed in the human placenta. The promoter region of HSD17B1 in various species possesses a well-conserved SP1 site that was activated in human placental cell line JEG-3 cells. However, DNA methylation analyses in the ovine placenta showed that the SP1-site in the promoter region of HSD17B1 was completely methylated. These results indicate that epigenetic regulation of HSD17B1 expression is important for species-specific placental sex steroid production. Because human HSD17B1 showed strong activity for the conversion of androstenedione into testosterone, similar to HSD17B1/Hsd17b1 in other species, we also discuss the biological significance of human placental HSD17B1 based on the symptoms of aromatase-deficient patients. [ABSTRACT FROM AUTHOR]

The role of estrogens and progesterone in the development and progression of endometrial cancer is well-established, but there are very little data about the role of androgens. There are five different androgens produced in women: dehydroepiandrosterone sulphate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T) and dihydrotestosterone (DHT). The most potent hormones are T and DHT, the latter being mainly produced from T in peripheral tissues, including endometrium. Although they are considered to exert antiproliferative effects in many settings and the expression of their receptors is more often associated with a good prognosis in EC, it is still unknown in which specific settings androgens have carcinogenic or protective effects in EC. [ABSTRACT FROM AUTHOR]

Background: Children with attention-deficit/hyperactivity disorder (ADHD) might have similar problems as in autism spectrum disorder (ASD) and show impairment in social behaviour. Also, there is a relationship between social relationship skills and ToM (theory of mind) skills of children with ADHD. Besides, ASD is associated with prenatal exposure to high levels of androgens, and oxytocin plays a role in the modulation of emotions, coping with stress, and social behaviour like ASD. In this study, the relationship between autistic traits and serum oxytocin, testosterone, and androstenedione levels in prepubertal male drug naive children with ADHD has been investigated. Method: Eighty-three prepubertal children, who were diagnosed with ADHD between the ages of 6-10 years old, are included in the study. For the study, intelligence levels were evaluated by using WISC-4, and autistic traits were measured by using both social responsiveness scale and theory of mind tests. In addition, serum oxytocin, testosterone, and androstenedione levels were measured by using ELISA. Results: It has been found that serum testosterone levels of patients with lower autistic traits are significantly lower than those with moderate and severe autistic traits, while the serum oxytocin levels are significantly higher. Also, patients with severe autistic traits have had significantly higher serum androstenedione levels than those with lower and moderate autistic traits. Conclusion: This study suggests that patients who have higher autistic traits have elevated testosterone and androstenedione levels and lower serum oxytocin levels. Further studies are needed to clarify this relationship. [ABSTRACT FROM AUTHOR]

Objective: Patients with congenital adrenal hyperplasia (CAH) in developing countries have limited access to appropriate laboratory facilities for diagnosis and follow‐up. The aim of this study is to evaluate steroid measurement in hair as a diagnostic tool to identify and monitor CAH in these patients. Design: A method was developed to measure steroids in hair, the stability of steroids in hair was assessed, and the concentration range in healthy volunteers was determined. Hair samples of patients, before and after starting therapy, were transported at ambient temperature to The Netherlands for analysis. Patients: Twenty‐two Indonesian CAH patients and 84 healthy volunteers participated. Measurements: Cortisol, 17‐hydroxyprogesterone (17OHP), androstenedione, and testosterone in hair were measured by liquid chromatography with tandem mass spectrometry. Results: Steroids in hair could be measured and remained stable (<4.9% deviation) for at least 3 weeks at 4°C and 30°C. In each of the untreated patients, hair concentrations of 17OHP (9.43–1135 pmol/g), androstenedione (36.1–432 pmol/g), and testosterone (2.85–69.2 pmol/g) were all above the upper limit of the corresponding range in healthy volunteers; 5.5 pmol/g, 13 pmol/g, and 1.8 pmol/g, respectively. After starting glucocorticoid treatment, the steroid concentrations in the hair of CAH patients decreased significantly for androstenedione (73%) and testosterone (59%) after 6 months. Conclusions: CAH could be confirmed in Indonesian patients based on the concentration of 17OHP, androstenedione, and testosterone in hair, and a treatment effect was observed. These findings open up opportunities to diagnose and/or monitor CAH in developing countries with a simple noninvasive technique. [ABSTRACT FROM AUTHOR]

Objective: Differentiation of an adrenal from an ovarian source of hyperandrogenemia can be challenging. Recent studies have highlighted the importance of 11-oxygenated C19 steroids to the androgen pool in humans. The aim of this study was to confirm the origin of 11-oxygenated androgens in females and to explore their potential use in the diagnostics of hyperandrogenic disorders. Methods: We measured testosterone and its precursors (dehydroepiandrosterone-sulfate and androstenedione) and 11-oxygenated androgens (11β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT)) in the periphery, adrenal and ovarian veins in four different cases of hyperandrogenism in females (polycystic ovary syndrome (PCOS), primary bilateral macronodular adrenal hyperplasia, Sertoli-Leydig cell tumor and ovarian steroid cell tumor). Results: Two patients demonstrate excessive testosterone secretion in neoplastic ovarian tumors which was not paralleled by a significant secretion of 11-oxygenated androgens as determined by adrenal and ovarian vein sampling. In androgen-secreting bilateral adrenal macronodular hyperplasia, steroid profiles were characterized by elevated 11-KT and 11-OHA4 concentrations in adrenal veins and the periphery. In the patient with PCOS, peripheral 11-KT concentrations were slightly elevated in comparison to the other patients, but the 11-KT and 11-OHA4 concentrations were comparable in ovarian veins and in the periphery. Conclusion: This study confirms that 11-OHA4 and 11-KT are not biosynthesized by the ovary. We propose that the testosterone/11-KT ratio as well as 11-OHA4 could help identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source. Significance statement This study confirms that 11 β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT) are not biosynthesized by the human ovary. We propose that the testosterone/11-KT ratio as well as 11-OHA4 could help to identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source. [ABSTRACT FROM AUTHOR]

The study aimed to familiarise primary care physicians and specialists with the minimum hormonal diagnostic tests necessary to assay isolated micropenis in healthy children without any phenotypic abnormality. Children aged 6–15 years (mean 11.6 ± 1.68) were assessed from May 2010 to September 2021 (N = 247). Multiple regression analysis showed correlations between stretched penile length (SPL) and hormonal assays as follows: follicle‐stimulating hormone (FSH): r = 0.097, p = 0.035; luteinizing hormone (LH): r = 0.139, p = 0.012, thyroid‐stimulating hormone (TSH): r = −0.001, p = 0.321; testosterone (T): r = 0.118, p = 0.004; dihydrotestosterone (DHT): r = 0.002, p = 0.243; androstenedione (Δ4And): r = −0.004, p = 0.502; insulin‐like growth factor I (IGF‐I): r = −0.003, p = 0.062; and IFG‐binding protein 3 (IGF‐BP3): r = 0.052, p = 0.051. The most hormonal disorder was testosterone deficiency. TSH, Δ4And, and DHT were normal in all boys. SPL was significantly correlated with FSH, LH, and T, but there was no significant correlation between SPL and TSH, DHT, Δ4And, IGF‐I, and IGF‐BP3. Whenever the isolated micropenis is seen without other anomalies, it is sufficient to assay testosterone, FSH, and LH in the first step. [ABSTRACT FROM AUTHOR]

Background: The production of androstenedione (AD) from phytosterols by Mycolicibacterium neoaurum is a multi-step biotransformation process, which requires degradation of sterol side chains, accompanied by the production of propionyl-CoA. However, the transient production of large amounts of propionyl-CoA can accumulate intracellularly to produce toxic effects and severely inhibit AD production. Results: In the present study, the intracellular propionyl-CoA concentration was effectively reduced and the productivity of the strain was improved by enhancing the cytosolic methyl-branched lipid synthesis pathway and increasing the expression level of nat operator gene, respectively. Subsequently, the application of a pathway combination strategy, combined and the inducible regulation strategy, further improved AD productivity with a maximum AD conversion rate of 96.88%, an increase of 13.93% over the original strain. Conclusions: Overall, we provide a new strategy for reducing propionyl-CoA stress during biotransformation for the production of AD and other steroidal drugs using phytosterols. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine condition in women, impacting several aspects of a woman's life, including reproductive, mental, cardiovascular, and metabolic health. Antidiabetic drugs may have beneficial effects on the endocrine and metabolic states in women with PCOS. Objective: This study aimed to compare the effects of oral antidiabetic drugs on reproductive hormones, metabolic and anthropometric markers, and menstrual frequency, in patients with PCOS using network meta-analysis. Methods: PubMed, EMBASE, and CENTRAL were searched for studies published up to May 31, 2021. Randomised clinical trials enrolling participants with PCOS were included, for which sodium-glucose cotransporter 2 (SGLT-2) inhibitors, metformin (Met), dipeptidyl peptidase 4 (DPP-4) inhibitors, alpha-glucosidase inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), and thiazolidinediones (TZDs) (alone or in combination) were compared with either each other, placebo, or no treatment. A network meta-analysis using a Bayesian approach was performed. The outcomes included changes in endocrine outcomes, metabolic results, menstrual frequency, and anthropometric findings. All research was conducted according to a protocol registered in the PROSPERO database (CRD42021248314). Results: In total, we retrieved 3383 studies, of which 47 articles enrolling 2626 participants were included for the network meta-analysis. In comparison to the control groups, Met (MD − 0.41, 95% CI − 0.73 to − 0.09) was more beneficial in reducing serum total testosterone, and GLP-1RAs+Met (MD − 5.44, 95% CI − 10.06 to − 0.89) reduced free androgen index (FAI) more effectively. Thiazolidinediones (MD 9.33, 95% CI 0.15 to 17.99) had a greater effect on sex hormone-binding globulin (SHBG) than Met. For decreasing androstenedione, Met (MD − 1.87, 95% CI − 2.73 to − 1.01), DPP-4 inhibitors (MD − 2.64, 95% CI − 4.77 to − 0.49), GLP-1RAs (MD − 3.06, 95% CI − 5.53 to − 0.62), and GLP-1RAs+Met (MD − 2.97, 95% CI − 5.85 to − 0.09) were more effective than TZDs. The confidence in evidence was often low or very low. Conclusions: In this network meta-analysis, GLP-1 receptor agonists in combination with metformin appear to be preferable for improving hyperandrogenaemia. Metformin and TZDs offer the added benefit of improving fasting blood glucose (FBG) and low-density lipoprotein-cholesterol (LDL-C) when compared to the control groups. Metformin combined with GLP-1 receptor agonists or TZDs could be associated with a beneficial effect on menstrual recovery. [ABSTRACT FROM AUTHOR]

Simple Summary: Generally male mammals are more aggressive than their female peers. In these males, aggressive behavior is linked to levels of androgens; higher levels of testosterone are predictive of higher aggression rates or more severe aggression. There are some species where the pattern of sex-specific aggression is reversed, and it was hypothesized that high levels of androgens may be responsible for social dominance and aggressiveness in these females. Studies so far found that females of species with sex-reversed aggression patterns (e.g., spotted hyenas and ring-tailed lemurs) had lower plasma testosterone levels than their male peers, but a precursor of testosterone, androstenedione, was comparable or even higher in females than in males. This supported the idea that selection for female aggressiveness may be facilitated through augmented androgen secretion. Here we show that in two sister species, bonobos and chimpanzees, that differ in terms of sex-specific aggression patterns, females have lower plasma testosterone levels and higher plasma androstenedione levels than their male peers. Thus, our data do not support a theory of a role of female androgen levels on the expression of sex-specific patterns of aggression. In most animals, males are considered more aggressive, in terms of frequency and intensity of aggressive behaviors, than their female peers. However, in several species this widespread male-biased aggression pattern is either extenuated, absent, or even sex-reversed. Studies investigating potential neuro-physiological mechanisms driving the selection for female aggression in these species have revealed an important, but not exclusive role of androgens in the expression of the observed sex-specific behavioral patterns. Two very closely related mammalian species that markedly differ in the expression and degree of sex-specific aggression are the two Pan species, where the chimpanzee societies are male-dominated while in bonobos sex-biased aggression patterns are alleviated. Using liquid chromatography–mass spectrometry (LC-MS) methods, we measured levels of plasma testosterone and androstenedione levels in male and female zoo-housed bonobos (N = 21; 12 females, 9 males) and chimpanzees (N = 41; 27 females, 14 males). Our results show comparable absolute and relative intersexual patterns of blood androgen levels in both species of Pan. Plasma testosterone levels were higher in males (bonobos: females: average 0.53 ± 0.30 ng/mL; males 6.70 ± 2.93 ng/mL; chimpanzees: females: average 0.40 ± 0.23 ng/mL; males 5.84 ± 3.63 ng/mL) and plasma androstenedione levels were higher in females of either species (bonobos: females: average 1.83 ± 0.87 ng/mL; males 1.13 ± 0.44 ng/mL; chimpanzees: females: average 1.84 ± 0.92 ng/mL; males 1.22 ± 0.55 ng/mL). The latter result speaks against a role of androstenedione in the mediation of heightened female aggression, as had been suggested based on studies in other mammal species where females are dominant and show high levels of female aggressiveness. [ABSTRACT FROM AUTHOR]

Androgen excess in women typically presents clinically with hirsutism, acne or androgenic alopecia. In the vast majority of cases, the underlying aetiology is polycystic ovary syndrome (PCOS), a common chronic condition that affects up to 10% of all women. Identification of women with non‐PCOS pathology within large cohorts of patients presenting with androgen excess represents a diagnostic challenge for the endocrinologist, and rare pathology including nonclassic congenital adrenal hyperplasia, severe insulin resistance syndromes, Cushing's disease or androgen‐secreting tumours of the ovary or adrenal gland may be missed in the absence of a pragmatic screening approach. Detailed clinical history, physical examination and biochemical phenotyping are critical in risk‐stratifying women who are at the highest risk of non‐PCOS disorders. Red flag features such as rapid onset symptoms, overt virilization, postmenopausal onset or severe biochemical disturbances should prompt investigations for underlying neoplastic pathology, including dynamic testing and imaging where appropriate. This review will outline a proposed diagnostic approach to androgen excess in women, including an introduction to androgen metabolism and provision of a suggested algorithmic strategy to identify non‐PCOS pathology according to clinical and biochemical phenotype. [ABSTRACT FROM AUTHOR]

Purpose: To determine the variation in anti-Mullerian hormone (AMH) and androstenedione (A4) concentrations in adolescent girls, with or without menstrual cycle disorder in relation to phenotypic features of. PCOS.Methods: Adolescent girls (n = 129), age range 14-19 years, were recruited in the cohort study. All participants were in the 4th or 5th year after menarche. Sixty-eight had menstrual irregularities, usually oligomenorrhea (OM), and 61 had regular menstruation (RM). AMH and A4 concentrations were measured. Hirsutism was recorded. Polycystic ovarian morphology (PCOM) was evaluated by transabdominal pelvic ultrasonography. Polycystic ovary syndrome (PCOS) features were defined according to Rotterdam consensus criteria.Results: AMH and A4 were significantly higher in adolescent girls with OM than in girls with RM (p < 0.05). A4 and body mass index (BMI) of adolescents with OM was significantly higher in those with hirsutism than those without hirsutism (p = 0.01 and 0.008, respectively). There was a positive correlation between A4 and BMI (r: 0.327, p < 0.01). Logistic regression showed that the frequency of OM in the presence of PCOM was 10.8 times (95% CI 2.04-12.09) compared to those without PCOM. The highest AMH concentrations were found in girls with OM, hirsutism, and PCOM (p < 0.05).Conclusions: AMH and A4 are elevated in adolescents with oligomenorrhoea. High A4 is more prominent in the presence of hirsutism and is associated with increased BMI. PCOM, increases the likelihood of oligomenorrhea by about 10 times. AMH increase as the combination of clinical features of PCOS increases in adolescents with menstrual irregularity. [ABSTRACT FROM AUTHOR]

Objective: Treatment of congenital adrenal hyperplasia (CAH) patients with glucocorticoids is often challenging since there is a delicate balance between over‐ and undertreatment. Treatment can be monitored noninvasively by measuring salivary androstenedione (A4) and 17‐hydroxyprogesterone (17‐OHP). Optimal treatment monitoring requires the establishment of reference values in saliva. Design: A descriptive study. Patients: For this study saliva of 255 healthy paediatric and adult volunteers with an age range of 4–75 years old was used. Measurements: We developed a sensitive liquid chromatography‐tandem mass spectrometry method, assessed salivary A4 and 17‐OHP stability, and measured A4 and 17‐OHP concentrations in saliva collected in the morning, afternoon, and evening. Results: We quantified A4 and 17‐OHP concentrations in the morning, afternoon, and evening and demonstrated that there is a significant rhythm with the highest levels in the morning and decreasing levels over the day. A4 and 17‐OHP concentrations display an age‐dependent pattern. These steroids remain stable in saliva at ambient temperature for up to 5 days. Conclusions: Good stability of the steroids in saliva enables saliva collection by the patient at home. Since salivary A4 and 17‐OHP display a diurnal rhythm and age‐dependent pattern, we established reference values for both children and adults at three time points during the day. These reference values support treatment monitoring of children and adults with CAH. [ABSTRACT FROM AUTHOR]

Background: This meta‐analysis was conducted to evaluate the effect of statins combined or not combined with metformin on polycystic ovary syndrome (PCOS). Methods: Databases were systematically searched from inception to February 2022. Meta‐analysis was conducted by using STATA 12.0 software. In the study, standard mean difference (SMD) and 95% confidence intervals (CI) were computed as the effect size. A random effect model was used. Results: Meta‐analysis showed significant decline of total testosterone, free testosterone, dehydroepiandrosterone sulphate, androstenedione, luteinizing hormone (LH), LH to follicle‐stimulating hormone (FSH) ratio, and prolactin in statin group. Our study also demonstrated significant decline of total cholesterol, low‐density lipoprotein cholesterol, and triglycerides in statin group. Moreover, we found significant decline of fasting glucose, insulin sensitivity index, and high‐sensitivity C‐reactive protein. Conclusion: The meta‐analysis showed that statin therapy was good for women with PCOS, and could improve clinical signs of PCOS. [ABSTRACT FROM AUTHOR]

Study Question: What are the downstream endocrine and paracrine consequences of letrozole (LZ) cotreatment during ovarian stimulation and is follicle growth and recruitment affected?Summary Answer: Letrozole cotreatment induces marked changes in both the follicular and luteal phase endocrinology causing potentiation of follicle diameter and an improved corpus luteum function without affecting the secondarily recruited follicle cohort.What Is Known Already: Letrozole is a third-generation aromatase inhibitor that is well-established as an effective ovulatory agent, while its possible benefits in standard in vitro fertilization protocols are less thoroughly investigated.Study Design, Size, Duration: This study included a double-blinded, placebo-controlled, randomized study with LZ or placebo intervention during ovarian stimulation for IVF treatment, an observational preceding baseline natural cycle and a succeeding follow-up visit. Participants were enrolled between August 2016 and November 2018. Data from the randomized, stimulated cycle were part of a larger RCT, which was previously published.Participants/materials, Setting, Methods: The study was conducted at a public fertility clinic at Herlev Hospital, Denmark, including 31 healthy, normo-responding women eligible for IVF treatment. They underwent a natural baseline cycle and were subsequently randomized to receive either LZ 5 mg (n = 16) or placebo (n = 15) daily during ovarian stimulation from cycle day (CD) 2-3 until induction of ovulation. Throughout both cycles, monitoring was performed every third day with transvaginal ultrasound for assessment of follicle count and diameter, and blood analyses for the determination of twelve endocrine and paracrine parameters. A follow-up assessment was performed at CD2-3 in the succeeding cycle. In the randomized part of the study, we determined differences in blood parameters, follicle recruitment, and follicle diameter. In the observational part of the study, we assessed follicle recruitment in between cycles and its correlation to endocrine parameters.Main Results and the Role Of Chance: Letrozole cotreatment significantly suppressed oestradiol (E2) concentrations in the follicular phase (area under the curve (AUC) -58% (95% CI [-70%; -43%], P < 0.001)) and luteal phase (AUC -39% [-63%; -1%], P = 0.046). This had a marked effect on the endocrine and paracrine output with increased follicular phase luteinizing hormone (AUC +37% [3%; 82%], P = 0.033), androstenedione (AUC +36% [6%; 74%], P = 0.016), testosterone (AUC +37% [7%; 73%], P = 0.013) and 17-OH-progesterone (AUC +114% [10%; 318%], P = 0.027). Furthermore, follicle-stimulating hormone (FSH) was increased at stimulation day 5 in the LZ group (P < 0.05). In the luteal phase, increased corpus luteum output was reflected by elevated progesterone (AUC +44% [1%; 104%], P = 0.043), inhibin A (AUC +52% [11%; 108%], P = 0.011), androstenedione (AUC +31% [9%; 58%], P = 0.006) and testosterone (AUC +29% [6%; 57%], P = 0.012) in the LZ group. The altered balance between oestrogens and androgens was reflected in a markedly reduced SHBG concentration in the LZ group throughout the luteal phase (AUC -35% [-52%; -11%], P = 0.009). Endocrine and paracrine parameters were similar between groups at the follow-up visit. Letrozole cotreatment significantly increased the mean number of follicles >16 mm at oocyte retrieval (7.2 vs 5.2, difference: 2.0, 95% CI [0.1; 3.8], P = 0.036), while the mean total number of follicles at oocyte retrieval was the same (23.7 vs 23.5, difference: 0.2 [-5.8; 6.1], P = 0.958), and the mean FSH consumption during the stimulated cycle was similar (1500 vs 1520 IU, difference -20 IU [-175; 136], P = 0.794). Between cycles, the mean antral follicle count at CD2-3 was unchanged (natural cycle 19.0, stimulated cycle 20.9, follow-up cycle 19.7, P = 0.692) and there was no effect of LZ cotreatment on the recruitment of the next follicle cohort (test for interaction, P = 0.821).Limitations, Reasons For Caution: This study included a relatively small, selected group of healthy women with an expected normal ovarian function and reserve, and the effects of LZ may therefore be different in other patient groups.Wider Implications Of the Findings: We confirm some previous findings concerning increased follicle growth and increased endogenous FSH and androgen production, which support the rationale for further studies on the use of LZ cotreatment, for example, as a form of endogenous androgen priming sensitizing the follicle to FSH. Letrozole appears to improve the luteal phase with better stimulation of corpus luteum and progesterone secretion.Study Funding/competing Interest(s): The authors declare no conflicts of interest relating to the present work.Trial Registration Number: NCT02939898. [ABSTRACT FROM AUTHOR]

17-β-estradiol, involved in mesothelioma pathogenesis, and its precursors were explored as potential biomarkers for the early diagnosis of mesothelioma. Using enzyme-linked immunosorbent assay(ELISA) for 17-β-estradiol and ultra-high performance liquid chromatography/tandem mass spectrometry(UHPLC-MS/MS) for 19 17-β-estradiol precursors, a comprehensive analysis of 20steroid hormones was conducted in the serum of mesothelioma patients(n=67), asbestos-exposed healthy subjects(n=39), and non-asbestos-exposed healthy subjects(n=35). Bioinformatics analysis explored three potential serum biomarkers: 17-β-estradiol, DHEA-S, and androstenedione. The results revealed significant differences in 17-β-estradiol levels between mesothelioma patients and both non-asbestos-exposed and asbestos-exposed healthy subjects. No significant variations in serum 17-β-estradiol levels were observed among mesothelioma patients at different stages, suggesting its potential as an early diagnostic marker. 17-β-estradiol levels were similar in mesothelioma patients with environmental and occupational asbestos exposure, while males with occupational asbestos exposure exhibited significantly higher levels of 17-β-estradiol compared to females. Significant reduction in androstenedione and an increase in DHEA-S were observed in asbestos-exposed individuals compared to non-asbestos-exposed individuals. The analysis of DHEA-S-androstenedione-17-β-estradiol signature score showed an increase in asbestos-exposed individuals and mesothelioma patients compared to non-asbestos-exposed individuals, and this score effectively distinguished between the groups. The Cancer Genome Atlas data was utilized to analyze the expression of 5-α-reductase1 and hydroxysteroid-17β-dehydrogenase2 genes. The findings indicated that mesothelioma patients with elevated gene values for 5-α-reductase1 and hydroxysteroid-17β-dehydrogenase2 have a worse or better prognosis on overall survival, respectively. In conclusion, this study suggests 17-β-estradiol, DHEA-S, and androstenedione as biomarkers for mesothelioma risk and early diagnosis of mesothelioma in asbestos-exposed individuals, aiding timely intervention and improved care. [Display omitted] • E2 increased in healthy asbestos-exposed subjects and MPM patients. • DHEA-S-androstenedione-E2 signature score increased in asbestos-exposed subjects. • The signature differentiates subjects exposed to asbestos from those not exposed. • DHEA-S-androstenedione-E2 as biomarkers of MPM risk and early diagnosis of MPM. [ABSTRACT FROM AUTHOR]

Capillary dried blood spot (DBS) analysis coupled with multi-analyte steroid liquid chromatography mass spectrometry (LCMS) is attractive for field studies, home-based self-sampling as well as clinical trials by eliminating costly and laborious sample processing involving venipuncture and frozen storage/shipping while providing multiple steroid measurements from a single small sample. We investigated steroid measurements in DBS samples stored for four years at room temperature prior to analysis compared with the original venipuncture serum samples. Healthy women (n=12) provided paired DBS and blood samples over two weeks run-in before seven days treatment with daily transdermal T gel (12.5 mg) and after the end of treatment on days 0, 1, 2, 4, 7 and 14. Compliance with treatment and sampling was high and no adverse effects were reported. Testosterone (T), androstenedione (A 4), 17 hydroxyprogesterone (17OHP) and progesterone (P 4) were measured in extracted DBS samples as whole blood concentrations with and without adjustment for hematocrit. Using the same LCMS methods, DBS T and A 4 measurements had high correlation with minimal bias from prior serum measurements with DBS T displaying the same pattern as serum, with or without hematocrit adjustment. However, serial whole blood measurements of T without hematocrit adjustment provided the best fitting model compared with serum, urine, or hematocrit-adjusted whole blood T measurements. These finding facilitate and simplify DBS methodology for wider field and home-based self-sampling studies of reproductive steroids indicating the need for hematocrit adjustment may be superfluous. [ABSTRACT FROM AUTHOR]

Androstenedione (ADD), an important precursor for steroid hormone drug synthesis, can be obtained through the transformation of phytosterols by members of the Mycobacteria genus. In this study, multidirectional pathway engineering of Mycobacterium neoaurum LY-2 was applied to improve ADD production from phytosterols. Initially, the nonessential gene KasB encoding a cell wall β-ketoacyl acyl carrier protein synthase in Mycobacterium neoaurum LY-2 was knocked out, and the production of ADD was increased by 21.0%. Then, the key enzymes involved in ADD synthetic metabolism were systematically explored. These assays revealed that propionyl coenzyme A carboxylase (PCC) and Hsd4A played important roles in the synthesis of ADD. In addition, the heterologous expression of Vitreoscilla hemoglobin (VHb), a protein with oxygen-binding capacity, was successfully realized in Mycobacterium neoaurum LY-2, and the ADD concentration reached 4.42 g/L. Finally, the recombinant strain LY-2- ΔKasB-hsd4A-pcc-vgb with high ADD production was constructed by combining the above strategies. Through optimization of conversion conditions, the recombinant strain LY-2-Δ KasB - hsd4A - pcc-vgb produced an ADD concentration of 11.12 g/L when adding 20 g/L phytosterols. [Display omitted] • Mycobacterium neoaurum LY-2 efficiently catalyzes phytosterols to produce ADD. • Deletion of KasB enhanced the productivity of M. neoaurum LY-2. • PCC, Hsd4A, and VHb were co-expressed in the recombinant strain LY-2-Δ KasB. • The recombinant strain LY-2-Δ KasB - hsd4A - pcc-vgb produced 11.12 g/L of ADD. [ABSTRACT FROM AUTHOR]

• A unified total synthetic route to 18- and 19-trideuteromethyl steroids is described. • The method can also be used to prepare 18,19-hexadeuteromethyl steroids. • Compounds are useful for preparing calibration curves for mass spec analysis of these steroid hormones. • Compounds are useful for distinguishing between these endogenous and exogenous steroids under various conditions. A unified total synthesis route has been used to prepare 18- and 19-trideuterated testosterone, androstenedione and progesterone. The 18-trideuterated steroid synthetic method starts with the synthesis of 2-(methyl- d 3)-1,3-cyclopentanedione from CD 3 I and 1,3-cyclopentanedione and is subsequently converted into the Hajos-Parrish ketone for synthesis of these trideuterated steroids. The 19-trideuterated steroid synthesis proceeds through non-deuterated Hajos-Parrish ketone with incorporation of the 19-methyl- d 3 group from CD 3 I at a later stage of the same synthetic route. Utilization of CD 3 I at both the initial and later stages of the synthesis provides a route to 18,19-hexadeuterated steroids. The deuterated steroids are useful for studies of steroid biosynthesis and metabolism. [ABSTRACT FROM AUTHOR]

New methods for testosterone production from phytosterol were developed based on its cascade two-stage transformation by actinobacteria Mycolicibacterium neoaurum VKM Ac-1815D and Nocardioides simplex VKM Ac-2033D. Efficient oxidation of the phytosterol side chain by M. neoaurum resulted in formation of the main and side products: androst-4-en-3,20-dione (AD) and androsta-1,4-dien-3,20-dione (ADD), respectively, which were subsequently converted to testosterone by N. simplex. The latter reaction was reversible and catalyzed by the membrane-associated 17β-hydroxysteroid dehydrogenase (17β-HSD) capable of both oxidation and reduction of androstendione at C17. Addition of glucose and limited aeration were found to be the key factors providing for a shift of the 17β-HSD activity towards reduction in whole N. simplex cells. Testosterone production from phytosterol was realized using two approaches: (i) based on M. neoaurum cells inactivation after phytosterol conversion and application of the resting N. simplex biomass for androstenedione reduction and (ii) based on sequential application of the two living cultures. Under optimized conditions, the total yield of testosterone from phytosterol (10 g/L) reached 53 mol %. The results exceeded those reported so far for cascade phytosterol bioconversion to testosterone and may be used as a basis for development of new biotechnologies for production of the valuable steroid compounds, intermediates in the synthesis of modern medical preparations. [ABSTRACT FROM AUTHOR]

Objective: Since there is no gold standard laboratory variable for adjustment of treatment in congenital adrenal hyperplasia (CAH), the aim was to assess the use of a 4-hour profile of serum 17-hydroxyprogesterone (17-OHP) to determine the most appropriate sample time and level of 17-OHP in predicting the metabolic control and evaluate the role of sex hormone-binding globulin (SHBG) in hyperandrogenemia. Methods: This study included children with salt-wasting CAH. Measurements for 17-OHP and cortisol were made from samples obtained before and 1, 2, and 4 hours after the morning dose of hydrocortisone. Patients were designated to have poor metabolic control when androstenedione levels according to age and sex-specific reference intervals were high and annual height standard deviation score (SDS) changes were ≥0.5. Results: The study cohort was 16 children (9 girls) with a median age of 7-years old. Premedication 17-OHP levels were strongly correlated with 17-OHP levels 1, 2, and 4 hours after the morning dose (rs =0.929, p<0.01; rs =0.943, p<0.01; rs =0.835, p<0.01, respectively). 17-OHP profiles (0, 1, 2, 4 hours) of poor (n=6) and good (n=10) metabolically controlled cases were similar. Among the patients with poor metabolic control, two cases had 17-OHP levels <2 ng/mL at all times. The remaining patients with poor metabolic control had median 17-OHP levels above 104 ng/mL, 82 ng/mL, 14 ng/mL, and 4 ng/mL, for baseline and 1, 2, and 4 hours, respectively. Differences between the poor and well-controlled group were androstenedione levels with respect to upper limit of normal [1.8 (1.5) and 0.5 (1.5) ng/mL, respectively p=0.03], annual change in height SDS [0.7 (0.2) and -0.03 (0.8) SDS, respectively, p=0.001], and daily hydrocortisone doses [7 (6) and 16 (8) mg/m² /day, respectively, p=0.02]. Androstenedione and SHBG levels were negatively correlated in the pubertal children (rs =-0.7, p=0.04). Conclusion: We conclude that: (i) a 4-hour 17-OHP profile is not useful in predicting hyperandrogenemia; (ii) suppressed levels of 17- OHP do not always indicate overtreatment; (iii) reference intervals of 17-OHP for different time periods might be of importance; (iv) low hydrocortisone doses should be avoided; and (v) SHBG could be used in pubertal children as an indicator of hyperandrogenemia. [ABSTRACT FROM AUTHOR]

Simple Summary: Microorganisms are able to grow on substrates of the most diverse nature. One of the most practical habitats, in terms of cultural heritage conservation, is fine art objects such as tempera or oil paintings on canvas. Since tempera paints are produced on the basis of egg yolk, which is one of the richest sources of cholesterol in nature (up to 2% of dry weight), and in the process of aging of tempera materials, changes in cholesterol do not affect the core structure of the steroid nucleus, the group of fungi that we have isolated are tempera painting destructors is seen as a promising object for screening for their possible steroid-transforming activities. In this regard, the purpose of our work was to determine the ability to transform pharmaceutically significant steroids with dominant fungi-destructors of tempera paintings, previously isolated in the State Tretyakov Gallery. Consequently, we have demonstrated for the first time that fungi-destructors of tempera paintings have steroid-transforming activity and are promising microorganisms for screening for biotechnologically significant transformations of steroids with further industrial use. The transformation of steroids by microorganisms is widely used in medical biotechnology. A huge group of filamentous fungi is one of the most promising taxa for screening new biocatalytic reactions in order to obtain pharmaceutically significant steroids. In this work, we screened 10 filamentous fungi-destructors of egg tempera for the ability to biotransform androst-4-en-3,17-dione (AD) during cultivation in a liquid nutrient medium or in a buffer solution. These taxonomically unrelated strains, belonging to the classes Eurotiomycetes, Dothideomycetes and Sordariomycetes, are dominant representatives of the microbiome from halls where works of tempera painting are stored in the State Tretyakov Gallery (STG, Moscow, Russia). Since the binder of tempera paints, egg yolk, contains about 2% cholesterol, these degrading fungi appear to be a promising group for screening for steroid converting activity. It turned out that all the studied fungi-destructors are able to transform AD. Some strains showed transformation efficiency close to the industrial strain Curvularia lunata RNCIM F-981. In total, 33 steroids formed during the transformation of AD were characterized, for 19 of them the structure was established by gas chromatography/mass spectrometry analysis. In this work, we have shown for the first time that fungi-destructors of tempera paintings can efficiently transform steroids. [ABSTRACT FROM AUTHOR]

Androstenedione (AD) is a key intermediate in the body's steroid metabolism, used as a precursor for several steroid substances, such as testosterone, estradiol, ethinyl estradiol, testolactone, progesterone, cortisone, cortisol, prednisone, and prednisolone. The world market for AD and ADD (androstadienedione) exceeds 1000 tons per year, which stimulates the pharmaceutical industry's search for newer and cheaper raw materials to produce steroidal compounds. In light of this interest, we aimed to investigate the progress of AD biosynthesis from phytosterols by prospecting scientific articles (Scopus, Web of Science, and Google Scholar databases) and patents (USPTO database). A wide variety of articles and patents involving AD and phytosterol were found in the last few decades, resulting in 108 relevant articles (from January 2000 to December 2021) and 23 patents of interest (from January 1976 to December 2021). The separation of these documents into macro, meso, and micro categories revealed that most studies (articles) are performed in China (54.8%) and in universities (76%), while patents are mostly granted to United States companies. It also highlights the fact that AD production studies are focused on "process improvement" techniques and on possible modifications of the "microorganism" involved in biosynthesis (64 and 62 documents, respectively). The most-reported "process improvement" technique is "chemical addition" (40%), which means that the addition of solvents, surfactants, cofactors, inducers, ionic liquids, etc., can significantly increase AD production. Microbial genetic modifications stand out in the "microorganism" category because this strategy improves AD yield considerably. These documents also revealed the main aspects of AD and ADD biosynthesis: Mycolicibacterium sp. (basonym: Mycobacterium sp.) (40%) and Mycolicibacterium neoaurum (known previously as Mycobacterium neoaurum) (32%) are the most recurrent species studied. Microbial incubation temperatures can vary from 29 °C to 37 °C; incubation can last from 72 h to 14 days; the mixture is agitated at 140 to 220 rpm; vegetable oils, mainly soybean, can be used as the source of a mixture of phytosterols. In general, the results obtained in the present technological prospecting study are fundamental to mapping the possibilities of AD biosynthesis process optimization, as well as to identifying emerging technologies and methodologies in this scenario. [ABSTRACT FROM AUTHOR]

Objective: To assess the effects of aging on the features of polycystic ovary syndrome (PCOS).Design: Cohort study.Setting: Tertiary care center.Patient(s): Women with PCOS, diagnosed according to the 2003 Rotterdam criteria, who visited our outpatient clinic repeatedly.Intervention(s): Comparisons were made between the first visit and consecutive visits.Main Outcome Measure(s): Change in PCOS phenotype groups in terms of clinical and endocrine characteristics.Result(s): A total of 596 women visited the outpatient clinic repeatedly. An estimated change per 5-year age showed a decrease in the prevalence of phenotype A and an increase in the prevalence of not having PCOS. The serum levels of testosterone, androstenedione, and dehydroepiandrosterone sulfate as well as the free androgen index decreased significantly. Clinical characteristics showed an increase in terms of body mass index and waist circumference, whereas plasma glucose levels, insulin levels, and insulin resistance did not change significantly.Conclusion(s): The prevalence of PCOS phenotype groups changes over time. There is an important age effect that indicates a more regular menstrual cycle, decrease in the serum androgen levels, and improvement in polycystic ovarian morphology when aging occurs in women with PCOS. [ABSTRACT FROM AUTHOR]

Introduction: androgens play an important role in the pathogenesis of acne vulgaris. They cause hyperkeratinization of the pilosebaceous follicles and seborrhea. Endocrine diseases characterized by increased levels of androgens often present with acne vulgaris. A correlation between serum androgen levels and acne severity exists, and the assessment of serum androgen levels is therefore essential in women with severe acne vulgaris and treatment resistant acne. Methods: the study was conducted in the Dermatology Clinic of the University of Nigeria Teaching Hospital, Ituku Ozalla. Seventy females with acne vulgaris and seventy females without acne vulgaris were recruited as subjects and controls respectively. Blood samples were taken from subjects and controls to measure levels of serum testosterone, dehydroepiandrosterone sulfate (DHEAS) and androstenedione. Acne severity was measured using global acne grading system (GAGS). Results: the median levels of DHEAS and androstenedione (1.20^g/ml and 1.80ng/ml respectively) were higher in subjects than 1.00^g/ml and 1.70ng/ml in controls respectively, although these findings were not statistically significant. There was also no significant difference between the levels of serum testosterone in both the subjects and the controls. No correlation existed between levels of serum androgens and acne severity. Conclusion: there was no statistically significant difference in the serum androgen levels between the subjects and the control population, and no relationship between androgen levels and severity of acne vulgaris was demonstrated. [ABSTRACT FROM AUTHOR]

Testosterone biosynthesis from its precursor androstenedione is thought to be exclusively catalysed by the 17β-hydroxysteroid dehydrogenases—HSD17B3 in testes, and AKR1C3 in the ovary, adrenal and peripheral tissues. Here we show for the first time that the glucocorticoid activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) can also catalyse the 17β-reduction of androstenedione to testosterone, using a combination of in vitro enzyme kinetic assays, mathematical modelling, and molecular docking analysis. Furthermore, we show that co-expression of HSD11B1 and AKR1C3 increases testosterone production several-fold compared to the rate observed with AKR1C3 only, and that HSD11B1 is likely to contribute significantly to testosterone production in peripheral tissues. [ABSTRACT FROM AUTHOR]

• Influence of ethanol consumption and food intake on serum concentrations of endogenous steroids. • Ethanol consumption increased testosterone/androstenedione ratio in blood. • Meal-induced ACTH and cortisol peaks coincided with pulsatile androstenedione peaks. • Female testosterone levels are more susceptible to perturbations by ethanol or ACTH. Steroid biosynthesis and biotransformation are based on a cascade of enzymatic processes being highly sensitive to various external influences. Amongst those, ethanol was shown to affect testosterone metabolism. For doping analyses, athlete steroid profiles comprise seven urinary steroid metabolites, of which relevant ratios are significantly increased following ethanol consumption. This effect is presumably based on the lack of hepatic NAD+-coenzyme as a consequence of ethanol oxidation. Only recently, testosterone (T) and androstenedione (A4) blood profiles have been introduced as additional approach for doping control. However, a potential influence of ethanol intake on testosterone biosynthesis and thus on blood steroid profiles has not been investigated so far. Therefore, steroid concentrations from 10 males and 10 females receiving an ethanol infusion up to a breath alcohol concentration of 0.5 mg/L which was hold as a plateau for two hours were conducted. Blood samples were drawn every 15 min for steroid quantification. An ethanol-dependent T/A4 increase up to 385 % resulting from A4 suppression was observed in 14 volunteers. In addition, we observed sporadic A4 increases coinciding with cortisol and ACTH pulses pointing to a meal-induced adrenal stimulation. While testosterone levels in males showed diurnal variation solely, testosterone levels in some females were found to be susceptible to ethanol- and ACTH-dependent perturbations, which is thought to be due to its predominant adrenal synthesis in females. In conclusion, the results of the present study emphasize the importance of blood sampling at a sufficient time interval from food and ethanol intake. This is of interest if T and A4 are used for diagnostics in doping control. [ABSTRACT FROM AUTHOR]

Objective: To document associations between anti‐Müllerian hormone (AMH) and circulating androgens in nonhealthcare‐seeking premenopausal women. Design: Community‐based, cross‐sectional study. Setting: Eastern states of Australia. Participants: Women aged 18–39 years not using systemic hormones, not pregnant or breastfeeding within 3 months, and not postmenopausal. Measurements: AMH, measured by the Beckman Access 2, 2 site immunometric assay from fresh samples, and testosterone, androstenedione, dehydroepiandrosterone (DHEA) and 11‐oxygenated C19 steroids, measured by liquid chromatography–tandem mass spectrometry. Results: Data were available for 794 women, median age of 33 years (range: 18–39). 76.1% were of European ancestry and 48.2% were parous. Serum AMH was positively associated with testosterone (rho =.29, p <.001) androstenedione (rho =.39, p <.001) and DHEA (rho =.10, p =.005) but not 11‐ketoandrostenedione or 11‐ketotestosterone. When adjusted for age, body mass index and smoking, using quantile regression, independent positive associations remained between AMH and testosterone (β coefficient: 20.90, 95% confidence interval [CI]: 13.79–28.03; p <.001) and androstenedione (β coefficient: 5.90, 95% CI: 3.76–8.03; p <.001). The serum concentration of testosterone was greater at the top AMH quintile than other quintiles (0.56 nmol/L [range: 0.21–1.90] vs. 0.36 nmol/L [range: 0.13–0.87]; p =.001) in women with self‐reported polycystic ovary syndrome. Conclusions: The positive associations between serum testosterone and androstenedione and AMH in premenopausal women is consistent with androgens directly or indirectly influencing AMH production during follicular development. As the highest AMH concentrations are most likely to be seen in women with multifollicular ovaries, it would be expected that women with multifollicular ovaries would have higher serum testosterone. Therefore, whether hyperandrogenemia and multifollicular ovaries should be considered independent characteristics of polycystic ovary syndrome warrants review. [ABSTRACT FROM AUTHOR]

Aim: We investigated longitudinal adrenal androgen concentrations and any relationship between gestational age, birth size, anthropometric parameters and adrenal androgen concentrations during childhood in boys born moderate to late preterm.Methods: This longitudinal, prospective study included 58 boys born at 32+0 to 36+6 weeks of gestation. Dehydroepiandrosterone sulphate and androstenedione were analysed by liquid chromatography-tandem mass spectrometry, and anthropometric data were recorded from 5 to 10 years of age.Results: Dehydroepiandrosterone sulphate concentrations correlated with weight standard deviations scores (SDS) from 7 to 10 years of age and waist-to-height ratios at seven and 10 years of age. Androstenedione correlated with weight SDS from 7 to 10 years of age and waist-to-height ratios at 10 years of age. Longitudinal analysis showed a relationship between weight SDS and waist-to-height SDS and dehydroepiandrosterone sulphate (p < 0.001 and p < 0.001, respectively) and androstenedione (p = 0.002 and p = 0.003, respectively), independently of age.Conclusion: The trajectories of anthropometric parameters and adrenal androgen secretion were consistent from 5 to 10 years of age in this cohort. The body composition reflected by current weight and the waist-to-height ratio, rather than gestational age and birth size, was associated with adrenal androgen secretion. [ABSTRACT FROM AUTHOR]

Aim: The aim of research was to evaluate the maternal serum concentration of selected endogenous steroid hormones during spontaneous parturition at term and to determinate their association with the need for oxytocin augmentation. Methods: Blood of 108 healthy pregnant women whose parturition started with the regular spontaneous uterine contractions was drawn at the beginning of the labor. Liquid chromatography coupled to the tandem mass spectrometry device was utilized for measurement of sex hormone binding globulin, aldosterone, androstenedione, cortisol, cortisone, corticosterone, dehydroepiandrosterone, dehydroepiandrosteron sulphate, 17‐hydroxyprogesterone, progesterone, and testosterone. Mann–Whitney U test, chi‐square test, univariate and multivariate logistic regression, and receiver operating characteristic (ROC) analysis were used for the data analysis. Results: Reference ranges of the selected hormones assessed by liquid chromatography coupled to the tandem mass spectrometry in maternal serum were established. Statistically significant differences in the serum concentration of corticosterone, dehydroepiandrosterone, and androstenedione between mothers requiring oxytocin augmentation and the rest of women having spontaneous parturition were found (p = 0.002, p = 0.008, and p = 0.04, respectively). Concentrations were lower in the group of mothers who required oxytocin infusion for progression of labor. ROC analysis showed that all the mothers with dehydroepiandrosterone serum concentration above 21.6 nmol/L have lower chance to use oxytocin infusion for the labor progression (area under the curve (AUC) = 0.649, sensitivity = 71.7%, specificity = 59.6%, p = 0.006). Conclusion: This research provided reference ranges for the selected maternal serum steroid hormones at the beginning of parturition. Association of corticosterone, dehydroepiandrosterone, and androstenedione with the need for the oxytocin infusion usage has been established. Dehydroepiandrosterone could be potential predictor of oxytocin infusion augmentation for progression of the parturition. [ABSTRACT FROM AUTHOR]

Natural products have been attracting increasing attention in human diet, both due to the possible negative effects of synthetic food additives on human health and the increased consumer perception. Apricot seeds contain a wide variety of bioactive components and their consumption is associated with a reduced risk of chronic diseases. The objective of the present study was to evaluate the effect of consumption of bitter apricot seeds on blood lipid and endocrine profile in Slovak women (n = 18, 41.60 ± 11.28 years) of reproductive age. Volunteers consumed 60 mg.kg−1 of body weight of bitter apricot seeds divided into 8-12 doses daily for 42 days. During the experiment, three blood collections were carried out (at the beginning of the experiment - day 0, and after 21 and 42 days of consumption apricot seeds). Lipid profile was measured in terms of – total cholesterol (T-C, enzymatic photometric method), low-density cholesterol (LDL-C, calculated using the Friedewald equation), high-density cholesterol (HDL-C, direct clearance method), triglycerides (TG, enzymatic colorimetric method) whereas endocrine profile - follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), 17β-estradiol (E2), testosterone, and androstenedione was assessed by ELISA. The blood levels of T-C, HDL-C and T-C did not change significantly (P > 0.05), however, the level of LDL-C decreased significantly (P < 0.05) after 42 days. On the other hand, there was a significant (P < 0.05) increase of T-C and TG after 21 days. The blood level of FSH, testosterone and androstenedione increased significantly (P < 0.05) although the levels of LH, PRL, P4 and E2 did not change (P > 0.05) after 42 days. The level of PRL and testosterone significantly (P < 0.05) increased and E2 significantly decreased after 21 days of apricot seeds consumption. The study suggests that daily consumption of apricot seeds may affect plasma lipid and endocrine profile in women of reproductive age. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17‐hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH). Methods: A nonlinear mixed‐effect modelling approach was used to analyse cortisol, 17‐hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (n = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an Imax model. Results: Cortisol was characterized by a one‐compartment model with apparent clearance and volume of distribution estimated at 22.9 L/h/70 kg and 41.1 L/70 kg, respectively. The IC50 values of cortisol concentrations for cortisol, 17‐hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 μg/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC50 values were higher in salt‐wasting subjects than simple virilizers. Production rates of cortisol, 17‐hydroxyprogesterone and androstenedione were higher in simple‐virilizer subjects. Half‐lives of cortisol, 17‐hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively. Conclusion: Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17‐hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC‐above‐threshold, time‐within‐range, etc. Our long‐range goal is to uncover dose–exposure–outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing. [ABSTRACT FROM AUTHOR]

[Display omitted] • Uemura-Doyle reaction of a 3,5-diene steroid moiety to give 6β-hydroxytestosterone. • Mechanistic studies using isotope-labeling support: (i) molecular oxygen plays a role and (ii) C3-H abstraction is partially rate-limiting. • The hydroxylation product of androstenedione by P450 3A4 matched the retention time of the synthesized 6β-hydroxyandrostenedione standard by liquid chromatography mass spectrometry. 6β-Hydroxytestosterone is a biomarker for the activity of human cytochrome P450 3A4 (P450 3A4), the major drug metabolizing cytochrome P450 enzyme. Despite its significance, efficient routes for the chemical synthesis of 6β-hydroxytestosterone are rare. In this study, 6β-hydroxytestosterone was synthesized through the oxidation of a 3,5-diene precursor under the Uemura-Doyle reaction conditions using a dirhodium catalyst in the presence of tert -butylhydroperoxide. Mechanistic studies showed that some oxygen is incorporated from molecular oxygen and C H abstraction is partially rate-limiting. This reaction was used to synthesize 6β-hydroxyandrostenedione, which was used as a standard to test the hypothesis of whether P450 3A4 catalyzes the hydroxylation of androstenedione. Upon incubation of P450 3A4 with androstenedione, a hydroxylated product was formed, which matched the retention time of synthetic 6β-hydroxyandrostenedione. This reaction can be exploited to study other biochemical processes involving compounds with a 6 β -hydroxy-3-keto-Δ4 steroid backbone. [ABSTRACT FROM AUTHOR]

Background: Adverse prenatal conditions can exert a long-lasting impact in later life. Patients and Methods: Thirty-eight post-pubertal monozygotic twin pairs (16 female pairs) with divergent birthweight (bw) due to twin-to-twin transfusion syndrome were examined at a median of 15.1 years. Auxological and endocrine parameters were measured. To evaluate effects of intra-twin bw and hormone differences on mental health, adolescents and their parents completed the Strengths and Difficulties Questionnaire (SDQ), identifying psychological problems. Twins answered the questionnaire on health-related quality of life (HrQoL, KIDSCREEN-52). Results: Parents attributed a higher number of psychological challenges to the formerly smaller twins, for example, total difficulties (8.8 vs. 6.5, p = 0.009). Differences in bw were associated with differences in parental evaluation of problems, for example, peer relationship problems (r = −0.57 and p = 0.0001). In contrast, bw differences did not affect subjects' self-assessment of psychological factors but on physical well-being (r = 0.42, p = 0.017). The formerly smaller discordant twins showed significantly lower HrQoL regarding psychological well-being (24.9 vs. 26.6, T1,15 = −2.2, and p = 0.043) and moods and emotions (29.8 vs. 32.0, T1,15 = −2.3, p = 0.039). Higher concentrations of androstenedione were linked to greater psychological well-being (r = 0.39 and p = 0.036) in all twin pairs. Conclusion: Our results show that the prenatal environment leading to bw differences exerts a long-lasting impact on diverging parental evaluation of mental health. Formerly smaller discordant twins showed significantly lower HrQoL regarding psychological well-being and moods and emotions. Higher androstenedione concentrations were linked to greater psychological well-being. [ABSTRACT FROM AUTHOR]

Quantitation of endogenous steroids and their precursors is essential for diagnosis of a wide range of endocrine disorders. Usually, these analyses have been carried out using immunoassays. However, immunoassays often overestimate concentrations due to assay interference by other endogenous steroids, especially for low concentrations. Mass spectrometry based methods offer superior specificity, accuracy, and sensitivity. We therefore present a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with automated sample preparation for determination of 17α-hydroxyprogesterone (17OHP), cortisol, cortisone, dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), testosterone (T), and estrone sulfate (E1S). Samples were prepared using protein precipitation and 96-well filter plates, fully automated in a pipetting robot and analyzed by LC-MS/MS. Serum samples from 187 healthy children and adolescents aged 5-18 years were used to study hormone changes in relation to sex and pubertal stage. Lower limit of quantification for 17OHP was 0.7 nmol/L, for cortisol 11 nmol/L, for cortisone 2 nmol/L, for DHEAS 0.1 µmol/L, and for A4, T, and E1S, 0.2 nmol/L. This study showed a general increase in 17OHP, DHEAS, A4, T and E1S in both genders during puberty. In boys, A4 and T increased significantly throughout pubertal development. Girls had significantly higher A4 and E1S concentrations, while boys had higher T concentrations. No sex- or puberty-specific differences were seen in cortisol or cortisone concentrations. To the best of our knowledge, this is the first presentation of changes in serum E1S concentrations during pubertal development in healthy children. [ABSTRACT FROM AUTHOR]

Subarachnoid hemorrhage (SAH) is a serious neurological event associated with high morbidity and mortality. Computed tomography of the cerebrum (CTC) is the diagnostic method of choice, but in case of negative CTC but strong suspicion of SAH, lumbar puncture with spectrophotometric analysis of cerebrospinal fluid (CSF) for xanthochromia is performed. We wanted to examine the diagnostic properties of CSF spectrophotometry for xanthochromia testing. We performed a retrospective study of the diagnostic properties of CSF analysis for xanthochromia using spectrophotometry in the diagnosis of SAH. A total of 489 CSF samples were analyzed for xanthochromia, according to international guidelines, from 2009 until 2014 and for 411 of these the patient files were retrieved and examined for final clinical diagnosis and result of CTC. One patient with SAH did not have a positive spectrophotometry report and another patient with SAH had an equivocal report. In four patients did initial CTC not correctly identify SAH. For patients with a negative CTC within six hours of symptom onset spectrophotometry for xanthochromia in the CSF had a diagnostic sensitivity of 100% and a diagnostic specificity of 98.5%. The positive predictive value was 16.7% and the negative predictive value 100%. We conclude that spectrophotometry of CSF for xanthochromia is a sensitive and specific test for diagnosing SAH. However, it seems that an initial CTC identifies almost all patients with SAH. This suggests that in our and similar diagnostic settings, lumbar puncture and testing for xanthochromia might only be relevant in very few cases, if not obsolete. [ABSTRACT FROM AUTHOR]