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mRNA vaccine technologies introduced following the SARS-CoV-2 pandemic have highlighted the need to better understand the interaction of adjuvants and the early innate immune response. Type I interferon (IFN-I) is an integral part of this early innate response that primes several components of the adaptive immune response. Women are widely reported to respond better than men to tri- and quadrivalent influenza vaccines. Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production, and female pDCs produce more IFN-I than male pDCs since the upstream pattern recognition receptor Toll-like receptor 7 (TLR7) is encoded by X chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains several putative androgen response elements, and androgens have been reported to suppress pDC IFN-I in vitro. Unexpectedly, therefore, we recently observed that male adolescents mount stronger antibody responses to the Pfizer BNT162b2 mRNA vaccine than female adolescents after controlling for natural SARS-CoV-2 infection. We here examined pDC behaviour in this same cohort to determine the impact of IFN-I on anti-spike and anti-receptor-binding domain IgG titres to BNT162b2. Through flow cytometry and least absolute shrinkage and selection operator (LASSO) modelling, we determined that serumfree testosterone was associated with reduced pDC IFN-I, but contrary to the well-described immunosuppressive role for androgens, the most bioactive androgen dihydrotestosterone was associated with increased IgG titres to BNT162b2. Also unexpectedly, we observed that co-vaccination with live attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together, these data support a model where systemic IFN-I increases vaccine-mediated immune responses, yet for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently improve vaccine-driven immunity. [ABSTRACT FROM AUTHOR]

Purpose: To study the histological changes of the preputial tissue from birth to prepubertal age in order to define unnoticed morphological changes. Materials and Methods: Prepuce samples were obtained from 79 healthy boys who underwent routine ritual circumcision. Specimens were divided into six groups according to the boys' age: newborn, 0-1 year of age, 2-3 years of age, 4-5 years of age, 6-7 years of age, and 8-9 years of age. Histologic analysis of the specimens was performed by H&E, Masson's trichrome, Verhoeff-Von Gieson, immunohistochemical staining. Results: Microscopic examinations showed that average epithelial thickness increased after the neonatal period (p=0.001). When collagen fiber density was evaluated, no significant differences between groups were found (p=0.083). When the elastic fibers in the dermis were evaluated, it was determined that the number and thickness of elastic fibers increased with age. Immunohistochemical examinations showed that the number of peripheral nerves marked with S100 was lower in the neonatal period than at other ages (p=0.048). When the vessels marked with CD105 antibody were counted, there was no significant difference between the groups (p=0.078). Conclusions: This is the first study to examine the age-related structure of connective tissue elements in the foreskin. Our results showed that the prepuce's prepubertal maturation process is continuous, and the first 2 years of life are appropriate not only in relation to the physiological effects of age but also the optimum structural changes for wound healing, such as vessel diameter, epithelium thickness, peripheral nerve count. [ABSTRACT FROM AUTHOR]

Endocrine therapy is widely used to treat cancers whose growth is dependent on hormonal stimulation, most commonly breast, prostate and endometrial cancers. The principles behind its use, indications, different medications available and some of the evidence to support its use are described. Endocrine therapies avoid the toxicities associated with chemotherapy, but do have recognized side effects that can impact on quality of life. [ABSTRACT FROM AUTHOR]

As a synthetic androgen, 17α‐methyltestosterone (MT) is widely used in aquaculture to induce sex reversal and may pose a potential risk to aquatic organisms. This ecological risk has attracted the attention of many scholars, but it is not comprehensive enough. Thus, the adverse effects of MT on zebrafish (Danio rerio) were comprehensively evaluated from gonadal histology, as well as the mRNA expression levels of 47 genes related to hypothalamic‐pituitary‐gonadal (HPG) axis, germ cell differentiation, sex determination, and hypothalamus‐pituitary‐thyroid (HPT) axis. Adult zebrafish with a female/male ratio of 5:7 were exposed to a solvent control (0.001% dimethyl sulfoxide) and three measured concentrations of MT (5, 51 and 583 ng/L) for 50 days. The results showed that MT had no significant histological effects on the ovaries of females, but the frequency of late‐mature oocytes (LMO) showed a downward trend, indicating that MT could induce ovarian suppression to a certain extent. The transcriptional expression of activating transcription factor 4b1 (atf4b1), activating transcription factor 4b2 (atf4b2), calcium/calmodulin‐dependent protein kinase II delta 1 (camk2d1), calcium/calmodulin‐dependent protein kinase II delta 2 (camk2d2) and calcium/calmodulin‐dependent protein kinase II inhibitor 2 (camk2n2) genes in the brain of females increased significantly at all treatment groups of MT, and the mRNA expression of forkhead box L2a (foxl2) and ovarian cytochrome P450 aromatase (cyp19a1a) genes in the ovaries were down‐regulated by 5 and 583 ng/L group, which would translate into inhibition of oocyte development. As compared to females, MT had relatively little effects on the reproductive system of males, and only the transcriptional alterations of synaptonemal complex protein 3 (sycp3) and 17‐alpha‐hydroxylase/17,20‐lyase (cyp17) genes were observed in the testes, not enough to affect testicular histology. In addition, MT at all treatments strongly increased corticotropin‐releasing hormone (crh) transcript in the brain of females, as well as deiodinase 2 (dio2) transcript in the brain of males. The paired box protein 8 (pax8) gene was significantly decreased at 51 or 583 ng/L of MT in both female and male brains. The above results suggest that MT can pose potential adverse effects on the reproductive and thyroid endocrine system of fish. [ABSTRACT FROM AUTHOR]

Perfluorooctanoic acid (PFOA) is a commonly used short‐chain synthetic perfluoroalkyl agent. Immature Leydig cells (ILCs) are localized in the testis and responsible for androgen biosynthesis and metabolism. Although PFOA shows toxicity in the reproductive system, it is not clear if it disrupts the function of ILCs. In the present study, primary ILCs were isolated from 35‐day‐old rats and exposed to a range of PFOA concentrations (0, 0.01, 0.1, or 1 μM). It was determined that 0.1 or 1 μM PFOA reduced total androgen biosynthesis in ILCs. Specifically, 22R‐hydroxycholesterol (22R), and pregnenolone (P5) mediated androgen biosynthesis were reduced by 0.1 μM PFOA. PFOA also selectively downregulated mRNA and protein expressions of steroidogenic enzymes including LHCGR, CYP11A1, 3β‐HSD1, and NR5A1 at 0.01, 0.1, or 1 μM. Further analysis revealed that 0.1 μM PFOA inhibited CYP11A1 and 3β‐HSD1 enzyme activities. However, PFOA did not significantly affect androgen metabolism and turnover under any of the conditions tested. And PFOA gavaging to 35‐day‐old rats at 5 or 10 mg/kg for 7 or 14 days also reduced serum androgen levels secreted by ILCs. Moreover, PFOA gavaging also downregulated the mRNA and protein expression levels of LHCGR, CYP11A1, 3β‐HSD1, and NR5A1 in vivo. Taken together, these findings suggest that PFOA inhibits androgen biosynthesis in ILCs by selectively targeting key enzymes in the synthesis pathway. [ABSTRACT FROM AUTHOR]

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Hyperandrogenism is a clinical state consequent to excess androgen production by the ovary, adrenals, or increased peripheral conversion of androgens. The varied manifestations of hyperandrogenism include seborrhea, acne, infertility, hirsutism, or overt virilization of which adult female acne, hirsutism, and female pattern hair loss are of clinical relevance to dermatologists. We limited our narrative review to literature published during period from 1 January 1985 to Dec 2022 and searched PubMed/MEDLINE, Web of Science (WOS), Scopus, and Embase databases with main search keywords were 'Hyperandrogenism,' 'Female,' 'Biochemical,' 'Dermatological', and 'Dermatology.' We detail the common etiological causes, nuances in interpretation of biochemical tests and imaging tools, followed by an algorithmic approach which can help avoid extensive tests and diagnose the common causes of hyperandrogenism. Based on current data, total testosterone, sex hormone binding globulin, DHEAS, prolactin, free androgen index, and peripheral androgenic metabolites like 3-alpha diol and androsterone glucuronide are ideal tests though not all are required in all patients. Abnormalities in these biochemical investigations may require radiological examination for further clarification. Total testosterone levels can help delineate broadly the varied causes of hyperandrogenism. Serum AMH could be used for defining PCOM in adults. [ABSTRACT FROM AUTHOR]

Abstract Background Prostate cancer (PCa) patients with elevated level of androgen receptor (AR) correlate with higher metastatic incidence. Protein expression of AR and its target gene prostate‐specific antigen (PSA) are elevated in metastatic prostate tumors as compared to organ‐confined tumors. Androgen treatment or elevation of AR promotes metastasis of PCa in cell culture and murine model. However, under androgen depleted condition, AR suppressed cell mobility and invasiveness of PCa cells. Androgen deprivation therapy in PCa patients is associated with higher risk of cancer metastasis. We therefore investigated the dual roles of AR and miRNAs on PCa metastasis. Methods The PC‐3AR (PC‐3 cells re‐expressing AR) and LNCaP cells were used as PCa cell model. Transwell migration and invasion assay, wound‐healing assay, zebrafish xenotransplantation assay, and zebrafish vascular exit assay were used to investigate the role of AR and androgen on PCa metastasis. Micro‐Western Array, co‐immunoprecipitation and Immunofluorescence were applied to dissect the molecular mechanism lying underneath. The miRNA array, miRNA inhibitors or plasmid, and chromatin immunoprecipitation assay were used to study the role of miRNAs on PCa metastasis. Results In the absence of androgen, AR repressed the migration and invasion of PCa cells. When androgen was present, AR stimulated the migration and invasion of PCa cells both in vitro and in zebrafish xenotransplantation model. Androgen increased phospho‐AR Ser81 and yes‐associated protein 1 (YAP), decreased phospho‐YAP Ser217, and altered epithelial‐mesenchymal transition (EMT) proteins in PCa cells. Co‐IP assay demonstrated that androgen augmented the interaction between YAP and AR in nucleus. Knockdown of YAP or treatment with YAP inhibitor abolished the androgen‐induced migration and invasion of PCa cells, while overexpression of YAP showed opposite effects. The miRNA array revealed that androgen decreased hsa‐miR‐5001‐5p but increased hsa‐miR‐203a and hsa‐miR‐210‐3p in PC‐3AR cells but not PC‐3 cells. Treatment with inhibitors targeting hsa‐miR‐203a/hsa‐miR‐210‐3p, or overexpression of hsa‐miR‐5001‐5p decreased YAP expression as well as suppressed the androgen‐induced migration and invasion of PCa cells. Chromatin immunoprecipitation (ChIP) assay demonstrated that AR binds with promoter region of has‐miR‐210‐3p in the presence of androgen. Conclusions Our observations indicated that miRNAs 203a/210‐3p/5001‐5p regulate the androgen/AR/YAP‐induced PCa metastasis.

Abstract Objective This study aimed to translate and validate the Estro-Androgenic-Symptom Questionnaire in Women (EASQ-W) into Brazilian Portuguese language, as we hypothesized that this tool would be consistent for addressing the specific context of hormonal symptoms in menopause. Methods In a cross-sectional study, a total of 119 women with Genitourinary Syndrome of Menopause (GSM) and 119 climacteric women without GSM were included. The EASQ-W was translated, and its psychometric properties were rigorously examined. Participants completed questionnaires covering sociodemographic details, the EASQ-W, and the Menopause Rating Scale (MRS). A subgroup of 173 women was re-invited after 4 weeks for test-retest analysis of the EASQ-W. Additionally, the responsiveness of the questionnaire was evaluated in 30 women who underwent oral hormonal treatment. Results The internal consistency of the EASQ-W was found to be satisfactory in both GSM and control groups (Cronbach’s alpha ≥ 0.70). Notably, a floor effect was observed in both groups; however, a ceiling effect was only evident in the sexual domain of the GSM group. Construct validity was established by comparing the EASQ-W with the MRS, yielding statistically significant correlations (0.33831-0.64580, p < 0.001). The test-retest reliability over a 4-week period was demonstrated to be satisfactory in both the GSM and control groups (ICC 0.787-0.977). Furthermore, the EASQ-W exhibited appropriate responsiveness to oral hormonal treatment (p < 0.001). Conclusion This study successfully translated and validated the Estro-Androgenic-Symptom Questionnaire in Women (EASQ-W) into Brazilian Portuguese, with satisfactory internal consistency, test-retest reliability, and construct validity.

IntroductionCongenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) or 11-hydroxylase deficiency (11OHD) is characterized by underproduction of cortisol and overproduction of adrenal androgens. These androgens lead to a variable degree of virilization of the female external genitalia in 46,XX individuals. Especially in developing countries, diagnosis is often delayed and 46,XX patients might be assigned as males. This study aims to describe the clinical and biochemical characteristics of a unique cohort of untreated male-reared 46,XX classic CAH patients from Indonesia and discusses treatment challenges.MethodsNine untreated classic CAH patients with 46,XX genotype and 21OHD (n=6) or 11OHD (n=3), aged 3-46 years old, were included. Biometrical parameters, clinical characteristics, and biochemical measurements including glucocorticoids, renin, androgens, and the pituitary-gonadal axis were evaluated.ResultsAll patients had low early morning serum cortisol concentrations (median 89 nmol/L) without significant increase after ACTH stimulation. Three patients with salt wasting 21OHD reported one or more periods with seizures and/or vomiting in their past until the age of 6, but not thereafter. The remaining patients reported no severe illness or hospitalization episodes, despite their decreased capacity to produce cortisol. In the 21OHD patients, plasma renin levels were elevated compared to the reference range, and in 11OHD patients renin levels were in the low-normal range. All adult patients had serum testosterone concentrations within the normal male reference range. In 21OHD patients, serum 11-oxygenated androgens comprised 41-60% of the total serum androgen concentrations. Glucocorticoid treatment was offered to all patients, but they refused after counseling as this would reduce their endogenous androgen production and they did not report complaints of their low cortisol levels.DiscussionWe describe a unique cohort of untreated classic 46,XX male CAH patients without overt clinical signs of cortisol deficiency despite their cortisol underproduction and incapacity to increase cortisol levels after ACTH stimulation. The described adolescent and adult patients produce androgen levels within or above the normal male reference range. Glucocorticoid treatment will lower these adrenal androgen concentrations. Therefore, in 46,XX CAH patients reared as males an individual treatment approach with careful counseling and clear instructions is needed.

Steroid 5α-reductase1/2 (SRD5A1/2) is an androgen protein that resembles the plant DET2 and is responsible for the conversion of testosterone to the more active dihydrotestosterone (DHT). Both proteins share functional homology and have a common ancestor. In mammals, the SRD5A1/2 can reduce a wide range of steroid substrates, such as testosterone, progesterone, and aldosterone, by reducing the Δ4 in ring A. The plant DET2 catalyzes the conversion of campesterol (CR) to campestanol (CN) by reducing the Δ5 in ring B during brassinosteroid (BRs) biosynthesis. We compared the evolution, structural, and functional homology of the SRD5A family and tried to identify the origin and functional diversification of duplicated genes in eukaryotes. We presented a detailed phylogeny that includes representative species from all eukaryotic groups. Our study indicated that protist is a common ancestor for all the subgroups of the SRD5A family. However, not all protists possess SRD5A1/2/DET2 or other homologs, suggesting that some protists may have lost these gene families during evolution. Lineage-specific duplication leads Caenorhabditis elegance to have three SRD5A1/2 genes but none was found in Drosophila melanogaster. We also identified a new subclass, DET2-like (DET2L), in plants that closely resemble SRD5A1/2/DET2. The hypothesized reductase DET2L showed no phenotypic enhancement when expressed in Arabidopsis det2 mutants, suggesting its possible role in the reduction of polyprenol or other substrates.

Advancements in lymphoma treatment have increased the number of long-term survivors who may experience late effects such as impaired sexual function and testosterone deficiency. The aim of this review was to determine the prevalence of testosterone deficiency and sexual dysfunction among male lymphoma survivors; and associations between the two. A systematic search identified 20 articles for inclusion. The prevalence of low total testosterone was 0%–50 %, with mean values within reference levels, and for luteinizing hormone above reference levels in 0%–80 %. Four studies included SHBG and free testosterone, with mixed results. Compromised sexual health was found in 23%–61 %. Overall, total testosterone and sexual health were associated. The risk of bias (ROBINS-E and RoB 2) was high/very high, leading to low/very low overall confidence in the bulk of evidence (GRADE). Longitudinal studies evaluating biologically active testosterone and sexual health are needed, to develop evidence based standard procedures for follow-up of sexual health.

Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.

Androgen receptor (AR) signaling is crucial for driving prostate cancer (PCa), the most diagnosed and the second leading cause of death in male patients with cancer in the United States. Androgen deprivation therapy is initially effective in most instances of AR-positive advanced or metastatic PCa. However, patients inevitably develop lethal castration-resistant PCa (CRPC), which is also resistant to the next-generation AR signaling inhibitors. Most CRPCs maintain AR expression, and blocking AR signaling remains a main therapeutic approach. GATA2 is a pioneer transcription factor emerging as a key therapeutic target for PCa because it promotes AR expression and activation. While directly inhibiting GATA2 transcriptional activity remains challenging, enhancing GATA2 degradation is a plausible therapeutic strategy. How GATA2 protein stability is regulated in PCa remains unknown. Here, we show that constitutive photomorphogenesis protein 1 (COP1), an E3 ubiquitin ligase, drives GATA2 ubiquitination at K419/K424 for degradation. GATA2 lacks a conserved [D/E](x)xxVP[D/E] degron but uses alternate BR1/BR2 motifs to bind COP1. By promoting GATA2 degradation, COP1 inhibits AR expression and activation and represses PCa cell and xenograft growth and castration resistance. Accordingly, GATA2 overexpression or COP1 mutations that disrupt COP1-GATA2 binding block COP1 tumor-suppressing activities. We conclude that GATA2 is a major COP1 substrate in PCa and that COP1 promotion of GATA2 degradation is a direct mechanism for regulating AR expression and activation, PCa growth, and castration resistance.

The next-generation antiandrogen drugs such as enzalutamide and abiraterone extend survival times and improve quality of life in patients with advanced prostate cancer. However, resistance to both drugs occurs frequently through mechanisms that are incompletely understood. Wnt signaling, particularly through Wnt5a, plays vital roles in promoting prostate cancer progression and induction of resistance to enzalutamide and abiraterone. Development of novel strategies targeting Wnt5a to overcome resistance is an urgent need. In this study, we demonstrated that Wnt5a/FZD2-mediated noncanonical Wnt pathway is overexpressed in enzalutamide-resistant prostate cancer. In patient databases, both the levels of Wnt5a and FZD2 expression are upregulated upon the development of enzalutamide resistance and correlate with higher Gleason score, biochemical recurrence, and metastatic status, and with shortened disease-free survival duration. Blocking Wnt5a/FZD2 signal transduction not only diminished the activation of noncanonical Wnt signaling pathway, but also suppressed the constitutively activated androgen receptor (AR) and AR variants. Furthermore, we developed a novel bioengineered BERA-Wnt5a siRNA construct and demonstrated that inhibition of Wnt5a expression by the BERA-Wnt5a siRNA significantly suppressed tumor growth and enhanced enzalutamide treatment in vivo. These results indicate that Wnt5a/FZD2 signal pathway plays a critical role in promoting enzalutamide resistance, and targeting this pathway by BERA-Wnt5a siRNA can be developed as a potential therapy to treat advanced prostate cancer.

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.SignificanceUnderstanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.

The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.

Background: In individuals with coronavirus disease 2019 (COVID-19), male subjects have consistently beenlinked to poor severity and prognosis. Data on sex hormones in non-critical COVID-19-infected patients are scarce.The aim of this study was to assess the status of total testosterone (TT) and dehydroepiandrosterone sulfate (DHEAS)among noncritical patients with COVID-19 according to sex and their associations with clinical and biochemicalfeatures.Materials and Methods: This cross-sectional observational study was done in the COVID-19 unit of a Universityhospital during the period of September 2021 to February 2022 among 91 adults (18-65 years) with reverse transcriptase-polymerase chain reaction confirmed noncritical COVID-19 patients. Blood was drawn by venipuncturebefore receiving steroids between 07:00 to 09:00 a.m. in a fasting state to measure serum TT and DHEAS by chemiluminescentmicroparticle immunoassay. Diagnosis and classification of COVID-19 were done according to WorldHealth Organization’s interim guidance. Age- and sex-specific laboratory reference values were used to classify theTT and DHEAS status of the patients.Results: Only three males (8.1%) had low TT and the rest had normal TT. On the other hand, 15 (27.8%) of the femaleshad high TT with normal levels in the rest. Similarly, 11 (29.7%) males had low DHEAS. Females had low, normal,and high DHEAS in four (7.4%), 48 (88.9%), and two (3.7%) cases respectively. Males with moderate severity ofCOVID-19 had significantly lower DHEAS (post hoc P=0.038) than the mild group. Both TT (P=0.008) and DHEAS(P=0.023) significantly correlated with neutrophils/lymphocytes ratio and only DHEAS with platelets/lymphocytesratio (P=0.044) in males. In females, TT significantly correlated with serum sodium (P=0.034).Conclusion: In noncritical COVID-19 patients, substantial gender variations in TT and DHEAS were detected andcorrelated with severity markers in males.

To evaluate the initial impact of a combined oral contraceptive (COC) containing norgestimate (NGM) on female sexuality and on circulating androgen levels in users. Six months modification in the McCoy Female Sexuality Questionnaire (MFSQ) and testosterone (T) and dehydroepiandrosterone sulphate (DHEAS) serum levels in women starting a monophasic pill containing ethinyl-estradiol (EE) 35 µg and NGM 0.250 mg. The study was completed by 36 subjects. There was a significant increase in MFSQ during treatment (p < 0.0001) (and its domains with the exclusion of vaginal lubrication domain) with concomitant decreases in T (−4.45%, p < 0.0001) and DHEAS (−19.41%, p < 0.0001) serum levels. Contraception with EE/NGM was associated with a short term non-deteriorating effect on sexuality despite the evident decrease in androgen levels. Female sexuality during COC use is a complex topic and is not only linked with changes in serum androgen levels. EE/NGM treatment has a short term non-deteriorating effect on sexuality despite the evident decrease in androgen serum levels. [ABSTRACT FROM AUTHOR]

Objective: Sex steroids exert important biological functions within the CNS, but the underlying mechanisms are poorly understood. The contribution of circulating sex steroids to the levels in CNS tissue and cerebrospinal fluid (CSF) has been sparsely investigated in human and with inconclusive results. This could partly be due to lack of sensitive validated assays. To address this, we validated a gas chromatography–tandem mass spectrometry (GC-MS/MS) assay for quantification of sex steroid hormones/precursors in CSF. Methods: GC-MS/MS quantification of dihydrotestosterone (DHT, CSF lower limit of quantification, 1.5 pg/mL), testosterone (4.9), estrone (E1, 0.88), estradiol (E2, 0.25), dehydroepiandrosterone (DHEA, 38.4), androstenedione (4D, 22.3), and progesterone (P, 4.2) in CSF, and corresponding serum samples from 47 men. Results: Analyses of CSF revealed that DHEA was the major sex steroid (73.5 ± 31.7 pg/mL) followed by 4D (61.4 ± 29.6 pg/mL) and testosterone (49.5 ± 18.9 pg/mL). The CSF levels of DHT, E2, and E1 were substantially lower, and P was in general not detectable in CSF. For all sex steroids except E2, strong associations between corresponding CSF and serum levels were observed. We propose that testosterone in CSF is derived from circulating testosterone, DHT in CSF is from local conversion from testosterone, while E2 in CSF is from local conversion from 4D in CNS. Conclusions: We describe the first thoroughly validated highly sensitive mass spectrometric assay for a broad sex steroid hormone panel suitable for human CSF. This assay constitutes a new tool for investigation of the role of sex steroid hormones in the human CNS. Significance statement In this study, a fully validated highly sensitive mass spectrometric assay for sex steroids was applied to human CSF. The results were used to describe the relative contribution of peripheral circulating sex steroids together with locally transformation of sex steroids to the levels in CSF. The results are of importance to understand the biological processes of the human brain.

(1) Background: HASPIN kinase is involved in regulating spindle function and chromosome segregation, as well as phosphorylating histone H3 at Thr3 in mitotic cells. Several HASPIN inhibitors suppress cancer cell proliferation. It was recently reported that coumestrol from bean sprouts inhibits HASPIN, and a cultivation method for bean sprouts containing large amounts of coumestrol has been established. Here, we showed the effects of bean sprout ingestion on intestinal polyp development, cachexia, and hypogonadism in a mouse model of familial adenomatous polyposis (ApcMin/+). (2) Methods: ApcMin/+ mice were randomized into control and treatment groups. Mice in the control group were given the standard diet, while those in the treatment group were given the same standard diet with the addition of 15% bean sprouts. Treatments were commenced at 7 weeks old and analyses were performed at 12 weeks old. (3) Results: ingesting bean sprouts suppressed the development of intestinal polyps, cachexia, and hypogonadism, and also increased serum levels of testosterone in male wild-type and ApcMin/+ mice. (4) Conclusions: ingesting bean sprouts helps prevent cancer and increases serum levels of testosterone in a mouse model. These results are expected to be applicable to humans.

UNLABELLED: African-American (AA) men are more likely to be diagnosed with and die from prostate cancer than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in prostate cancer, little is known about the contribution of epigenetics to observed racial disparities. We performed AR chromatin immunoprecipitation sequencing on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA prostate cancer are enriched for lipid metabolism and immune response genes. Integration with transcriptomic and metabolomic data demonstrated coinciding upregulation of lipid metabolism gene expression and increased lipid levels in AA prostate cancer. In a metastatic prostate cancer cohort, upregulated lipid metabolism associated with poor prognosis. These findings offer the first insights into ancestry-specific differences in the prostate cancer AR cistrome. The data suggest a model whereby increased androgen signaling may contribute to higher levels of lipid metabolism, immune response, and cytokine signaling in AA prostate tumors. Given the association of upregulated lipogenesis with prostate cancer progression, our study provides a plausible biological explanation for the higher incidence and aggressiveness of prostate cancer observed in AA men. SIGNIFICANCE: With immunotherapies and inhibitors of metabolic enzymes in clinical development, the altered lipid metabolism and immune response in African-American men provides potential therapeutic opportunities to attenuate racial disparities in prostate cancer.

Aberrant transcriptional activity of androgen receptor (AR) is one of the dominant mechanisms for developing of castration-resistant prostate cancer (CRPC). Analyzing AR-transcriptional complex related to CRPC is therefore important towards understanding the mechanism of therapy resistance. While studying its mechanism, we observed that a transmembrane protein called neuropilin-2 (NRP2) plays a contributory role in forming a novel AR-transcriptional complex containing nuclear pore proteins. Using immunogold electron microscopy, high-resolution confocal microscopy, chromatin immunoprecipitation, proteomics, and other biochemical techniques, we delineated the molecular mechanism of how a specific splice variant of NRP2 becomes sumoylated upon ligand stimulation and translocates to the inner nuclear membrane. This splice variant of NRP2 then stabilizes the complex between AR and nuclear pore proteins to promote CRPC specific gene expression. Both full-length and splice variants of AR have been identified in this specific transcriptional complex. In vitro cell line-based assays indicated that depletion of NRP2 not only destabilizes the AR-nuclear pore protein interaction but also inhibits the transcriptional activities of AR. Using an in vivo bone metastasis model, we showed that the inhibition of NRP2 led to the sensitization of CRPC cells toward established anti-AR therapies such as enzalutamide. Overall, our finding emphasize the importance of combinatorial inhibition of NRP2 and AR as an effective therapeutic strategy against treatment refractory prostate cancer.

Introduction: Individuals with 17-beta-hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency face a multitude of challenges, primarily concerning genital appearance, potential malignancy risks, and fertility issues. This study reports our findings from an investigation involving five individuals affected by 17β-HSD3 deficiency, ranging in age from pre-adolescence to adolescence. Notably, we identified four previously unreported mutations in these subjects. Methods: Our study included a comprehensive evaluation to determine the potential occurrence of testicular tumors. The methods involved clinical examinations, genetic testing, hormone profiling, and patient history assessments. We closely monitored the progress of the study subjects throughout their treatment. Results: The results of this evaluation conclusively ruled out the presence of testicular tumors among our study subjects. Moreover, four of these individuals successfully underwent gender transition. Furthermore, we observed significant improvements in genital appearance following testosterone treatment, particularly among patients in the younger age groups who received appropriate treatment interventions. Discussion: These findings underscore the critical importance of early intervention in addressing concerns related to genital appearance, based on our extensive clinical experience and assessments. In summary, our study provides insights into the clinical aspects of 17β-HSD3 deficiency, emphasizing the vital significance of early intervention in addressing genital appearance concerns. This recommendation is supported by our comprehensive clinical assessments and experience. [ABSTRACT FROM AUTHOR]

This article provides information on the management of hepatocellular adenomas (HCAs) in different populations, specifically focusing on polycystic ovary syndrome (PCOS), exogenous testosterone use, and transgender women. HCAs are benign liver tumors that are more commonly seen in women and are associated with hormonal factors. The article emphasizes the need for clinical management guidelines in these populations and suggests strategies such as discontinuing contraceptive use, weight loss, and surgical resection. It also highlights the increased risk of malignant transformation in men and transgender women with HCAs. The text discusses the importance of weight management for overweight/obese patients, including those undergoing gender-affirming hormone therapy, and addresses the management of endometrial hyperplasia in postmenopausal women. The article emphasizes the need for further research on the natural history of HCAs in different populations and suggests tailored management approaches based on hormone-related risks and the use of exogenous hormones and hormone-modifying therapies. [Extracted from the article]

Background and Aims: Sex steroid hormones and sex hormone-binding globulin (SHBG) have a role in predisposing individuals to nonalcoholic fatty liver disease (NAFLD), but their effects are known to differ between men and women. The testosterone- to-estradiol ratio (T/E2 ratio) and free androgen index (FAI) were known biomarkers for the hormonal milieu. We investigated whether sex steroid hormones, T/E2 ratio, FAI, and SHBG were associated with NAFLD in US adults. Methods: A cross-sectional analysis using the 2013--2016 National Health and Nutrition Examination Survey (NHANES) was performed. NAFLD was defined by utilizing the Hepatic Steatosis Index (HSI) and the US fatty liver index (USFLI) without other causes of chronic liver disease. Results: Out of 8687 subjects (49.5% male), low total testosterone levels were associated with progressively higher odds of NAFLD in men. Increasing T/E2 ratio was inversely associated with higher odds of NAFLD in men. Low serum SHBG levels were independently associated with an increased risk of NAFLD regardless of sex and menopausal status. Increasing FAI was independently associated with NAFLD. When we additionally adjusted for SHBG, T/E2 ratio, not total testosterone, was inversely associated with NAFLD in a dose-dependent manner. Increasing FAI was associated with higher odds of NAFLD in premenopausal women and marginally associated with NAFLD in postmenopausal women. Conclusion: The T/E2 ratio and SHBG were inversely associated with an increased risk of NAFLD in men. In women, increasing FAI was associated with NAFLD, whereas SHBG was inversely associated with NAFLD. [ABSTRACT FROM AUTHOR]

With the increasing number of transgender and gender diverse (TGD) individuals who are seeking gender-affirming care, there is a clear need for the development and collection of evidence-based data to establish guidelines for patient care. TGD individuals are estimated to represent 0.3 to 4.5% of the world population. Gender-affirming care that includes hormone therapy helps to align the body of a transgender person with their gender identity. Hormone therapy requires monitoring for both safety and efficacy. The extent to which gender-affirming hormone therapy alters cancer risk remains unknown. Because of a lack of comprehensive data collection pertaining to this patient population, endocrine cancer data including incidence and outcomes is limited. Dedicated research is needed to help address the gap in knowledge pertaining to the risk of cancer in the TGD population. [ABSTRACT FROM AUTHOR]

Oxidative stress has been linked with lead toxicity, including lead-induced sexual dysfunction. On the contrary, sodium acetate has been proven to exert antioxidant activity. However, the effect of sodium acetate on lead-induced sexual dysfunction has not been fully explored. This study investigated the effect of sodium acetate on lead-induced sexual dysfunction, exploring the involvement of testosterone, eNOS/NO/cGMP, and Nrf2/HO-1 signaling. Twenty male Wistar rats with similar weights were randomly assigned into four groups (n = 5 rats/group) after two weeks of acclimatization. Animals were vehicle-treated (0.5 ml/day of distilled water, per os), acetate-treated (200 mg/kg/day, per os), lead-treated (20 mg/kg/day, per os), or lead + acetate-treated. The results revealed that sodium acetate treatment attenuated lead-induced rise in penile lead, malondialdehyde and oxidized glutathione concentrations, and acetylcholinesterase activity. In addition, lead exposure prolonged mount, intromission, and ejaculation latency and reduced mount, intromission, and ejaculation frequency, as well as the motivation to mate and penile reflex, which were improved by acetate treatment. More so, acetate treatment ameliorated lead-induced reductions in absolute and relative penile weight, eNOS, NO, cGMP, luteinizing hormone, follicle-stimulating hormone, testosterone, dopamine, Nrf2, HO-1, and reduced glutathione concentrations, as well as glutathione reductase, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase, and catalase activities. In conclusion, this study demonstrates that sodium acetate attenuated lead-induced sexual dysfunction by upregulating testosterone-dependent eNOS/NO/cGMP and Nrf2/HO-1 signaling. Despite the compelling data presented in this study, other possible associated mechanisms in the protective role of acetate should be explored. [ABSTRACT FROM AUTHOR]

Background Arteries from boys with hypospadias demonstrate hypercontractility and impaired vasorelaxation. The role of sex hormones in these responses in unclear. Aims We compared effects of sex steroids on vascular reactivity in healthy boys and boys with hypospadias. Methods Excess foreskin tissue was obtained from 11 boys undergoing hypospadias repair (cases) and 12 undergoing routine circumcision (controls) (median age [range], 1.5 [1.2-2.7] years) and small resistance arteries were isolated. Vessels were mounted on wire myographs and vascular reactivity was assessed in the absence/presence of 17β-estradiol, dihydrotestosterone (DHT), and testosterone. Results In controls, testosterone and 17β-estradiol increased contraction (percent of maximum contraction [Emax]: 83.74 basal vs 125.4 after testosterone, P <.0002; and 83.74 vs 110.2 after estradiol, P =.02). 17β-estradiol reduced vasorelaxation in arteries from controls (Emax: 10.6 vs 15.6 to acetylcholine, P <.0001; and Emax: 14.6 vs 20.5 to sodium nitroprusside, P <.0001). In hypospadias, testosterone (Emax: 137.9 vs 107.2, P =.01) and 17β-estradiol (Emax: 156.9 vs 23.6, P <.0001) reduced contraction. Androgens, but not 17β-estradiol, increased endothelium-dependent and endothelium-independent vasorelaxation in cases (Emax: 77.3 vs 51.7 with testosterone, P =.02; and vs 48.2 with DHT to acetylcholine, P =.0001; Emax: 43.0 vs 39.5 with testosterone, P =.02; and 39.6 vs 37.5 with DHT to sodium nitroprusside, P =.04). Conclusion In healthy boys, testosterone and 17β-estradiol promote a vasoconstrictor phenotype, whereas in boys with hypospadias, these sex hormones reduce vasoconstriction, with androgens promoting vasorelaxation. Differences in baseline artery function may therefore be sex hormone-independent and the impact of early-life variations in androgen exposure on vascular function needs further study. [ABSTRACT FROM AUTHOR]

to investigate the serum levels of decorin, a small leucine-rich proteoglycan, in women diagnosed with polycystic ovary syndrome (PCOS) and concurrently presenting with moderate to severe acne vulgaris. PATIENTS AND METHODS: Sixty patients with acne vulgaris symptoms, subsequently diagnosed with PCOS according to the revised Rotterdam criteria, were enrolled in the study. Acne severity was assessed using the acne global severity scale (AGSS), with patients fitting AGSS category 4 (moderate) and 5 (severe) grouped into two separate cohorts of 30 individuals each. The moderate acne group comprised patients with few inflammatory lesions and a minor nodule alongside predominantly non-inflammatory lesions, whereas the severe group contained patients with multiple nodules and a mix of non-inflammatory and inflammatory lesions. A control group of twenty healthy women without acne vulgaris or PCOS was also established. The study measured serum testosterone, follicle- stimulating hormone (FSH), Luteinizing Hormone (LH), and insulin levels, and calculated insulin resistance via the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) formula. Quantitative sandwich enzyme immunoassay was employed to determine decorin levels from venous blood samples. RESULTS: While age, body mass index (BMI), serum FSH, LH, testosterone, and HOMA-IR values demonstrated similarity between the moderate and severe acne cohorts, comparisons between the control and both acne groups (AGSS-4 and AGSS-5) revealed significantly elevated values in the latter, excluding age, BMI, and FSH. Importantly, the serum decorin levels in both acne groups were substantially higher than in controls. A significant positive correlation was observed between serum decorin levels and both HOMA-IR (r=7.88, p<0.01) and testosterone (r=0.813, p<0.01). CONCLUSIONS: This study suggests that elevated circulating decorin levels play a pivotal role in the manifestation of acne vulgaris in women with PCOS. [ABSTRACT FROM AUTHOR]

Currently, immunotherapy based on PD-1/PD-L1 pathway blockade has improved survival of non-small cell lung cancer (NSCLC) patients. However, differential responses have been observed by sex, where men appear to respond better than women. Additionally, adverse effects of immunotherapy are mainly observed in women. Studies in some types of hormone-dependent cancer have revealed a role of sex hormones in anti-tumor response, tumor microenvironment and immune evasion. Estrogens mainly promote immune tolerance regulating T-cell function and modifying tumor microenvironment, while androgens attenuate anti-tumor immune responses. The precise mechanism by which sex and sex hormones may modulate immune response to tumor, modify PD-L1 expression in cancer cells and promote immune escape in NSCLC is still unclear, but current data show how sexual differences affect immune therapy response and prognosis. This review provides update information regarding anti-PD-1/PD-L immunotherapeutic efficacy in NSCLC by sex, analyzing potential roles for sex hormones on PD-L1 expression, and discussing a plausible of sex and sex hormones as predictive response factors to immunotherapy. [ABSTRACT FROM AUTHOR]

Background: It has been shown that methylation in the promoter region of eNOS can downregulate eNOS expression resulting in the endothelial dysfunction. However, it is unclear whether low androgen levels and type 1 diabetes cause ED by methylating the promoter region of eNOS in the penile corpus cavernosum. Objective: To clarify the effects of type 1 diabetes and hypo‐androgen status on the methylation level of the promoter region of the eNOS gene in penile cavernous tissue and their relationship with the erectile function. Methods: Fifty‐eight eight‐week‐old male Sprague–Dawley rats were randomly divided into six groups (n = 6): sham operation group, castration group, castration+testosterone (cast+T) group, normoglycemia group, diabetic group, and diabetic+methyltransferase inhibitor (5‐aza‐dc, 1.5 mg/kg) group. The ICPmax/MAP, serum T, the concentration of nitric oxide (NO), the expression of DNMT1, DNMT3a, DNMT3b, and eNOS, and the methylation level of the eNOS promoter region in penile corpus cavernosum of rat were examined 4 weeks after surgery in the sham‐operated group, the castration group, and the castration + testosterone replacement group. Those tests were examined after 6 weeks using of methylation inhibitors in the normoglycemic group, the diabetic group, and the diabetic + methylation inhibitor group. Results: ICPmax/MAP, DNMT1, DNMT3a, DNMT3b, eNOS, and NO levels were significantly lower in castrated rats than in sham and cast+T rats (P < 0.05). ICPmax/MAP, eNOS, and NO levels were lower, and DNMT1, DNMT3a, and DNMT3b expression levels were significantly increased in the diabetic group compared with the normoglycemic and diabetic+methyltransferase inhibitor groups (P < 0.05). There was no significant difference in the methylation level of the promoter region of eNOS in penile cavernous tissue of castrated rats compared with the sham group or the testosterone replacement group. The methylation level of the promoter region of eNOS in penile cavernous tissue was significantly higher in the diabetic group than in the normoglycemic group and diabetic+methyltransferase inhibitor group (P < 0.05). Conclusion: Although low androgen status inhibited the level of methyltransferase in rat penile cavernous tissue, did not affect the level of methylation in the promoter region of eNOS. Hyperglycemia inhibits the NO level in the penile cavernous tissue and the erectile function of rats by upregulating the methyltransferase level in the penile cavernous tissue and the methylation level in the promoter region of eNOS. Methylation inhibitors can partly improve the erectile function in type 1 diabetic rats. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome （PCOS） is characterized by high heterogeneity and heredity, and its exact pathogenesis is still not clear. Some studies have shown that epigenetic disorders, such as hyperandrogen-induced methylation or acetylation of lysine at different sites （K4, K9, and K27） in histone H3, methylation and demethylation modification of genes related to steroids, hormone receptors and follicular development, and transcriptional control of microRNA or long noncoding RNA, play a central role in the occurrence and development of PCOS. This article reviews the research advances in epigenetic mechanisms （histone modifications, DNA methylation, and noncoding RNA） of PCOS, in order to provide a reference for the prediction and early prevention of PCOS. [ABSTRACT FROM AUTHOR]

Background: In individuals with coronavirus disease 2019 (COVID-19), male subjects have consistently been linked to poor severity and prognosis. Data on sex hormones in non-critical COVID-19-infected patients are scarce. The aim of this study was to assess the status of total testosterone (TT) and dehydroepiandrosterone sulfate (DHEAS) among noncritical patients with COVID-19 according to sex and their associations with clinical and biochemical features. Materials and Methods: This cross-sectional observational study was done in the COVID-19 unit of a University hospital during the period of September 2021 to February 2022 among 91 adults (18-65 years) with reverse transcriptase- polymerase chain reaction confirmed noncritical COVID-19 patients. Blood was drawn by venipuncture before receiving steroids between 07:00 to 09:00 a.m. in a fasting state to measure serum TT and DHEAS by chemiluminescent microparticle immunoassay. Diagnosis and classification of COVID-19 were done according to World Health Organization's interim guidance. Age- and sex-specific laboratory reference values were used to classify the TT and DHEAS status of the patients. Results: Only three males (8.1%) had low TT and the rest had normal TT. On the other hand, 15 (27.8%) of the females had high TT with normal levels in the rest. Similarly, 11 (29.7%) males had low DHEAS. Females had low, normal, and high DHEAS in four (7.4%), 48 (88.9%), and two (3.7%) cases respectively. Males with moderate severity of COVID-19 had significantly lower DHEAS (post hoc P=0.038) than the mild group. Both TT (P=0.008) and DHEAS (P=0.023) significantly correlated with neutrophils/lymphocytes ratio and only DHEAS with platelets/lymphocytes ratio (P=0.044) in males. In females, TT significantly correlated with serum sodium (P=0.034). Conclusion: In noncritical COVID-19 patients, substantial gender variations in TT and DHEAS were detected and correlated with severity markers in males. [ABSTRACT FROM AUTHOR]

Simple Summary: Localized prostate cancer has a favorable prognosis and can be effectively treated with radiotherapy, as well as therapies that target hormone production and signaling. However, if the disease progresses past these treatments, treatment options are limited, and the disease often becomes fatal. In this review, we discuss the changes in treatment as prostate cancer develops, as well as the genetic mutations that accompany advanced prostate cancer. We highlight how these mutations can provide clinical opportunities to manipulate the DNA damage response for therapeutic gain using cancer-specific alterations in the genome and new therapeutic agents that are under development or entering clinical trials. Prostate cancers that progress despite androgen deprivation develop into castration-resistant prostate cancer, a fatal disease with few treatment options. In this review, we discuss the current understanding of prostate cancer subtypes and alterations in the DNA damage response (DDR) that can predispose to the development of prostate cancer and affect its progression. We identify barriers to conventional treatments, such as radiotherapy, and discuss the development of new therapies, many of which target the DDR or take advantage of recurring genetic alterations in the DDR. We place this in the context of advances in understanding the genetic variation and immune landscape of CRPC that could help guide their use in future treatment strategies. Finally, we discuss several new and emerging agents that may advance the treatment of lethal disease, highlighting selected clinical trials. [ABSTRACT FROM AUTHOR]

The acyclic linear monoterpenes Linalool (Lin) and Linalyl acetate (LinAc) occur in nature as major constituents of various essential oils such as lavender oils. A potential endocrine activity of these compounds was discussed in literature including premature thelarche and prepubertal gynecomastia due to lavender product use. This study aims to follow-up on these critical findings reported by testing Lin and LinAc in several studies in line with current guidance and regulatory framework. No relevant anti-/ER and AR-mediated activity was observed in recombinant yeast cell-based screening tests and guideline reporter gene in vitro assays in mammalian cells. Findings in the screening test suggested an anti-androgenic activity, which could not be confirmed in the respective mammalian cell guideline assay. Mechanistic guideline in vivo studies (Uterotrophic and Hershberger assays) with Lin did not show significant dose related changes in estrogen or androgen sensitive organ weights and a guideline reproductive toxicity screening study did not reveal evident effects on sex steroid hormone sensitive organ weights, associated histopathological findings and altered sperm parameters. Estrous cycling and mating/fertility indices were not affected and no evident Lin-related steroid hormone dependent effects were found in the offspring. Overall, the initial concerns from literature were not confirmed. Findings in the yeast screening test were aberrant from follow-up guideline in vitro and in vivo studies, which underlines the need to apply careful interpretation of single in vitro test results to support a respective line of evidence and to establish a biologically plausible link to an adverse outcome. [ABSTRACT FROM AUTHOR]

A suite of in vitro assays and in silico models were evaluated to identify which best detected the endocrine-disrupting (ED) potential of 10 test chemicals according to their estrogenic, androgenic and steroidogenic (EAS) potential compared to the outcomes from ToxCast. In vitro methods included receptor-binding, CALUX transactivation, H295R steroidogenesis, aromatase activity inhibition and the Yeast oestrogen (YES) and Yeast androgen screen (YAS) assays. The impact of metabolism was also evaluated. The YES/YAS assays exhibited a high sensitivity for ER effects and, despite some challenges in predicting AR effects, is a good initial screening assay. Results from receptor-binding and CALUX assays generally correlated and were in accordance with classifications based on ToxCast assays. ER agonism and AR antagonism of benzyl butyl phthalate were abolished when CALUX assays included liver S9. In silico final calls were mostly in agreement with the in vitro assays, and predicted ER and AR effects well. The efficiency of the in silico models (reflecting applicability domains or inconclusive results) was 43–100%. The percentage of correct calls for ER (50–100%), AR (57–100%) and aromatase (33–100%) effects when compared to the final ToxCast call covered a wide range from highly reliable to less reliable models. In conclusion, Danish (Q)SAR, Opera, ADMET Lab LBD and ProToxII models demonstrated the best overall performance for ER and AR effects. These can be combined with the YES/YAS assays in an initial screen of chemicals in the early tiers of an NGRA to inform on the MoA and the design of mechanistic in vitro assays used later in the assessment. Inhibition of aromatase was best predicted by the Vega, AdmetLab and ProToxII models. Other mechanisms and exposure should be considered when making a conclusion with respect to ED effects. [ABSTRACT FROM AUTHOR]

In males of many vertebrate species, sexual selection has led to the evolution of sexually dimorphic traits, which are often developmentally controlled by androgen signaling involving androgen response elements (AREs). Evolutionary changes in the number and genomic locations of AREs can modify patterns of receptor regulation and potentially alter gene expression. Here, we use recently sequenced primate genomes to evaluate the hypothesis that the strength of sexual selection is related to the genome-wide number of AREs in a diversifying lineage. In humans, we find a higher incidence of AREs near male-biased genes and androgen-responsive genes when compared with randomly selected genes from the genome. In a set of primates, we find that gains or losses of AREs proximal to genes are correlated with changes in male expression levels and the degree of sex-biased expression of those genes. In a larger set of primates, we find that an increase in one indicator of sexual selection, canine size sexual dimorphism, is correlated with genome-wide ARE counts. Our results suggest that the responsiveness of the genome to androgens in humans and their close relatives has been shaped by sexual selection that arises from competition among males for mating access to females. [ABSTRACT FROM AUTHOR]

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Purpose: Polycystic ovarian syndrome (PCOS) is an endocrine-metabolic condition affecting 5–10% of reproductive-aged women and characterized by hyperandrogenism, insulin resistance (IR), and hyperinsulinemia. CFTR is known to be regulated by steroid hormones, and our previous study has demonstrated an essential role of CFTR in β-cell function. This study aims to investigate the contribution of androgen and CFTR to hypersecretion of insulin in PCOS and the underlying mechanism. Methods: We established a rat PCOS model by subcutaneously implanting silicon tubing containing Dihydrotestosterone (DHT). Glucose tolerance test with insulin levels was performed at 9 weeks after implantation. A rat β-cell line RINm5F, a mouse β-cell line β-TC-6, and mouse islets were treated with DHT, and with or without the androgen antagonist flutamide for CFTR and insulin secretion-related functional assays or mRNA/protein expression measurement. The effect of CFTR inhibitors on DHT-promoted membrane depolarization, glucose-stimulated intracellular Ca2+ oscillation and insulin secretion were examined by membrane potential imaging, calcium imaging and ELISA, respectively. Results: The DHT-induced PCOS model showed increased body weight, impaired glucose tolerance, and higher blood glucose and insulin levels after glucose stimulation. CFTR was upregulated in islets of PCOS model and DHT-treated cells, which was reversed by flutamide. The androgen receptor (AR) could bind to the CFTR promoter region, which was enhanced by DHT. Furthermore, DHT-induced membrane depolarization, enhanced glucose-stimulated Ca2+ oscillations and insulin secretion, which could be abolished by CFTR inhibitors. Conclusions: Excessive androgen enhances glucose-stimulating insulin secretion through upregulation of CFTR, which may contribute to hyperinsulinemia in PCOS. [ABSTRACT FROM AUTHOR]

Background The abuse of androgens is common among visitors to fitness centers. Prospective data regarding patterns of androgen abuse and predictors of future use are not well studied. Methods This is a 2-year prospective observational cohort study among 100 male androgen abusers. The median age of the subjects was 31 years (range, 19-67 years). Participants were meticulously characterized and observed for 1 year before, during, and after the use of a cycle of androgens. They remained in follow-up for a second year to study subsequent androgen abuse. Using multivariable regression analysis we aimed to identify baseline sociodemographic factors and cycle characteristics that would predict future androgen abuse. Results Ninety-seven (97%) men completed the second year of follow-up. Sixty-three subjects (65%) abused androgens again and 16 (16%) for the entire duration of the second year. The variables that were positively associated with the cumulative time of androgen abuse during the 2 years of follow-up were historical cumulative androgen exposure and the intention to take part in bodybuilding competitions. Cycle duration in year 1 and training time at baseline were positively associated with repeated use in year 2. Cycle duration in the first year was also positively associated with the cumulative time of androgen abuse in the second year. For all the other investigated baseline variables and cycle characteristics, no associations with future use were found. Conclusion The results of this study support the assumption that body building competitions are a driver for androgen abuse. Most androgen abusers use androgens repeatedly. The factors that predict future androgen abuse may assist in harm reduction strategies that aim to minimize long-term health problems in androgen abusers. [ABSTRACT FROM AUTHOR]

Androgen is a kind of steroid hormone that plays a vital role in reproductive system and homeostasis of the body. Disrupted androgen balance serves as the causal contributor to a series of physiological disorders and even diseases. Flavonoids, as an extremely frequent family of natural polyphenols, exist widely in plants and foods and have received great attention when considering their inevitable consumption and estrogen-like effects. Mounting evidence illustrates that flavonoids have a propensity to interfere with androgen synthesis and metabolism, and also have a designated improvement effect on androgen disorders. Therefore, flavonoids were divided into six subclasses based on the structural feature in this paper, and the literature about their effects on androgens published in the past ten years was summarized. It could be concluded that flavonoids have the potential to regulate androgen levels and biological effects, mainly by interfering with the hypothalamic-pituitary-gonadal axis, androgen synthesis and metabolism, androgen binding with its receptors and membrane receptors, and antioxidant effects. The faced challenges about androgen regulation by flavonoids masterly include target mechanism exploration, individual heterogeneity, food matrixes interaction, and lack of clinical study. This review also provides a scientific basis for nutritional intervention using flavonoids to improve androgen disorder symptoms. [ABSTRACT FROM AUTHOR]

Objective: Sex steroid hormones are associatedwith the advancement ofmetabolic diseases such as dyslipidemia. This cross-sectional study aimed to investigate the relationship between dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone levels and the risk of dyslipidemia in people with type 2 diabetes mellitus. Materials and Methods: The analysis included 1,927 patients with type 2 diabetes mellitus. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone levels were determined using lipid chromatography-tandem mass spectrometry. Multivariable analyses were performed to investigate the association between the variables and dyslipidemia. Results: The multivariable-adjusted odds ratio (OR) and 95% confidence interval (CI) of dyslipidemia across DHEA tertiles were 0.39 and 0.24-0.64, respectively (p trend = 0.001). This relationship was still maintained when analyzed as a continuous variable (odds ratio, 0.96; 95% confidence interval, 0.92-0.99; P < 0.01). However, in males with type 2 diabetes mellitus, no significant correlations were found between rising levels of dehydroepiandrosterone sulfate, androstenedione, and total testosterone and the risk of dyslipidemia (all P > 0.05). Furthermore, there was no significant association between androgen precursors and total testosterone with regard to the risk of developing dyslipidemia (all P > 0.05). Conclusions: Serum dehydroepiandrosterone levels were substantially and adversely correlated with dyslipidemia in adult men with T2DM. These results indicated that dehydroepiandrosterone may have an essential role in the development of dyslipidemia. More prospective research is required to validate this link. [ABSTRACT FROM AUTHOR]

To establish a cutoff level of AMH which could help for the diagnosis of PCOS, to investigate the predictive value of AMH combined with androgens in Chinese women to diagnose PCOS. This is a prospective case control study, 550 women recruited (aged 20–40 years), in which 450 PCOS women recruited according to the Rotterdam criteria and 100 non-PCOS women in the control group were from the women for the pregnancy preparation examination. AMH were measured by the Elecsys AMH Plus immunoassay. Androgens and other sex hormone were measured. The validity of AMH toward the diagnosis of PCOS, or AMH combined with total testosterone, free testosterone, bioavailable testosterone and androstenedione was estimated by receiver operating characteristic (ROC)curves, and correlations between paired variables was estimated by Spearman's rank correlation coefficient. The cutoff value of AMH in Chinese reproductive-age women with PCOS is 4.64 ng/mL, AUC under the curve is 0.938, with 81.6% sensitivity, and 92.0% specificity. Total testosterone, free testosterone, bioactive testosterone, and androstenedione are significantly higher in women with PCOS of reproductive age than in controls. The combination of AMH and free testosterone resulted in a higher AUC of 94.8%, with higher sensitivity (86.1%) and excellent specificity (90.3%) for the prediction of PCOS. The Elecsys AMH Plus immunoassay, with a cutoff of 4.64 ng/mL, is a robust method for identifying PCOM to aid in PCOS diagnosis. The combination of AMH and free testosterone resulted in a higher AUC of 94.8% for the diagnose of PCOS. [ABSTRACT FROM AUTHOR]

The purpose of the study is to investigate the role of sex hormones, androgen receptors (ARs) and miRNA/CSF-1 in occurrence and recurrence of calcium oxalate (CaOx) renal urolithiasis. In this prospective study, 74 patients with CaOx stones; stone formers group (SFG) and 40 healthy subjects; control group were compared. SFG includes both de novo and recurrent cases. Steroid sex hormone plasma assay including testosterone, free testosterone, dihydrotestosterone, estradiol, and sex hormone binding globulin was analyzed. ARs, miRNA-185-5p and CSF-1 expression were compared between the groups. SFG showed significant higher ARs and miRNA-185-5p expression (3.7 ± 1.3, 1.8 ± 0.4, respectively) than control group (1 ± 0.08 and 1 ± 0.07, respectively) (p < 0.05). However, CSF-1 expression was significantly lower in stone formers than control group (0.4 ± 0.19 vs 1 ± 0.1, respectively) (p < 0.05). No differences were detected between de novo and recurrent SFG regarding sex hormones, AR, miRNA or CSF-1 expression. Our data suggest the important role of AR, miRNA and CSF-1 signaling in human nephrolithiasis pathogenesis. [ABSTRACT FROM AUTHOR]

In recent years, the effects of androgens on metabolic and body weight regulation systems and their underlying mechanisms have been gradually revealed in females. In women and experimental animals of reproductive age, androgen excess can adversely affect metabolic functioning, appetite, and body weight regulation. In addition, excess androgens can increase the risk of metabolic disorders, such as obesity, insulin resistance, and diabetes. These unfavorable effects of androgens are induced by alterations in the actions of hypothalamic appetite-regulatory factors, reductions in energy expenditure, insulin resistance in skeletal muscle, and β-cell dysfunction. Interestingly, these unfavorable effects of androgens on metabolic and body-weight regulation systems are neither observed nor evident in ovariectomized animals and post-menopausal women, indicating that the adverse effects of androgens might be dependent on the estrogen milieu. Recent findings may provide novel sex- and age-specific strategies for treating metabolic diseases. [ABSTRACT FROM AUTHOR]

To explore the prognostic value of red blood cell distribution width (RDW) in newly diagnosed aplastic anemia (AA) patients treated with cyclosporine A (CsA) plus androgen or CsA alone. We retrospectively analyzed the clinical outcome of 220 patients with AA. According to the baseline level of RDW before treatment, the patients were divided into the high-RDW group (RDW ≥ 15%) and the normal-RDW group (RDW < 15%). The median RDW of non-severe AA (NSAA) and severe AA (SAA) patients was 15.65% and 15.35%, respectively; this were significantly higher than that of very severe AA (VSAA) patients (13.35%). With median follow-up being 46 months, AA patients in the high-RDW group showed better 5-year OS and PFS than the normal-RDW group (93%: 75.3%; 74.3%: 61%). There was a higher ORR in the high-RDW group than the normal-RDW group (68.7%: 52.3%). The ORR of NSAA patients in the high-RDW group was better than that in the normal RDW group (75.8%: 60%). The 5-year OS of SAA/VSAA patients in the high-RDW group was significantly higher than the normal-RDW group (81.8%: 50.8%). This is the first documentation on the prognostic value of RDW in AA patients receiving CsA treatment with long-term follow-up, which had shown that high RDW at diagnosis was a better prognostic factor. [ABSTRACT FROM AUTHOR]