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Journal of Molecular Endocrinology Mar 2021Steroid hormones, including glucocorticoids and androgens, exert a wide variety of effects in the body across almost all tissues. The steroid A-ring 5β-reductase...
Steroid hormones, including glucocorticoids and androgens, exert a wide variety of effects in the body across almost all tissues. The steroid A-ring 5β-reductase (AKR1D1) is expressed in human liver and testes, and three splice variants have been identified (AKR1D1-001, AKR1D1-002, AKR1D1-006). Amongst these, AKR1D1-002 is the best described; it modulates steroid hormone availability and catalyses an important step in bile acid biosynthesis. However, specific activity and expression of AKR1D1-001 and AKR1D1-006 are unknown. Expression of AKR1D1 variants were measured in human liver biopsies and hepatoma cell lines by qPCR. Their three-dimensional (3D) structures were predicted using in silico approaches. AKR1D1 variants were overexpressed in HEK293 cells, and successful overexpression confirmed by qPCR and Western blotting. Cells were treated with either cortisol, dexamethasone, prednisolone, testosterone or androstenedione, and steroid hormone clearance was measured by mass spectrometry. Glucocorticoid and androgen receptor activation were determined by luciferase reporter assays. AKR1D1-002 and AKR1D1-001 are expressed in human liver, and only AKR1D1-006 is expressed in human testes. Following overexpression, AKR1D1-001 and AKR1D1-006 protein levels were lower than AKR1D1-002, but significantly increased following treatment with the proteasomal inhibitor, MG-132. AKR1D1-002 efficiently metabolised glucocorticoids and androgens and decreased receptor activation. AKR1D1-001 and AKR1D1-006 poorly metabolised dexamethasone, but neither protein metabolised cortisol, prednisolone, testosterone or androstenedione. We have demonstrated the differential expression and role of AKR1D1 variants in steroid hormone clearance and receptor activation in vitro. AKR1D1-002 is the predominant functional protein in steroidogenic and metabolic tissues. In addition, AKR1D1-001 and AKR1D1-006 may have a limited, steroid-specific role in the regulation of dexamethasone action.
Topics: Alternative Splicing; Amino Acid Sequence; Androgens; Cell Line, Tumor; Female; Gene Expression Profiling; Gene Expression Regulation; Glucocorticoids; HEK293 Cells; Humans; Liver; Male; Mutant Proteins; Oxidoreductases; Proteasome Endopeptidase Complex; RNA, Messenger; Testis
PubMed: 33502336
DOI: 10.1530/JME-20-0160 -
Clinical Endocrinology Mar 2023Some 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...
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.
Topics: Female; Humans; Androgens; Polycystic Ovary Syndrome; Androstenedione; Metabolic Syndrome; Luteinizing Hormone; Cluster Analysis; Testosterone
PubMed: 36372554
DOI: 10.1111/cen.14847 -
The Journal of Steroid Biochemistry and... Feb 2023Both excessive ovarian production of AMH and androgen are important features of polycystic ovary syndrome (PCOS). Present study aimed to explore the direct effect of AMH...
Both excessive ovarian production of AMH and androgen are important features of polycystic ovary syndrome (PCOS). Present study aimed to explore the direct effect of AMH on androgen production in human theca cells. Primary cultured human theca cells were treated with AMH, an ALK2 (the BMP type 1 receptor) inhibitor and an ALK5 (the TGFβ type 1 receptor) inhibitor. AMH significantly suppresses the expression of the androgen synthesis-related enzyme CYP17A1 and reduces the production of androstenedione and testosterone in normal human theca cells and PCOS theca cells. Inhibitors of ALK2/3 and ALK5 antagonize the effect of AMH on the expression of CYP17A1. Although both ALK5 and ALK2 interact with AMHR2 in the presence of AMH, AMH activated neither TGFβR-Smads (Smad 2/3) nor BMPR-Smads (Smad 1/5/8). Our data suggested that AMH suppresses androgen synthesis-related enzyme CYP17A1 expression and inhibits androgen production in human theca cells, which process may be mediated by ALK2 and ALK5.
Topics: Female; Humans; Androgens; Polycystic Ovary Syndrome; Theca Cells; Anti-Mullerian Hormone; Androstenedione
PubMed: 36356855
DOI: 10.1016/j.jsbmb.2022.106216 -
The Science of the Total Environment Mar 2024The aim of this study was to investigate the effect of solid fuel use on serum sex hormone levels. Furthermore, the effects of improved kitchen ventilation and duration...
PURPOSE
The aim of this study was to investigate the effect of solid fuel use on serum sex hormone levels. Furthermore, the effects of improved kitchen ventilation and duration of cooking time on the relationship between solid fuel use and serum sex hormone levels will be further explored.
METHODS
In this cross-sectional study, 5386 individuals were recruited. Gender and menopausal status modified associations between solid fuel type and serum sex hormone levels was investigated through generalized linear models and further analyzed by improving kitchen ventilation and length of cooking time on the relationship between solid fuel use and serum sex hormone levels. To identify the causal association, mendelian randomization of two-sample was performed.
RESULTS
In observational analyses, for ln-17-hydroxyprogesterone, ln-testosterone, and ln-androstenedione among premenopausal women, the estimated β and 95 % CI of sex hormone levels for the effect of solid fuel users was -0.337 (-0.657, -0.017), -0.233 (-0.47, 0.005), and - 0.240 (-0.452, -0.028) respectively, and - 0.150 (-0.296, -0.004) in ln-progesterone among postmenopausal women. It was found that combining solid fuels with long cooking periods or no ventilation more effectively reduced testosterone and androstenedione in premenopausal women. We further found the adverse effects of using solid fuel on progesterone, testosterone, and androstenedione levels were enhanced with the increases of PM, PM, PM, and NO. Corresponding genetic, the causal risk effect of solid fuel were - 0.056 (-0.513, 0.4) and 0.026 (-3.495, 3.547) for testosterone levels and sex hormone binding globulin, respectively.
CONCLUSION
Using gas or solid fuel was negatively related to sex hormone levels. A combination of using solid fuels, cooking for a long time, or cooking without ventilation had a stronger effect on sex hormone levels. However, genetic evidence did not support causality for the associations. WHAT IS ALREADY KNOWN ON THIS TOPIC?: The mechanisms underlying these associations household air pollution (HAP) from incomplete combustion of such fuels and occurrence of chronic diseases remained obscure. Recent years, extensive evidences from animal as well as human researches have suggested that progestogen and androgen hormones are involved in the development of diabetes, hypertension, and cardiovascular disease, which indicated that changes in serum progestogen and androgen hormones levels might play a role in these pathological mechanisms. However, limited evidence exists examining the effect of HAP from solid fuel use on serum sex hormone levels.
Topics: Humans; Female; Air Pollution, Indoor; Cross-Sectional Studies; Progesterone; Progestins; Androgens; Androstenedione; Mendelian Randomization Analysis; Cooking; Testosterone; China
PubMed: 38316302
DOI: 10.1016/j.scitotenv.2024.170621 -
Hormone and Metabolic Research =... May 2022Estrogens and androgens are important regulators of sexual development and physiological processes in men and women, acting on numerous organs throughout the body....
Estrogens and androgens are important regulators of sexual development and physiological processes in men and women, acting on numerous organs throughout the body. Moreover, they can contribute to a variety of pathologies, including osteoporosis, cancer, and cardiovascular and neurologic diseases. Analysis of estrogens and androgens in biological samples has been commonly performed using immunoassays for many years. However, these assays are suboptimal, as there is cross-reactivity with similar analytes, and they have moderate specificity and sensitivity. Thus, there is a clinical need to develop highly sensitive and specific methods for the accurate measurement of estrogen and androgen concentrations. Herein, we describe the development of three liquid chromatography coupled tandem mass spectrometry-based methods that incorporate the use of a Triple Quadrupole Mass Spectrometer for quantitative measurement of endogenous concentrations of various steroid hormones in human serum samples: (1) the simultaneous measurement of testosterone, androstenedione, and cortisol, (2) dehydroepiandrosterone (DHEA), and (3) 17β-estradiol (E). The use of derivatizing reagents, Girard's reagent P and dansyl chloride, allowed for significant gains in sensitivity in the analysis of DHEA and E2, respectively, relative to the underivatized analyte. These procedures proved efficient and adequately sensitive for steroid hormone analysis in extracted patient sera samples from older men and postmenopausal women, providing reliable data down to low nanogram/ml and sub-nanogram/ml levels. Moreover, utilizing the combination of highly specific mass transitions associated with these analytes and their respective internal deuterated standards provided a high degree of specificity to the identity of these hormones.
Topics: Aged; Androgens; Androstenedione; Chromatography, Liquid; Dehydroepiandrosterone; Estrogens; Female; Humans; Male; Steroids; Tandem Mass Spectrometry; Testosterone
PubMed: 35352333
DOI: 10.1055/a-1768-0709 -
Gynecological Endocrinology : the... Dec 2023To 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...
OBJECTIVE
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.
MATERIALS AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
Topics: Humans; Female; Polycystic Ovary Syndrome; Androgens; Anti-Mullerian Hormone; Androstenedione; Case-Control Studies; East Asian People; Testosterone; Peptide Hormones
PubMed: 37141919
DOI: 10.1080/09513590.2023.2206927 -
International Journal of Developmental... Feb 2023Children with attention-deficit/hyperactivity disorder (ADHD) might have similar problems as in autism spectrum disorder (ASD) and show impairment in social behaviour....
The association between autistic traits and serum testosterone, oxytocin, and androstenedione levels in prepubertal male drug naive children with attention-deficit/hyperactivity disorder.
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.
Topics: Pregnancy; Female; Humans; Male; Child; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Androstenedione; Oxytocin; Autistic Disorder; Testosterone
PubMed: 36398591
DOI: 10.1002/jdn.10241 -
Acta Clinica Croatica Nov 2019Prostate cancer (PC) is known as an androgen-dependent tumor with testosterone as its natural growth factor, its action is mediated by the androgen receptor (AR)... (Review)
Review
Prostate cancer (PC) is known as an androgen-dependent tumor with testosterone as its natural growth factor, its action is mediated by the androgen receptor (AR) important for the biology and progression of PC. During aging a progressive decline in testosterone levels begins, caused by disability of aged Leydig cells to produce testosterone in response to luteinizing hormone. Surgical treatment of PC can influence the hypothalamic-pituitary-gonadal axis with less impact on it compared to patients treated with radiation. Patients with pre-operative low baseline testosterone level had mean Gleason score higher and AR expression was higher; significantly lower testosterone levels were recorded in patients with lymph node metastases. But some data are conflicting, and some results are opposite to those mentioned before. These data show that there is no significant association between all sex hormone in men and lethal PC or total mortality. In patients with metastatic PC, results showed that elevation of baseline androstenedione levels was predictive of prostate-specific antigen (PSA) response; higher baseline androstenedione levels were associated with an improved overall survival. In these patients, the relationship between serum testosterone and PC prognosis varies in different clinical settings and according to androgen deprivation therapy administration.
PubMed: 34975200
DOI: 10.20471/acc.2019.58.s2.10 -
Hormones (Athens, Greece) Dec 2022To date, no meta-analysis has been carried out to collect evidence from randomized placebo-controlled trials (RCTs) for the purpose of comprehensively summarizing the... (Meta-Analysis)
Meta-Analysis Review
The effect of androstenedione supplementation on testosterone, estradiol, body composition, and lipid profile: a systematic review and meta-analysis of randomized controlled trials.
OBJECTIVE
To date, no meta-analysis has been carried out to collect evidence from randomized placebo-controlled trials (RCTs) for the purpose of comprehensively summarizing the effect of androstenedione supplementation. Therefore, the aim of this research was to perform a systematic review and meta-analysis of all RCTs that explored the effect of androstenedione supplementation on individual hormonal, lipid, and anthropometric indices.
METHODS
We searched five databases (Web of Science, SCOPUS, Embase, PubMed/MEDLINE, and Google Scholar) using a combination of medical subject headings (MeSH) and non-MeSH terms. Using the random-effects model, we summarized the outcomes as weighted mean difference (WMD) with 95% confidence interval (CI).
RESULTS
Eight eligible articles were included in the meta-analysis. The pooled effect sizes suggested a significant effect of androstenedione supplementation on serum estradiol concentrations (WMD: 20.82 ng/ml, 95% CI: 7.25 to 34.38, p = 0.003), triglycerides (TG, WMD: -0.19 mg/dl, 95% CI: - 0.96, 0.57, p = 0.000), and high-density lipoprotein (HDL)-cholesterol (WMD: - 0.13 mg/dl, 95% CI: - 0.23 to - 0.03, p = 0.009); however, it had no effect on testosterone (WMD: 0.098 ng/ml, 95% CI: - 0.499 to 0.696, p = 0.748), body weight (WMD: 0.579 kg, 95% CI: - 4.02 to 5.17, p = 0.805), body mass index (BMI, WMD: - 0.73 kg/m, 95% CI: - 2.98, 1.50, p = 0.519), low-density lipoprotein (LDL)-cholesterol (WMD: - 0.074 mg/dl, 95% CI: - 0.37 to 0.22, p = 0.622), and total cholesterol (TC, WMD: - 0.15 mg/dl, 95% CI: - 0.49, 0.17, p = 0.198).
CONCLUSION
These findings indicate that androstenedione supplementation can lower TG and HDL-cholesterol and increase estradiol concentrations.
Topics: Humans; Androstenedione; Lipids; Testosterone; Estradiol; Dietary Supplements; Randomized Controlled Trials as Topic; Cholesterol, HDL; Cholesterol; Testosterone Congeners; Body Composition; Androgens
PubMed: 35841524
DOI: 10.1007/s42000-022-00385-8 -
The Journal of Clinical Endocrinology... Nov 2020Sex hormones have been linked with presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults, but it is unknown if they affect severity of pediatric...
CONTEXT
Sex hormones have been linked with presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults, but it is unknown if they affect severity of pediatric NAFLD.
OBJECTIVE
To examine associations of circulating SHBG, estrogens, and androgens with key histologic features of pediatric, biopsy-confirmed NAFLD.
DESIGN
Baseline assessment of longitudinal cohorts and randomized clinical trials.
SETTING
Nonalcoholic Steatohepatitis Clinical Research Network.
PATIENTS
Children and adolescents ≤18 years with liver biopsy-confirmed NAFLD in the United States.
MAIN OUTCOME MEASURES
We assayed SHBG, estrone, estradiol, dehydroepiandrosterone (DHEAS), androstenedione, and testosterone in relation to grade/stage of steatosis, portal inflammation, hepatic ballooning, fibrosis, and nonalcoholic steatohepatitis (NASH) severity using linear regression.
RESULTS
Mean age of 573 children at the time of biopsy was 13.1 years (SD 2.8). Lower SHBG was inversely associated with steatosis severity in boys and girls (P = 0.001), and with portal inflammation in girls only (P for sex interaction <0.001). Higher testosterone was related to improved features of steatosis and fibrosis (P for sex interaction = 0.003 and 0.01, respectively) in boys, but detrimental in girls. In boys and girls, higher estrone, estradiol, and testosterone were associated with lower portal inflammation grade; higher estradiol was positively associated with hepatic ballooning severity; DHEAS was inversely associated with hepatic ballooning and NASH severity (all P < 0.05). Androstenedione was not associated with NAFLD features.
CONCLUSIONS
Largely consistent with findings in adults, sex hormones are associated with distinct histologic features of NAFLD in children and adolescents. These hormone levels relate to differences with gender and pubertal change.
Topics: Adolescent; Age Factors; Androgens; Child; Cross-Sectional Studies; Estrogens; Female; Humans; Liver; Male; Non-alcoholic Fatty Liver Disease; Severity of Illness Index; Sex Hormone-Binding Globulin
PubMed: 32840311
DOI: 10.1210/clinem/dgaa574