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Molecular and Cellular Endocrinology Apr 2021Adrenal steroidogenesis has, for decades, been depicted as three biosynthesis pathways -the mineralocorticoid, glucocorticoid and androgen pathways with aldosterone,... (Review)
Review
Adrenal steroidogenesis has, for decades, been depicted as three biosynthesis pathways -the mineralocorticoid, glucocorticoid and androgen pathways with aldosterone, cortisol and androstenedione as the respective end products. 11β-hydroxyandrostenedione was not included as an adrenal steroid despite the adrenal output of this steroid being twice that of androstenedione. While it is the end of the line for aldosterone and cortisol, as it is in these forms that they exhibit their most potent receptor activities prior to inactivation and conjugation, 11β-hydroxyandrostenedione is another matter entirely. The steroid, which is weakly androgenic, has its own designated pathway yielding 11-ketoandrostenedione, 11β-hydroxytestosterone and the potent androgens, 11-ketotestosterone and 11-ketodihydrotestosterone, primarily in the periphery. Over the last decade, these C11-oxy C steroids have once again come to the fore with the rising number of studies contradicting the generally accepted notion that testosterone and it's 5α-reduced product, dihydrotestosterone, are the principal potent androgens in humans. These C11-oxy androgens have been shown to contribute to the androgen milieu in adrenal disorders associated with androgen excess and in androgen dependant disease progression. In this review, we will highlight these overlooked C11-oxy C steroids as well as the C11-oxy C steroids and their contribution to congenital adrenal hyperplasia, polycystic ovarian syndrome and prostate cancer. The focus is on new findings over the past decade which are slowly but surely reshaping our current outlook on human sex steroid biology.
Topics: Androgens; Androstenedione; Animals; Disease; Humans; Steroids
PubMed: 33539964
DOI: 10.1016/j.mce.2021.111189 -
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 -
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 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 -
Physiological Research Nov 2018The androgens dehydroepiandrosterone sulfate, dehydro-epiandrosterone, androstenedione and testosterone are routinely assessed in women, and circulating levels of these... (Review)
Review
The androgens dehydroepiandrosterone sulfate, dehydro-epiandrosterone, androstenedione and testosterone are routinely assessed in women, and circulating levels of these androgens reflect their production. These androgens are measured in most laboratories using various immuno-analytical methods. Recently, however, androgen assays have begun to be performed using gas or liquid chromatography combined with mass spectrometry. To better understand the difficulties and issues of androgen laboratory diagnostics, it is important to assess each of the methods used, how and why they were introduced into practice, and their advantages, limits, historic milestones and current status. It is also necessary to understand how reference ranges are determined and specifics arising from the physiology of individual androgens. Here we present a summary and discussion of these issues.
Topics: Androgens; Androstenedione; Biomarkers; Chromatography, Liquid; Dehydroepiandrosterone; Endocrine System Diseases; Female; Humans; Mass Spectrometry; Reference Values; Testosterone
PubMed: 30484665
DOI: 10.33549/physiolres.933964 -
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 -
Methods in Molecular Biology (Clifton,... 2017The chapter describes the bioconversion of phytosterols to androstenedione (AD) with Mycobacterium spp. in shake flasks and fermenters, as well as LC-MS based methods...
The chapter describes the bioconversion of phytosterols to androstenedione (AD) with Mycobacterium spp. in shake flasks and fermenters, as well as LC-MS based methods for analysis of phytosterols and steroid products.Phytosterols are derived as a by-product of vegetable oil refining and of manufacture of wood pulp. Phytosterols contain the same four-ring nucleus as steroids, and may be converted to high-value steroids by removing the side chain at C17 and minor changes at other sites in the ring structure.Many bacteria, including Mycobacterium spp., are able to degrade phytosterols. Mutants of Mycobacterium spp. unable of ring cleavage can, when growing on phytosterols, accumulate the steroid intermediates androstenedione (AD) and/or androstadienedione (ADD).The practical challenge with microbial conversion of phytosterols to steroids is that both the substrate and the product are virtually insoluble in water. In addition, some steroids, notably ADD, may be toxic to cells.Two main strategies have been employed to overcome this challenge: the use of two-phase systems, and the addition of chemically modified cyclodextrins. The latter method is used here.Defined cultivation and bioconversion media for both shake flask and fermenter are given, as well as suggestions to minimize the practical problems caused by the water-insoluble phytosterol. Sampling, sample extraction, and quantification of substrates and products using LC-MS analysis are described.
Topics: Androstenedione; Chromatography, Liquid; Fermentation; Mycobacterium; Phytosterols; Plant Oils; Tandem Mass Spectrometry
PubMed: 28710629
DOI: 10.1007/978-1-4939-7183-1_13 -
Journal of Inorganic Biochemistry Jul 2018Cytochrome P450 19 (CYP19, aromatase) catalyzes the conversion of androgens to estrogens in a sequence of three reactions that each depend on NADPH and O. Aromatase is a...
Cytochrome P450 19 (CYP19, aromatase) catalyzes the conversion of androgens to estrogens in a sequence of three reactions that each depend on NADPH and O. Aromatase is a phylogenetically-ancient enzyme and its breadth of expression in other species has highlighted distinct physiological functions. In songbirds, estrogen production is required for programming the neural circuits controlling song and in the determination of sex in fish and reptiles. This work describes the expression, purification, and biophysical characterization of Aptenodytes forsteri (Emperor penguin, af) aromatase. Using human cytochrome P450 reductase as a redox partner, afCYP19 displayed similar substrate turnover and LC/MS/MS confirmed that afCYP19 catalyzes the transformations through the intermediates 19-hydroxy- and 19-oxo-androstenedione. Androstenedione and anastrozole had the highest affinity for the enzyme and were followed closely by 19-hydroxyandrostenedione and testosterone. The affinity of 19-oxo-androstenedione for afCYP19 was ten-fold lower. The time-dependent changes in the Soret bands observed in stopped-flow mixing experiments of the steroidal ligands and the inhibitor anastrozole with afCYP19 were best described by a two-step binding mechanism. In summary, these studies describe the first biophysical characterization of an avian aromatase that displays strikingly similar enzyme kinetics and ligand binding properties to the human enzyme and could serve as a convenient model system for studies of the enigmatic transformation of androgens to estrogens.
Topics: Anastrozole; Androstenedione; Aromatase; Cytochrome P-450 Enzyme System; Spectrum Analysis, Raman; Testosterone
PubMed: 29684698
DOI: 10.1016/j.jinorgbio.2018.04.002