DOCSLIB.ORG

Heat-Map Visualization of Gas Chromatography-Mass Spectrometry Based Quantitative Signatures on Steroid Metabolism

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Heat-Map Visualization of Gas Chromatography-Mass Spectrometry Based Quantitative Signatures on Steroid Metabolism Heat-Map Visualization of Gas Chromatography-Mass Spectrometry Based Quantitative Signatures on Steroid Metabolism Ju-Yeon Moon,a,b Hyun-Jin Jung,a,b Myeong Hee Moon,b Bong Chul Chung,a and Man Ho Choia a Life Sciences Division, Korea Institute of Science and Technology, Seoul, Korea b Department of Chemistry, Yonsei University, Seoul, Korea Abnormalities in steroid hormones are responsible for the development and prevention of endocrine diseases. Due to their biochemical roles in endocrine system, the quantitative evaluation of steroid hormones is needed to elucidate altered expression of steroids. Gas chromatographic-mass spectrometric (GC-MS) profiling of 70 urinary steroids, containing 22 androgens, 18 estrogens, 15 corticoids, 13 progestins, and 2 sterols, were validated and its quantitative data were visualized using hierarchically clustered heat maps to allow “steroid signatures”. The devised method provided a good linearity (r2 Ͼ 0.994) with the exception of cholesterol (r2 ϭ 0.983). Precisions (% CV) and accuracies (% bias) ranged from 0.9% to 11.2% and from 92% to 119%, respectively, for most steroids tested. To evaluate metabolic changes, this method was applied to urine samples obtained from 59 patients with benign prostatic hyperplasia (BPH) versus 41 healthy male subjects. Altered concentrations of urinary steroids found and heat maps produced during this 70-compound study showed also differences between the ratios of steroid precursors and their metabolites (representing enzyme activity). Heat maps showed that oxidoreductases clustered (5␣-reductase, 3␣-HSD, 3␤-HSD, and 17␤-HSD, except for 20␣-HSD). These results support that data transformation is valid, since 5␣-reductase is a marker of BPH and 17␤-HSD is positively expressed in prostate cells. Multitargeted profiling analysis of steroids generated quantitative results that help to explain correlations between enzyme activities. The data transformation and visualization described may to be found in the integration with the mining biomarkers of hormone-dependent diseases. (J Am Soc Mass Spectrom 2009, 20, 1626–1637) © 2009 American Society for Mass Spectrometry ass spectrometry based metabolite profiling mone, two major types of enzymes are involved, cyto- reveals the metabolic states of biological sys- chrome P450 and steroid oxidoreductase. Abnormalities of Mtems and provides comprehensive insights by these enzymes often lead to hormonal imbalances that allowing comparisons between many metabolites si- have serious consequences, and which are responsible multaneously present in cells, tissues, or organisms [1, for the development of hormone-dependent diseases 2]. This technique promotes the establishment of rela- (see Supplementary Table 1, which can be found in the tionships between phenotypes and metabolisms by electronic version of this article). For example, concen- providing descriptions of the distributions of metabo- trations of corticoids and their metabolic ratios provide lites and their biological functions. In fact, quantitative diagnostic evidence of apparent mineralocorticoid ex- analyses of sets of metabolites in biochemical pathways cesses caused by 11␤-HSD deficiency [8] and congenital have been used for physiological monitoring, toxicolog- adrenal hyperplasia, which are caused by deficiencies ical evaluations, and clinical diagnosis [3–6]. of enzymes like hydroxylase (at C-11, 17, and 21) or Many naturally occurring steroids with similar 3␤-HSD [9]. In addition, enhanced androgen activity chemical structures could yield biological information generated by the conversion of testosterone to dihy- [7]. Endogenous steroids are divided into five groups, drotestosterone (DHT) by 5␣-reductase was utilized to namely, androgens, estrogens, corticoids, progestins, allow early therapeutic intervention in young men [10]. and sterols, which are generally synthesized from cho- Enzyme activity profiles can be used to describe the lesterol in the adrenal cortex, ovaries, and testes functional diversities of biological systems, which are (Scheme 1). In biosynthetic pathways of steroid hor- driven by genetic diversity. Although enzyme activities have been monitored by following reactions between targeted enzymes and substrate molecules, over- Address reprint requests to Dr. M. H. Choi, Life Sciences Division, Korea Institute of Science and Technology, 39-1 Hawolkok-dong, Seongbuk-ku, estimations by radioimmunoassay (RIA) and enzyme Seoul 136-791, Korea. E-mail: [email protected] immunoassay (EIA), because of cross reacting antibod- Published online May 5, 2009 © 2009 American Society for Mass Spectrometry. Published by Elsevier Inc. Received February 7, 2009 1044-0305/09/$32.00 Revised April 25, 2009 doi:10.1016/j.jasms.2009.04.020 Accepted April 28, 2009 J Am Soc Mass Spectrom 2009, 20, 1626–1637 QUANTITATIVE STEROID SIGNATURES BY GC-MS 1627 OH Progestins, Sterols OH Androgens HO H HO βββαβααααα-diol 24S-OH-Chol 17α-HSD O O OH O 3α-HSD 17β-HSD HO O OH HO β 5 -reductase O HO HO Chol H H H HO βββαβαααββββ 16ααα-OH-DHEA 5βββ−β−−−dione Etio -diol O O 20,22-desmolase H O 16α-hydroxylase O O 20ααα-OH-prog ααα O 5 -DHP O OH β OH α 3 -HSD 20α-HSD 17α-hydroxylase 17,20-lyase 17β-HSD 5 -reductase HO O 5α-reductase O HO H HO HO HO HO H 20α-HSD 3α-HSD H 5ααα−α−−−dione Epi-An Preg 17ααα-OH-Preg DHEA A-diol 17β-HSD β α 3β-HSD 3β-HSD 3 -HSD 3β-HSD 3 -HSD HO HO O O O O OH OH OH O H H α P-diol P-one HO 11β-hydroxylase 17α-hydroxylase OH 17,20-lyase 17β-HSD 5α-reductase 3 -HSD 17β-HSD O O O HO HO H H H O O O ααααααββββ 11βββ-OH-Prog Prog 17ααα-OH-Prog A-dione T DHT -diol An 17α-HSD 3β-HSD OH OH 21-hydroxylase 21-hydroxylase aromatase O O O aromatase O HO OH OH OH H OH Epi-T αααβαβββββ-diol 5β-reductase β HO 3 -HSD O O O OH H 17β-HSD THDOC 11-DeoxyB 11-DeoxyF 11β-hydroxylase 11β-hydroxylase 11β-hydroxylase HO HO O O O O E1 17βββ-E2 OH HO HO OH HO HO OH OH OH 2-hydroxylase 4-hydroxylase 16-hydroxylase O O O OH OH 5α-reductase β β O O O 21 -hydroxylaseO OH 17 -HSD OH O H allo-DHB B Cortisol (F) 21-DeoxyF HO β α HO HO HO HO HO 11β-HSD 5 - / 5 -reductase 11β-HSD 3β-HSD 2-OH-E1 OH 4-OH-E1 16ααα-OH-E1 Estriol 16-keto-E2 O O O OH OH OH OH methyltransferase methyltransferase OH O HO OH O OH OH OH OH O OH O HO H CO HO HO O HO O 3 H 17-Epi-E3 16-Epi-E3 11-DehydroB THF / allo-THF, allo-DHF Cortisone (E) HO HO HO HO OH OCH 5β- / 5α-reductase 2-OH-E2 2-MeO-E1 4-OH-E2 3 4-MeO-E1 3β-HSD O OH methyltransferase OH methyltransferase OH O OH H3CO HO HO Corticoids H HO THE 2-MeO-E2 OCH3 4-MeO-E2 Estrogens Scheme 1. General scheme for steroid metabolism in man. See Supplementary Table 1 for the full names of steroid hormones. ies, limit the applicability of these assays, and further- groups have used GC-MS based steroid analysis for more, only single enzymes can be estimated at a time mining biomarkers, technical improvements that more [11–14]. In contrast to conventional enzyme assays, gas effectively allow the visualization of steroid metabolites chromatography-mass spectrometry (GC-MS)-based are required [26]. However, no studies have reported techniques have better quantitative reproducibility [15, MS-based steroid signatures generated by HCA to date. 16]. For these reasons, GC-MS profiling has been widely Here, we introduce the GC-MS quantitative profiling used for steroid analysis [17–20], and offers the basis for of 70 urinary steroids, including 22 androgens, 18 techniques that can be applied to large-scale clinical estrogens, 15 corticoids, 13 progestins, and 2 sterols, studies [21]. generated by HCA to evaluate metabolic changes and Clinical significances are generally expressed in ta- enzyme reactions in steroid analysis. The aim of this bles or bar graphs that show changes in analytes across study was to validate a GC-MS profiling method and a groups of interest. For studies involving few com- method that allows the quantitative visualization of pounds, these visualizations are enough to differentiate multiple urinary steroids. To visualize quantitative re- classes showing metabolic differences. However, quan- sults, a microarray map (a type of heat map) was titative datasets of multiple compounds are much more designed to present the urine sample results of 59 difficult to represent visually. Statistical clustering of- fers one such approach, and has been utilized to sup- patients with benign prostatic hyperplasia (BPH) and 41 port genomic and proteomic studies [22–24]. In a simi- healthy male subjects; BPH was chosen because steroid lar fashion, quantitative results obtained by metabolite metabolism is known to play a role in the progress of profiling can be directly compared between samples prostate diseases [27–29]. This study focused on illus- and utilized as metabolic biomarkers. In recent, MS- trating the usefulness of steroid signatures for explain- based quantitative data generated by hierarchical clus- ing both the concentrations of individual steroids and tering analysis (HCA) has been subjected to pattern the activities of enzymes correlated global steroidogen- analysis for metabolite profiling [2, 25]. The concept of esis in BPH, and suggest that enzyme activity profiling “metabolite signature” is a result of this process, and may be a useful diagnostic tool and provide a means of such signatures are useful for measuring and visualiz- identifying mining biomarkers in hormone-dependent ing the relative analyte concentrations. Although many diseases. 1628 MOON ET AL. J Am Soc Mass Spectrom 2009, 20, 1626–1637 Experimental tant biopsy and had either a suspicious finding by digitorectal examination or an elevated level of serum Chemicals and Materials prostate-specific antigen (PSA).
Load more

Recommended publications
  • Effect of Isopregnanolone on Rapid Tolerance to the Anxiolytic Effect of Ethanol Influência Da Isopregnenolona Na Tolerância R
    18 ORIGINAL ARTICLE Effect of isopregnanolone on rapid tolerance to the anxiolytic effect of ethanol Influência da isopregnenolona na tolerância rápida ao efeito ansiolítico do etanol Thaize Debatin,1 Adriana Dias Elpo Barbosa2 Original version accepted in Portuguese Abstract Objective: It has been shown that neurosteroids can either block or stimulate the development of chronic and rapid tolerance to the incoordination and hypothermia caused by ethanol consumption. The aim of the present study was to investigate the influence of isopregnanolone on the development of rapid tolerance to the anxiolytic effect of ethanol in mice. Method: Male Swiss mice were pretreated with isopregnanolone (0.05, 0.10 or 0.20 mg/kg) 30 min before administration of ethanol (1.5 g/kg). Twenty-four hours later, all animals we tested using the plus-maze apparatus. The first experiment defined the doses of ethanol that did or did not induce rapid tolerance to the anxiolytic effect of ethanol. In the second, the influence of pretreatment of mice with isopregnanolone (0.05, 0.10 or 0.20 mg/kg) on rapid tolerance to ethanol (1.5 g/kg) was studied. Conclusions: The results show that pretreatment with isopregnanolone interfered with the development of rapid tolerance to the anxiolytic effect of ethanol. Keywords: Ethanol; Drug tolerance; Anti-anxiety agents; Mice; Alcoholism Resumo Objetivo: Estudos prévios têm mostrado que os neuroesteróides podem bloquear ou estimular o desenvolvimento da tolerância rápida e crônica aos efeitos de incoordenação e hipotermia produzidos pelo etanol. O objetivo do presente estudo foi investigar a influência da isopregnenolona sobre o desenvolvimento da tolerância rápida ao efeito ansiolítico do etanol em camundongos.
    [Show full text]
  • Epipregnanolone and a Novel Synthetic Neuroactive Steroid Reduce Reduce Alcohol Self- Administration in Rats
    University of Texas at El Paso From the SelectedWorks of Laura Elena O'Dell 2005 Epipregnanolone and a novel synthetic neuroactive steroid reduce reduce alcohol self- administration in rats. Laura O'Dell, University of Texas at El Paso Available at: https://works.bepress.com/laura_odell/23/ Pharmacology, Biochemistry and Behavior 81 (2005) 543 – 550 www.elsevier.com/locate/pharmbiochembeh Epipregnanolone and a novel synthetic neuroactive steroid reduce alcohol self-administration in rats L.E. O’Della,b, R.H. Purdya,c,d, D.F. Coveye, H.N. Richardsona, M. Robertoa, G.F. Kooba,* aDepartment of Neuropharmacology, The Scripps Research Institute, CVN-7, 10550 North Torrey Pines Rd., La Jolla, CA, 92037, USA bDepartment of Psychology, The University of Texas at El Paso, El Paso, TX, USA cDepartment of Psychiatry, University of California San Diego, La Jolla, CA, USA dDepartment of Veterans Affairs Medical Center and Veterans Medical Research Foundation, San Diego, CA, USA eDepartment of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO, USA Received 6 September 2004; received in revised form 14 March 2005; accepted 31 March 2005 Available online 9 June 2005 Abstract This study was designed to compare the effects of several neuroactive steroids with varying patterns of modulation of g-aminobutyric acid (GABA)A and NMDA receptors on operant self-administration of ethanol or water. Once stable responding for 10% (w/v) ethanol was achieved, separate test sessions were conducted in which male Wistar rats were allowed to self-administer ethanol or water following pre-treatment with vehicle or one of the following neuroactive steroids: (3h,5h)-3-hydroxypregnan-20-one (epipregnanolone; 5, 10, 20 mg/kg; n =12), (3a,5h)-20-oxo-pregnane-3-carboxylic acid (PCA; 10, 20, 30 mg/kg; n =10), (3a,5h)-3-hydroxypregnan-20-one hemisuccinate (pregnanolone hemisuccinate; 5, 10, 20 mg/kg; n =12) and (3a,5a)-3-hydroxyandrostan-17-one hemisuccinate (androsterone hemisuccinate; 5, 10, 20 mg/kg; n =11).
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Epipregnanolone Item No. 34295 CAS Registry No.: 128-21-2 O Formal Name: (5β)-3β-hydroxy-pregnan-20-one Synonyms: NSC 21450, 5β-Pregnan-3β-ol-20-one MF: C21H34O2 FW: 318.5 H Purity: ≥98% H H Supplied as: A solid Storage: -20°C HO Stability: ≥2 years H Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Epipregnanolone is supplied as a solid. A stock solution may be made by dissolving the epipregnanolone in the solvent of choice, which should be purged with an inert gas. Epipregnanolone is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF). The solubility of epipregnanolone in ethanol is approximately 5 mg/ml and approximately 30 mg/ml in DMSO and DMF. Description Epipregnanolone is a neurosteroid and an active metabolite of the steroid hormone pregnenolone (Item No. 19864).1 It is enzymatically formed from prognenolone via the intermediates progesterone (Item No. 15876) and 5β-dihydroprogesterone in the placenta.2 Epipregnanolone inhibits spontaneous 3 contractions in myometrial strips isolated from at-term pregnant women (IC50 = 156 µM). Epipregnanolone (10 and 20 mg/kg) decreases operant alcohol self-administration in rats.4 Maternal plasma levels of epipregnanolone increase over the duration of pregnancy. References 1. Prince, R.J. and Simmonds, M.A. 5β-pregnan-3β-ol-20-one, a specific antagonist at the neurosteroid site of the GABAA receptor-complex. Neurosci. Lett. 135(2), 273-275 (1992). 2. Hill, M., Cibula, D., Havlíkova, H., et al. Circulating levels of pregnanolone isomers during the third trimester of human pregnancy.
    [Show full text]
  • Alteration of the Steroidogenesis in Boys with Autism Spectrum Disorders
    Janšáková et al. Translational Psychiatry (2020) 10:340 https://doi.org/10.1038/s41398-020-01017-8 Translational Psychiatry ARTICLE Open Access Alteration of the steroidogenesis in boys with autism spectrum disorders Katarína Janšáková 1, Martin Hill 2,DianaČelárová1,HanaCelušáková1,GabrielaRepiská1,MarieBičíková2, Ludmila Máčová2 and Daniela Ostatníková1 Abstract The etiology of autism spectrum disorders (ASD) remains unknown, but associations between prenatal hormonal changes and ASD risk were found. The consequences of these changes on the steroidogenesis during a postnatal development are not yet well known. The aim of this study was to analyze the steroid metabolic pathway in prepubertal ASD and neurotypical boys. Plasma samples were collected from 62 prepubertal ASD boys and 24 age and sex-matched controls (CTRL). Eighty-two biomarkers of steroidogenesis were detected using gas-chromatography tandem-mass spectrometry. We observed changes across the whole alternative backdoor pathway of androgens synthesis toward lower level in ASD group. Our data indicate suppressed production of pregnenolone sulfate at augmented activities of CYP17A1 and SULT2A1 and reduced HSD3B2 activity in ASD group which is partly consistent with the results reported in older children, in whom the adrenal zona reticularis significantly influences the steroid levels. Furthermore, we detected the suppressed activity of CYP7B1 enzyme readily metabolizing the precursors of sex hormones on one hand but increased anti-glucocorticoid effect of 7α-hydroxy-DHEA via competition with cortisone for HSD11B1 on the other. The multivariate model found significant correlations between behavioral indices and circulating steroids. From dependent variables, the best correlation was found for the social interaction (28.5%). Observed changes give a space for their utilization as biomarkers while reveal the etiopathogenesis of ASD.
    [Show full text]
  • Calcium-Engaged Mechanisms of Nongenomic Action of Neurosteroids
    Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Rebas, Elzbieta, Tomasz Radzik, Tomasz Boczek, and Ludmila Zylinska. 2017. “Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids.” Current Neuropharmacology 15 (8): 1174-1191. doi:10.2174/1570159X15666170329091935. http:// dx.doi.org/10.2174/1570159X15666170329091935. Published Version doi:10.2174/1570159X15666170329091935 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160234 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA 1174 Send Orders for Reprints to [email protected] Current Neuropharmacology, 2017, 15, 1174-1191 REVIEW ARTICLE ISSN: 1570-159X eISSN: 1875-6190 Impact Factor: 3.365 Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids BENTHAM SCIENCE Elzbieta Rebas1, Tomasz Radzik1, Tomasz Boczek1,2 and Ludmila Zylinska1,* 1Department of Molecular Neurochemistry, Faculty of Health Sciences, Medical University of Lodz, Poland; 2Boston Children’s Hospital and Harvard Medical School, Boston, USA Abstract: Background: Neurosteroids form the unique group because of their dual mechanism of action. Classically, they bind to specific intracellular and/or nuclear receptors, and next modify genes transcription. Another mode of action is linked with the rapid effects induced at the plasma membrane level within seconds or milliseconds. The key molecules in neurotransmission are calcium ions, thereby we focus on the recent advances in understanding of complex signaling crosstalk between action of neurosteroids and calcium-engaged events.
    [Show full text]
  • Comparison of Strategies for the Determination of Sterol Sulfates Via GC-MS Leading to a Novel Deconjugation-Derivatization Protocol
    molecules Article Comparison of Strategies for the Determination of Sterol Sulfates via GC-MS Leading to a Novel Deconjugation-Derivatization Protocol Julia Junker 1 , Isabelle Chong 1, Frits Kamp 2, Harald Steiner 2,3, Martin Giera 4 , Christoph Müller 1 and Franz Bracher 1,* 1 Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians University Munich, Butenandtstraße 5-13, 81377 Munich, Germany 2 Biomedical Center (BMC), Metabolic Biochemistry, Ludwig-Maximilians University Munich, Feodor-Lynen-Strasse 17, 81377 Munich, Germany 3 German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Strasse 17, 81377 Munich, Germany 4 Leiden University Medical Center, Center for Proteomics and Metabolomics, Albinusdreef 2, 2300 RC Leiden, The Netherlands * Correspondence: [email protected]; Tel.: +49-892-1807-7301 Academic Editor: Yasunori Yaoita Received: 27 April 2019; Accepted: 21 June 2019; Published: 26 June 2019 Abstract: Sulfoconjugates of sterols play important roles as neurosteroids, neurotransmitters, and ion channel ligands in health and disease. In most cases, sterol conjugate analysis is performed with liquid chromatography-mass spectrometry. This is a valuable tool for routine analytics with the advantage of direct sterol sulfates analysis without previous cleavage and/or derivatization. The complementary technique gas chromatography-mass spectrometry (GC-MS) is a preeminent discovery tool in the field of sterolomics, but the analysis of sterol sulfates is hampered by mandatory deconjugation and derivatization. Despite the difficulties in sample workup, GC-MS is an indispensable tool for untargeted analysis and steroid profiling. There are no general sample preparation protocols for sterol sulfate analysis using GC-MS. In this study we present a reinvestigation and evaluation of different deconjugation and derivatization procedures with a set of representative sterol sulfates.
    [Show full text]
  • Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research P
    Journal of Neuroendocrinology, 2016, 28, 10.1111/jne.12351 REVIEW ARTICLE © 2015 British Society for Neuroendocrinology Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research P. Porcu*, A. M. Barron†, C. A. Frye‡§, A. A. Walf‡§¶, S.-Y. Yang**, X.-Y. He**, A. L. Morrow††, G. C. Panzica‡‡ and R. C. Melcangi§§ *Neuroscience Institute, National Research Council of Italy (CNR), Cagliari, Italy. †Molecular Imaging Center, National Institute of Radiological Sciences, Anagawa, Inage-ku, Chiba, Japan. ‡IDEA Network of Biomedical Research Excellence and Department of Chemistry and Biochemistry, University of Alaska–Fairbanks, Fairbanks, AK, USA. §Department of Psychology, The University at Albany, Albany, NY, USA. ¶Department of Cognitive Science, Rensselaer Polytechnic Institute, Troy, NY, USA. **Department of Developmental Biochemistry, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA. ††Departments of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA. ‡‡Department of Neuroscience, University of Turin, and NICO – Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy. §§Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita degli Studi di Milano, Milan, Italy. Journal of Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter Neuroendocrinology neuronal excitability by binding to membrane
    [Show full text]
  • Reduced Progesterone Metabolites in Human Late Pregnancy
    Physiol. Res. 60: 225-241, 2011 https://doi.org/10.33549/physiolres.932077 REVIEW Reduced Progesterone Metabolites in Human Late Pregnancy M. HILL1,2, A. PAŘÍZEK2, R. KANCHEVA1, J. E. JIRÁSEK3 1,2Institute of Endocrinology, Prague, Czech Republic, 2Department of Obstetrics and Gynecology of the First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic, 3Department of Clinical Biochemistry and Laboratory Diagnostics of the First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic Received November 20, 2010 Accepted November 25, 2010 On-line November 29, 2010 Summary Corresponding author In this review, we focused on the intersection between steroid A. Pařízek, Department of Obstetrics and Gynecology of the metabolomics, obstetrics and steroid neurophysiology to give a First Faculty of Medicine and General Teaching Hospital, comprehensive insight into the role of sex hormones and Apolinářská 18, 128 51 Prague 2, Czech Republic. E-mail: neuroactive steroids (NAS) in the mechanism controlling [email protected] pregnancy sustaining. The data in the literature including our studies show that there is a complex mechanism providing synthesis of either pregnancy sustaining or parturition provoking Introduction steroids. This mechanism includes the boosting placental synthesis of CRH with approaching parturition inducing the Although the effects of neuroactive and excessive synthesis of 3β-hydroxy-5-ene steroid sulfates serving neuroprotective 5α/β-reduced progesterone metabolites primarily as precursors for placental synthesis of progestogens, were extensively studied, the physiological relevance of estrogens and NAS. The distribution and changing activities of these substances remains frequently uncertain due to the placental oxidoreductases are responsible for the activation or lack of metabolomic data.
    [Show full text]
  • Chronic Cigarette Smoking Alters Circulating Sex Hormones and Neuroactive Steroids in Premenopausal Women
    Physiol. Res. 61: 97-111, 2012 https://doi.org/10.33549/physiolres.932164 Chronic Cigarette Smoking Alters Circulating Sex Hormones and Neuroactive Steroids in Premenopausal Women M. DUŠKOVÁ1, K. ŠIMŮNKOVÁ1, M. HILL1,4, M. VELÍKOVÁ1, J. KUBÁTOVÁ1, L. KANCHEVA1, H. KAZIHNITKOVÁ1, H. HRUŠKOVIČOVÁ1, H. POSPÍŠILOVÁ1, B. RÁCZ1, M. SALÁTOVÁ1, V. CIRMANOVÁ1, E. KRÁLÍKOVÁ2,3, L. STÁRKA1, A. PAŘÍZEK4 1Institute of Endocrinology, Prague, Czech Republic, 2Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University, Prague, Czech Republic, 3Tobacco Dependence Treatment Centre, Third Medical Department – Department of Metabolism and Endocrinology, First Faculty of Medicine, Charles University, Prague, Czech Republic, 4Department of Obstetrics and Gynecology of the First Faculty of Medicine, Charles University, Prague, Czech Republic Received February 18, 2011 Accepted October 27, 2011 On-line December 20, 2011 Summary lutropin/follitropin ratio. In conclusion, chronic cigarette smoking Chronic smoking alters the circulating levels of sex hormones and augments serum androgens and their 5α/β-reduced metabolites possibly also the neuroactive steroids. However, the data (including GABAergic substances) but suppresses the levels of available is limited. Therefore, a broad spectrum of free and estradiol in the LP and SHBG and may induce hyperandrogenism conjugated steroids and related substances was quantified by in female smokers. The female smokers had pronouncedly GC-MS and RIA in premenopausal smokers and in age-matched increased serum progestogens but paradoxically suppressed (38.9±7.3 years of age) non-smokers in the follicular (FP) and levels of their GABA-ergic metabolites. Further investigation is luteal phases (LP) of menstrual cycle (10 non-smokers and needed concerning these effects.
    [Show full text]
  • The Sigma1 Protein As a Target for the Non-Genomic Effects of Neuro(Active)Steroids: Molecular, Physiological, and Behavioral Aspects François P
    J Pharmacol Sci 100, 93 – 118 (2006) Journal of Pharmacological Sciences ©2006 The Japanese Pharmacological Society Critical Review The Sigma1 Protein as a Target for the Non-genomic Effects of Neuro(active)steroids: Molecular, Physiological, and Behavioral Aspects François P. Monnet1 and Tangui Maurice2,* 1Unité 705 de l’Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 7157 du Centre National de la Recherche Scientifique, Université de Paris V et VII, Hôpital Lariboisière-Fernand Widal, 2, rue Ambroise Paré, 75475 Paris cedex 10, France 2Unité 710 de l’Institut National de la Santé et de la Recherche Médicale, Ecole Pratique des Hautes Etudes, Université de Montpellier II, cc 105, place Eugène Bataillon, 34095 Montpellier cedex 5, France Received December 15, 2005 Abstract. Steroids synthesized in the periphery or de novo in the brain, so called ‘neuro- steroids’, exert both genomic and nongenomic actions on neurotransmission systems. Through rapid modulatory effects on neurotransmitter receptors, they influence inhibitory and excitatory neurotransmission. In particular, progesterone derivatives like 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) are positive allosteric modulators of the γ-aminobutyric acid type A (GABAA) receptor and therefore act as inhibitory steroids, while pregnenolone sulphate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are negative modulators of the GABAA receptor and positive modulators of the N-methyl-D-aspartate (NMDA) receptor, therefore acting as excitatory neurosteroids. Some steroids also interact with atypical proteins, the sigma (σ) receptors. Recent studies particularly demonstrated that the σ1 receptor contributes effectively to their pharmaco- logical actions. The present article will review the data demonstrating that the σ1 receptor binds neurosteroids in physiological conditions.
    [Show full text]
  • Multidisciplinary Analysis of Biological Effects of Novel Analogs of The
    UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE des Sciences de la vie et de la santé (ED 414) INSERM UMR_S U1119 Biopathologies de la Myéline, Neuroprotection et Stratégies Thérapeutiques THÈSE En cotutelle avec l´Albert-Ludwigs-Universität Freiburg, Allemagne présentée par : Mona KAROUT soutenue le : 30 Septembre 2015 pour obtenir le grade de : Docteur de l’université de Strasbourg Discipline / Spécialité : Neurosciences Multidisciplinary analysis of biological effects of novel analogs of the neurosteroid allopregnanolone: evidence for a proliferative, neurogenic and ne uroprote ctive action THÈSE dirigée par : M. MENSAH-NYAGAN Ayikoé, Guy Professeur, Université de Strasbourg, France M. HOFMANN Hans-Dieter Professeur, Albert-Ludwigs-Universität Freiburg, Allemagne RAPPORTEURS : M. FISCHBACH Karl-Friedrich Professeur, Albert-Ludwigs-Universität Freiburg, Allemagne M. SCHWEMMLE Martin Professeur, Albert-Ludwigs-Universität Freiburg, Allemagne AUTRES MEMBRES DU JURY : M. DUFOUR André Professeur, Université de Strasbourg, France Mme. PATTE-MENSAH Christine Docteur, Université de Strasbourg, France !"# $%&'(%# To my parents A mes parents Acknowledgement ACKNOWLEDGEMENT First of all, I would like to express my appreciation and gratitude to all members of my thesis committee, Prof. Karl-Friedrich Fischbach, Prof. Martin Schwemmle, Prof. André Dufour and Dr. Christine Patte-Mensah for taking the time to evaluate my thesis. Furthermore, I would like to express my deepest gratitude to my two PhD supervisors Prof. Ayikoé Guy Mensah-Nyagan and Prof. Hans-Dieter Hofmann. I am very thankful to you Prof. Mensah-Nyagan for giving me a great opportunity for performing this joint French-German PhD. Thank you very much for the continuous support, for your patience, enthusiasm, passion for research and immense knowledge.
    [Show full text]
  • Research Article
    Available Online at http://www.recentscientific.com International Journal of CODEN: IJRSFP (USA) Recent Scientific International Journal of Recent Scientific Research Research Vol. 9, Issue, 6(E), pp. 27560-27565, June, 2018 ISSN: 0976-3031 DOI: 10.24327/IJRSR Research Article BIOSYNTHESIS OF NEUROSTEROID AND PHARMACOLOGYCAL ACTION Vandna Dewangan*., Trilochan Satapthy and Ram Sahu Department of Pharmacology, Columbia Institute of Pharmacy, Tekari, Near Vidhansabha, Raipur-493111(C.G.) India DOI: http://dx.doi.org/10.24327/ijrsr.2018.0906.2285 ARTICLE INFO ABSTRACT Article History: Over the past decade, it has become clear that the brain, like the gonad, adrenal and placenta, is a steroid genic organ. Neurosteroids are synthetized in the central and the peripheral nervous system, Received 20th March, 2018 in glial cells, and also in neurons, from cholesterol or steroidal precursors imported from peripheral Received in revised form 27th sources. However, unlike classic steroid genic tissues, the synthesis of steroids in the nervous April, 2018 system requires the coordinate expression and regulation of the genes encoding the steroid genic Accepted 5th May, 2018 enzymes in several different cell types (neurons and glia) at different locations in the nervous Published online 28th June, 2018 system, and at distances from the cell bodies. The steroids synthesized by the brain and nervous system, given the name neurosteroids Progesterone itself is also a neurosteroid, and a progesterone Key Words: receptor has been detected in peripheral and central glial cells. At different sites in the brain, Neurosteroid, Steroid hormones, neurosteroid concentrations vary according to environmental and behavioural circumstances, such as Progesterone, Glial Cell, Nuclear receptor, stress, sex recognition, or aggressiveness.
    [Show full text]