DOCSLIB.ORG

Reduced Progesterone Metabolites in Human Late Pregnancy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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. We attempted to elucidate the inactivation of the aforementioned steroids, which is role of sex hormones and neuroactive steroids (NAS) in compartment-specific (maternal and fetal compartments) and the mechanism controlling the pregnancy maintenance dependent on gestational age, with a tendency to shift the and parturition onset. production from the pregnancy-sustaining steroids to the parturition provoking ones with an increasing gestational age. Biosynthesis of neuroactive steroids in The fetal and maternal livers catabolize part of the bioactive human pregnancy steroids and also convert some precursors to bioactive steroids. Besides the progesterone, a variety of its 5α/β-reduced Steroid metabolism in fetal and maternal adrenal metabolites may significantly influence the maintenance of human pregnancy, provide protection against excitotoxicity Placental CRH regulate the steroid biosynthesis in following acute hypoxic stress, and might also affect the pain pregnancy perception in mother and fetus. The machinery regulating production of pregnancy steroids is based on the excessive placental Key words production of corticoliberin (CRH) (Fig. 1) (Goland et al. Neuroactive steroids • Pregnancy • Plasma • Metabolome • 1986, Rainey et al. 2004, Smith et al. 2009). Pregnant GC-MS women after luteo-placental shift produce CRH primarily in the placenta and instead of the negative feedback loop PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online) © 2011 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic Fax +420 241 062 164, e-mail: [email protected], www.biomed.cas.cz/physiolres 226 Hill et al. Vol. 60 Fig. 1. Simplified scheme of steroidogenesis in pregnancy. cortisol-ACTH-CRH; there is a positive one between Steroid metabolism in fetal and maternal liver cortisol and CRH, while the ACTH production stagnates. The rising CRH levels in the last four weeks of C-3, C-17 and C-20 oxidoreductive conversions pregnancy stimulate the synthesis of conjugated Δ5 The enzymes, catalyzing reversible C-3, C-17 and steroids in the fetal adrenal (Smith et al. 1998, Sirianni et C-20 oxidoreductive inter-conversions belong to either the al. 2005). CRH is as effective as ACTH at stimulating short-chain dehydrogenases/reductases (SDRs) or the aldo- sulfated dehydroepiandrosterone (DHEAS) production keto reductases (AKRs). Human liver contains various but is 70 % less potent than ACTH at stimulating cortisol isoforms of AKRs (AKR1C1, AKR1C2, AKR1C3, and production. The excessive production of placental CRH is AKR1C4) with 20α-, 17β-, 3α- or 3β-hydroxysteroid specific for primates and the boosting CRH production dehydrogenase-like activity (Shiraishi et al. 1998, Penning near term is specific only for humans and great apes et al. 2001, Jin et al. 2009). AKRs activities could control 5 (Power and Schulkin 2006). The sulfated Δ steroids, occupancy of the androgen- and GABAA-receptors originating in the fetal zone of the fetal adrenal (FZ), (Penning 1999) via reduction of oxo-groups mostly in the represent the largest fraction of steroids in pregnancy steroid C3 and C17 positions, respectively. In vivo, all (Ingelman-Sundberg et al. 1975, Lacroix et al. 1997, AKR1Cs preferentially work as reductases (Steckelbroeck Moghrabi et al. 1997, Leeder et al. 2005). The FZ is et al. 2004) and are capable to reduce estrone, similar to the adult zona reticularis but unlike the adult progesterone, and 3-oxo-pregnane/androstane steroids to zona reticularis, the FZ produces excessive amounts of estradiol, 20α-dihydroprogesterone, and GABAergic sulfated C-21 Δ5 steroids, including sulfates of 3α-hydroxy-5α/β-pregnane/androstane steroids, respecti- pregnenolone and 17-hydroxypregnenolone (Rainey et al. vely. On the other hand, AKR1Cs may decrease the 2004, Hill et al. 2010a,b). These substances serve as concentrations of GABAergic steroids by inactivating precursors for the placental production of estradiol (Smith allopregnanolone and eliminating the precursors like et al. 1998, Sirianni et al. 2005) and progesterone (Jaffe progesterone from the synthetic pathways via reduction of and Ledger 1966, Komatsuzaki et al. 1987, Walsh 1988, the 20-oxo-steroid group (Penning et al. 2000, Usami et al. Hill et al. 2010b). 2002). The AKR1C2 preferring 3α-reduction over the 3β- reduction may catalyze 3α-, 17β-, and 20α-hydroxysteroid 2011 Neuroactive Steroids in Late Pregnancy 227 dehydrogenase (HSD) reactions (HSD) (Penning et al. the highest levels in the liver. SRD5A1 converts 2000, Jin et al. 2001, 2009, Usami et al. 2002). AKR1C3 testosterone into 5α-dihydrotestosterone and progesterone catalyzes the reduction of 5α-dihydrotestosterone or corticosterone to their 5α-reduced counterparts. In the (5α-DHT), androstenedione, estrone and progesterone to peripheral tissues, including the liver, SRD5A1 and produce 5α-androstan-3α,17β-diol, testosterone, estradiol reductive 3α-HSD isoforms work consecutively and 20α-dihydroprogesterone, respectively (Penning et al. eliminating the androgens, protecting against the 2001). AKR1C4, the expression of which is specific for the hormone excess (Jin and Penning 2001) and producing liver (Nishizawa et al. 2000, Penning et al. 2000, 2004), GABAergic steroids, which are, however, extensively catalyzes the transformation of the 5α-DHT into sulfated in the liver. Liver 5β-reductase (AKR1D1) 5α-androstan-3α,17β-diol. Liver specific AKR1C4 shows belonging to AKRs, efficiently catalyzes the reduction of superior catalytic efficiency exceeding those obtained with both C-19 and C-21 3-oxo-Δ4 steroids to the the other isoforms by 10-30-fold. In contrast to the other corresponding 5β-reduced metabolites (Kochakian 1983, isoforms, the catalytic efficiency for AKR1C4 is Okuda and Okuda 1984). unaffected by steroid conjugation (Jin et al. 2009). From The higher levels of 5β-reduced progesterone the SDRs, the type 7 17β-HSD (HSD17B7), preferring the metabolites in the fetus than in maternal compartment, as reduction of the oxo-groups in 20-, 17- and 3-positions to well as the arteriovenous differences in the fetus indicate the corresponding 20α-hydroxy-, 17β-hydroxy-, and that steroid 5α/β-reductions in the fetal liver and not in 3α-hydroxy-counterparts, is also significantly expressed in the placenta are important for production of GABAergic the liver (Krazeisen et al. 1999, Torn et al. 2003) as well as 5α/β-reduced NAS in both maternal and fetal type 12 17β-HSD (HSD17B12) catalyzing the transfor- compartments (Hill et al. 2010a). mation of estrone into the estradiol (Sakurai et al. 2006). On the other hand, type 2 17β-HSD (HSD17B2), Steroid metabolism in placenta type 10 17β-HSD (HSD17B10) and type 11 17β-HSD (HSD17B11), which are also highly expressed in the liver, Steroid sulfatases and placental production of sex prefer the oxidative direction. HSD17B2 may contribute to hormones formation of 20-oxo- and 17-oxo-steroids from their 20α- The principal metabolic step that is and 17β- counterparts (Moghrabi et al. 1997). Type 6 indispensable for further placental metabolism of sulfated 17β-HSD (HSD17B6) prefers oxidoreductase and Δ5 steroids originating in FZ is their desulfation, which is 3(α→β)-hydroxysteroid epimerase activities and acts on catalyzed by the placental STS. Placental STS activity is both C-19 and C-21 3α-hydroxysteroids (Huang and Luu- independent of substrate concentration (Watanabe et al. The 2000). HSD17B10 being abundantly expressed in the 1990) and of gestational age (GA) (Ishida et al. 1985, liver, is capable of catalyzing the oxidation of steroid Fukuda et al. 1986, Leslie et al. 1994). The placental STS modulators of GABAA-r
Load more

Recommended publications
  • Pharmaceuticals and Endocrine Active Chemicals in Minnesota Lakes
    Pharmaceuticals and Endocrine Active Chemicals in Minnesota Lakes May 2013 Authors Mark Ferrey Contributors/acknowledgements The MPCA is reducing printing and mailing costs This report contains the results of a study that by using the Internet to distribute reports and characterizes the presence of unregulated information to wider audience. Visit our website contaminants in Minnesota’s lakes. The study for more information. was made possible through funding by the MPCA reports are printed on 100 percent post- Minnesota Clean Water Fund and by funding by consumer recycled content paper manufactured the U.S. Environmental Protection Agency without chlorine or chlorine derivatives. (EPA), which facilitated the sampling of lakes for this study. The Minnesota Pollution Control Agency (MPCA) thanks the following for assistance and advice in designing and carrying out this study: Steve Heiskary, Pam Anderson, Dereck Richter, Lee Engel, Amy Garcia, Will Long, Jesse Anderson, Ben Larson, and Kelly O’Hara for the long hours of sampling for this study. Cynthia Tomey, Kirsten Anderson, and Richard Grace of Axys Analytical Labs for the expert help in developing the list of analytes for this study and logistics to make it a success. Minnesota Pollution Control Agency 520 Lafayette Road North | Saint Paul, MN 55155-4194 | www.pca.state.mn.us | 651-296-6300 Toll free 800-657-3864 | TTY 651-282-5332 This report is available in alternative formats upon request, and online at www.pca.state.mn.us. Document number: tdr-g1-16 Contents Contents ...........................................................................................................................................
    [Show full text]
  • 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]
  • Pharmaceutical and Veterinary Compounds and Metabolites
    PHARMACEUTICAL AND VETERINARY COMPOUNDS AND METABOLITES High quality reference materials for analytical testing of pharmaceutical and veterinary compounds and metabolites. lgcstandards.com/drehrenstorfer [email protected] LGC Quality | ISO 17034 | ISO/IEC 17025 | ISO 9001 PHARMACEUTICAL AND VETERINARY COMPOUNDS AND METABOLITES What you need to know Pharmaceutical and veterinary medicines are essential for To facilitate the fair trade of food, and to ensure a consistent human and animal welfare, but their use can leave residues and evidence-based approach to consumer protection across in both the food chain and the environment. In a 2019 survey the globe, the Codex Alimentarius Commission (“Codex”) was of EU member states, the European Food Safety Authority established in 1963. Codex is a joint agency of the FAO (Food (EFSA) found that the number one food safety concern was and Agriculture Office of the United Nations) and the WHO the misuse of antibiotics, hormones and steroids in farm (World Health Organisation). It is responsible for producing animals. This is, in part, related to the issue of growing antibiotic and maintaining the Codex Alimentarius: a compendium of resistance in humans as a result of their potential overuse in standards, guidelines and codes of practice relating to food animals. This level of concern and increasing awareness of safety. The legal framework for the authorisation, distribution the risks associated with veterinary residues entering the food and control of Veterinary Medicinal Products (VMPs) varies chain has led to many regulatory bodies increasing surveillance from country to country, but certain common principles activities for pharmaceutical and veterinary residues in food and apply which are described in the Codex guidelines.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,284,263 B1 Place (45) Date of Patent: Sep
    USOO6284263B1 (12) United States Patent (10) Patent No.: US 6,284,263 B1 Place (45) Date of Patent: Sep. 4, 2001 (54) BUCCAL DRUG ADMINISTRATION IN THE 4,755,386 7/1988 Hsiao et al. TREATMENT OF FEMALE SEXUAL 4,764,378 8/1988 Keith et al.. DYSFUNCTION 4,877,774 10/1989 Pitha et al.. 5,135,752 8/1992 Snipes. 5,190,967 3/1993 Riley. (76) Inventor: Virgil A. Place, P.O. Box 44555-10 5,346,701 9/1994 Heiber et al. Ala Kahua, Kawaihae, HI (US) 96743 5,516,523 5/1996 Heiber et al. 5,543,154 8/1996 Rork et al. ........................ 424/133.1 (*) Notice: Subject to any disclaimer, the term of this 5,639,743 6/1997 Kaswan et al. patent is extended or adjusted under 35 6,180,682 1/2001 Place. U.S.C. 154(b) by 0 days. * cited by examiner (21) Appl. No.: 09/626,772 Primary Examiner Thurman K. Page ASSistant Examiner-Rachel M. Bennett (22) Filed: Jul. 27, 2000 (74) Attorney, Agent, or Firm-Dianne E. Reed; Reed & Related U.S. Application Data ASSciates (62) Division of application No. 09/237,713, filed on Jan. 26, (57) ABSTRACT 1999, now Pat. No. 6,117,446. A buccal dosage unit is provided for administering a com (51) Int. Cl. ............................. A61F 13/02; A61 K9/20; bination of Steroidal active agents to a female individual. A61K 47/30 The novel buccal drug delivery Systems may be used in (52) U.S. Cl. .......................... 424/435; 424/434; 424/464; female hormone replacement therapy, in female 514/772.3 contraception, to treat female Sexual dysfunction, and to treat or prevent a variety of conditions and disorders which (58) Field of Search ....................................
    [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]
  • Conjugated and Unconjugated Plasma Androgens in Normal Children
    Pediat. Res. 6: 111-118 (1972) Androstcncdionc sexual development dehydroepiandrosterone testosterone Conjugated and Unconjugated Plasma Androgens in Normal Children DONALD A. BOON,'291 RAYMOND E. KEENAN, W. ROY SLAUNWHITE, JR., AND THOMAS ACETO, JR. Children's Hospital, Medical Foundation of Buffalo, Roswell Park Memorial Institute, and Departments of Biochemistry and Pediatrics, School of Medicine, State University of New York at Buffalo, Buffalo, New York, USA Extract Methods developed in this laboratory permit measurement of the androgens, testos- terone (T), dehydroepiandrosterone (D), and androstenedione (A) on a 10-ml sample of plasma. We have determined concentrations of the unconjugated androgens (T, A, D) as well as of the sulfates of dehydroepiandrosterone (DS) and androsterone (AS) in the plasma of 85 healthy children of both sexes from birth through the age of 20 years. Our results are shown and summarized, along with those of other investigators. Mean plasma concentrations Sex and age ng/100 ml Mg/100 ml T A D AS DS Male Neonates 39 24 30 None detectable None detectable 1-8 years 25 58 64 2 11 9-20 years 231 138 237 28 74 Female Neonates 36 30 83 None detectable None detectable 1-8 years 11 69 54 5 20 9-20 years 28 84 164 22 44 Testosterone was elevated in both sexes in the newborn as compared with the 1-8- year-old group. In contrast, sulfated androgens, with one exception, were undetectable early in life. In males, there was a marked rise in all androgens, especially T, in the 9-18-year-old group.
    [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]
  • 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]