title: Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum.
abstract: A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice.
  
  
  CONCLUSIONS
  Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP.
authors.affiliation: Women's Health Academic Centre, King's College London, London, United Kingdom.
authors.forename: Shadi
authors.initials: S
authors.lastname: Abu-Hayyeh
authors.affiliation: Women's Health Academic Centre, King's College London, London, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ovadia
authors.affiliation: Monash Institute of Pharmaceutical Sciences and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia.
authors.forename: TinaMarie
authors.initials: T
authors.lastname: Lieu
authors.affiliation: Monash Institute of Pharmaceutical Sciences and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia.
authors.forename: Dane D
authors.initials: DD
authors.lastname: Jensen
authors.affiliation: Women's Health Academic Centre, King's College London, London, United Kingdom.|Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chambers
authors.affiliation: Women's Health Academic Centre, King's College London, London, United Kingdom.|Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dixon
authors.affiliation: Department of Clinical Chemistry, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Anita
authors.initials: A
authors.lastname: Lövgren-Sandblom
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Ruth
authors.initials: R
authors.lastname: Bolier
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Tolenaars
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, Amsterdam, The Netherlands.|Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kremer
authors.affiliation: Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, United Kingdom.
authors.forename: Argyro
authors.initials: A
authors.lastname: Syngelaki
authors.affiliation: Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
authors.forename: Muna
authors.initials: M
authors.lastname: Noori
authors.affiliation: Institute for Women's Health, University College London Hospitals, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Salamanca, Spain.
authors.forename: Jose J G
authors.initials: JJ
authors.lastname: Marin
authors.affiliation: Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Salamanca, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Monte
authors.affiliation: Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, United Kingdom.
authors.forename: Kypros H
authors.initials: KH
authors.lastname: Nicolaides
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Oude-Elferink
authors.affiliation: Women's Health Academic Centre, King's College London, London, United Kingdom.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Seed
authors.affiliation: Women's Health Academic Centre, King's College London, London, United Kingdom.
authors.forename: Lucy
authors.initials: L
authors.lastname: Chappell
authors.affiliation: Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: Monash Institute of Pharmaceutical Sciences and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia.|Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.affiliation: Women's Health Academic Centre, King's College London, London, United Kingdom.|Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Williamson
mesh_terms: D000328:Adult; D000818:Animals; D001522:Behavior, Animal; D001647:Bile Acids and Salts / Q000097:blood*; D016022:Case-Control Studies; D002780:Cholestasis, Intrahepatic / Q000097:blood / Q000175:diagnosis*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D006801:Humans; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000175:diagnosis*; D011256:Pregnancy Outcome; D011270:Pregnancy, Animal; D011374:Progesterone / Q000378:metabolism*; D011537:Pruritus / Q000175:diagnosis* / Q000378:metabolism; D012372:ROC Curve; D012720:Severity of Illness Index; D053719:Tandem Mass Spectrometry / Q000379:methods; D006113:United Kingdom
chemical_list: D001647:Bile Acids and Salts; D011374:Progesterone