Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum

Shadi Abu-Hayyeh; Caroline Ovadia; TinaMarie Lieu; Dane D Jensen; Jenny Chambers; Peter H Dixon; Anita Lövgren-Sandblom; Ruth Bolier; Dagmar Tolenaars; Andreas E Kremer; Argyro Syngelaki; Muna Noori; David Williams; Jose J G Marin; Maria J Monte; Kypros H Nicolaides; Ulrich Beuers; Ronald Oude-Elferink; Paul T Seed; Lucy Chappell; Hanns-Ulrich Marschall; Nigel W Bunnett; Catherine Williamson

doi:10.1002/hep.28265

Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum

Shadi Abu-Hayyeh, Caroline Ovadia, TinaMarie Lieu, Dane D Jensen, Jenny Chambers, Peter H Dixon, Anita Lövgren-Sandblom, Ruth Bolier, Dagmar Tolenaars, Andreas E Kremer, Argyro Syngelaki, Muna Noori, David Williams, Jose J G Marin, Maria J Monte, Kypros H Nicolaides, Ulrich Beuers, Ronald Oude-Elferink, Paul T Seed, Lucy ChappellHanns-Ulrich Marschall, Nigel W Bunnett, Catherine Williamson^*

^*Corresponding author for this work

Women & Children's Health

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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 (PG). ICP is characterised by raised serum bile acids, and complicated by spontaneous preterm labour and stillbirth. A biomarker for ICP would be invaluable for the 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 PG (group 2: ICP n=41, PG 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.

CONCLUSION: 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.

Original language	English
Pages (from-to)	1287-1298
Journal	Hepatology
Volume	63
Issue number	4
Early online date	28 Dec 2015
DOIs	https://doi.org/10.1002/hep.28265
Publication status	Published - 23 Mar 2016

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Abu-Hayyeh, S., Ovadia, C., Lieu, T., Jensen, D. D., Chambers, J., Dixon, P. H., Lövgren-Sandblom, A., Bolier, R., Tolenaars, D., Kremer, A. E., Syngelaki, A., Noori, M., Williams, D., Marin, J. J. G., Monte, M. J., Nicolaides, K. H., Beuers, U., Oude-Elferink, R., Seed, P. T., ... Williamson, C. (2016). Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology, 63(4), 1287-1298. https://doi.org/10.1002/hep.28265

@article{c3747cb0b33f41feb122caec8196b6c8,

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 (PG). ICP is characterised by raised serum bile acids, and complicated by spontaneous preterm labour and stillbirth. A biomarker for ICP would be invaluable for the 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 PG (group 2: ICP n=41, PG 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.CONCLUSION: 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.",

author = "Shadi Abu-Hayyeh and Caroline Ovadia and TinaMarie Lieu and Jensen, {Dane D} and Jenny Chambers and Dixon, {Peter H} and Anita L{\"o}vgren-Sandblom and Ruth Bolier and Dagmar Tolenaars and Kremer, {Andreas E} and Argyro Syngelaki and Muna Noori and David Williams and Marin, {Jose J G} and Monte, {Maria J} and Nicolaides, {Kypros H} and Ulrich Beuers and Ronald Oude-Elferink and Seed, {Paul T} and Lucy Chappell and Hanns-Ulrich Marschall and Bunnett, {Nigel W} and Catherine Williamson",

note = "{\textcopyright} 2015 by the American Association for the Study of Liver Diseases.",

year = "2016",

month = mar,

day = "23",

doi = "10.1002/hep.28265",

language = "English",

volume = "63",

pages = "1287--1298",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Wolters Kluwer Health",

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Abu-Hayyeh, S , Ovadia, C, Lieu, T, Jensen, DD, Chambers, J, Dixon, PH, Lövgren-Sandblom, A, Bolier, R, Tolenaars, D, Kremer, AE, Syngelaki, A, Noori, M, Williams, D, Marin, JJG, Monte, MJ, Nicolaides, KH, Beuers, U, Oude-Elferink, R, Seed, PT , Chappell, L, Marschall, H-U, Bunnett, NW & Williamson, C 2016, 'Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum', Hepatology, vol. 63, no. 4, pp. 1287-1298. https://doi.org/10.1002/hep.28265

TY - JOUR

T1 - Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum

AU - Abu-Hayyeh, Shadi

AU - Ovadia, Caroline

AU - Lieu, TinaMarie

AU - Jensen, Dane D

AU - Chambers, Jenny

AU - Dixon, Peter H

AU - Lövgren-Sandblom, Anita

AU - Bolier, Ruth

AU - Tolenaars, Dagmar

AU - Kremer, Andreas E

AU - Syngelaki, Argyro

AU - Noori, Muna

AU - Williams, David

AU - Marin, Jose J G

AU - Monte, Maria J

AU - Nicolaides, Kypros H

AU - Beuers, Ulrich

AU - Oude-Elferink, Ronald

AU - Seed, Paul T

AU - Chappell, Lucy

AU - Marschall, Hanns-Ulrich

AU - Bunnett, Nigel W

AU - Williamson, Catherine

PY - 2016/3/23

Y1 - 2016/3/23

N2 - 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 (PG). ICP is characterised by raised serum bile acids, and complicated by spontaneous preterm labour and stillbirth. A biomarker for ICP would be invaluable for the 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 PG (group 2: ICP n=41, PG 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.CONCLUSION: 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.

AB - 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 (PG). ICP is characterised by raised serum bile acids, and complicated by spontaneous preterm labour and stillbirth. A biomarker for ICP would be invaluable for the 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 PG (group 2: ICP n=41, PG 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.CONCLUSION: 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.

UR - http://www.scopus.com/inward/record.url?scp=84952836650&partnerID=8YFLogxK

U2 - 10.1002/hep.28265

DO - 10.1002/hep.28265

M3 - Article

C2 - 26426865

SN - 0270-9139

VL - 63

SP - 1287

EP - 1298

JO - Hepatology

JF - Hepatology

IS - 4

ER -

Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum

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