Skip to main content
SpringerLink
Log in

Nuclear Receptors in Pregnancy and Outcomes: Clinical Perspective

  • Chapter
  • First Online:
Nuclear Receptors in Human Health and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1390))

Abstract

Pregnancy is characterised by profound hormonal and metabolic changes in the mother. Both oestrogen and progesterone, along with their respective nuclear receptors, have an important role in maintaining a healthy pregnancy. Equally, other nuclear receptors such as LXR, FXR and the PPARs play important roles in the gradual alterations in metabolism that ensure survival of mother and fetus. Disruptions in nuclear receptor signalling can result in pregnancy disorders such as gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, hypertensive disorders of pregnancy and preterm labour, all of which have both immediate and long-term implications for maternal and fetal health. By reviewing data from human studies and animal models, this chapter will describe the contribution of nuclear receptors to normal pregnancy, their role in gestational disorders and their potential as therapeutic targets.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bustamante JJ, Copple BL, Soares MJ, Dai G (2010) Gene profiling of maternal hepatic adaptations to pregnancy. Liver Int 30(3):406–415

    Article  CAS  PubMed  Google Scholar 

  2. Brosens JJ, Parker MG, McIndoe A, Pijnenborg R, Brosens IA (2009) A role for menstruation in preconditioning the uterus for successful pregnancy. Am J Obstet Gynecol 200(6):615.e1–615.e6

    Article  Google Scholar 

  3. Okada H, Tsuzuki T, Murata H (2018) Decidualization of the human endometrium. Reprod Med Biol 17(3):220

    Article  PubMed  PubMed Central  Google Scholar 

  4. Gellersen B, Brosens I, Brosens J (2007) Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med 25(6):445–453

    Article  CAS  PubMed  Google Scholar 

  5. Butte NF (2000) Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am J Clin Nutr 71:1256S–1261S. American Society for Nutrition

    Article  CAS  PubMed  Google Scholar 

  6. Herrera E, Amusquivar E, López-Soldado I, Ortega H (2006) Maternal lipid metabolism and placental lipid transfer. Horm Res 65:59–64

    CAS  PubMed  Google Scholar 

  7. Hadden DR, McLaughlin C (2009) Normal and abnormal maternal metabolism during pregnancy. Semin Fetal Neonatal Med 14(2):66–71

    Article  PubMed  Google Scholar 

  8. Papacleovoulou G, Abu-Hayyeh S, Williamson C (2011) Nuclear receptor-driven alterations in bile acid and lipid metabolic pathways during gestation. Biochim Biophys Acta Mol basis Dis 1812(8):879–887

    Article  CAS  Google Scholar 

  9. Wu S-P, Li R, Demayo FJ (2018) Progesterone receptor regulation of uterine adaptation for pregnancy. Trends Endocrinol Metab 29(7):481–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lee K, Jeong J, Tsai M-J, Tsai S, Lydon JP, Demayo FJ (2006) Molecular mechanisms involved in progesterone receptor regulation of uterine function. J Steroid Biochem Mol Biol 102(1–5):41–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mullac-Jericevic B, Mullinax RA, DeMayo FJ, Lydon JP, Conneely OM (2000) Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science 289(5485):1751–1754

    Article  Google Scholar 

  12. Mulac-Jericevic B, Lydon JP, DeMayo FJ, Conneely OM (2003) Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci U S A 100(17):9744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fleisch MC, Chou YC, Cardiff RD, Asaithambi A, Shyamala G (2009) Overexpression of progesterone receptor a isoform in mice leads to endometrial hyperproliferation, hyperplasia and atypia. Mol Hum Reprod 15(4):241–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Aplin J (1991) Implantation, trophoblast differentiation and haemochorial placentation: mechanistic evidence in vivo and in vitro. J Cell Sci 99(4):681–692

    Article  PubMed  Google Scholar 

  15. Ji L, Brkić J, Liu M, Fu G, Peng C, Wang YL (2013) Placental trophoblast cell differentiation: physiological regulation and pathological relevance to preeclampsia. Mol Asp Med 34(5):981–1023

    Article  CAS  Google Scholar 

  16. Kadam L, Kohan-Ghadr HR, Drewlo S (2015) The balancing act – PPAR-γ’s roles at the maternal-fetal interface. Syst Biol Reprod Med 61(2):65–71

    Article  CAS  PubMed  Google Scholar 

  17. Fournier T, Handschuh K, Tsatsaris V, Guibourdenche J, Evain-Brion D (2008) Role of nuclear receptors and their ligands in human trophoblast invasion. J Reprod Immunol 77(2):161–170

    Article  CAS  PubMed  Google Scholar 

  18. Barak Y, Nelson MC, Ong ES et al (1999) PPARγ is required for placental, cardiac, and adipose tissue development. Mol Cell 4(4):585–595

    Article  CAS  PubMed  Google Scholar 

  19. Tarrade A, Schoonjans K, Pavan L et al (2001) PPARγ/RXRα heterodimers control human trophoblast invasion. J Clin Endocrinol Metab 86(10):5017–5024

    CAS  PubMed  Google Scholar 

  20. Fournier T, Handschuh K, Tsatsaris V, Evain-Brion D (2007) Involvement of PPARgamma in human trophoblast invasion. Placenta 28(8–9):974–976

    Article  Google Scholar 

  21. Fournier T, Thérond P, Handschuh K, Tsatsaris V (2008) Evain-Brion. PPARgamma and early human placental development. Curr Med Chem 15(28):3011–3024

    Article  CAS  PubMed  Google Scholar 

  22. Fournier T, Pavan L, Tarrade A et al (2002) The role of PPAR-γ/RXR-α heterodimers in the regulation of human trophoblast invasion. Ann N Y Acad Sci 973:26–30

    Article  CAS  PubMed  Google Scholar 

  23. Parast MM, Yu H, Ciric A, Salata MW, Davis V, Milstone DS (2009) PPARγ regulates trophoblast proliferation and promotes labyrinthine Trilineage differentiation. PLoS One 4(11):e8055

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Schaiff WT, Carlson MG, Smith SD, Levy R, Nelson DM, Sadovsky Y (2000) Peroxisome proliferator-activated receptor-gamma modulates differentiation of human trophoblast in a ligand-specific manner. J Clin Endocrinol Metab 85(10):3874–3881

    CAS  PubMed  Google Scholar 

  25. Calkin AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol 13(4):213–224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chawta A, Repa JJ, Evans RM, Mangelsdorf DJ (2001) Nuclear receptors and lipid physiology: Opening the x-files. Science (80-) 294(5548):1866–1870

    Article  Google Scholar 

  27. Weedon-Fekjaer MS, Duttaroy AK, Nebb HI (2005) Liver X receptors mediate inhibition of hCG secretion in a human placental trophoblast cell line. Placenta 26(10):721–728

    Article  CAS  PubMed  Google Scholar 

  28. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature 383(6602):728–731

    Article  CAS  PubMed  Google Scholar 

  29. Pavan L, Hermouet A, Tsatsaris V et al (2004) Lipids from oxidized low-density lipoprotein modulate human trophoblast invasion: involvement of nuclear liver X receptors. Endocrinology 145(10):4583–4591

    Article  CAS  PubMed  Google Scholar 

  30. Aye IL, Waddell BJ, Mark PJ, Keelan JA (2011) Oxysterols inhibit differentiation and fusion of term primary trophoblasts by activating liver X receptors. Placenta 32(2):183–191

    Article  CAS  PubMed  Google Scholar 

  31. Larkin JC, Sears SB, Sadovsky Y (2014) The influence of ligand-activated LXR on primary human trophoblasts. Placenta 35(11):919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sabol SL, Brewer HB, Santamarina-Fojo S (2005) The human ABCG1 gene: identification of LXR response elements that modulate expression in macrophages and liver. J Lipid Res 46(10):2151–2167

    Article  CAS  PubMed  Google Scholar 

  33. Venkateswaran A, Laffitte BA, Joseph SB et al (2000) Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα. Proc Natl Acad Sci U S A 97(22):12097–12102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kalaany NY, Mangelsdorf DJ (2006) LXRS AND FXR: The Yin and Yang of cholesterol and fat metabolism. Annu Rev Physiol 68(1):159–191

    Article  CAS  PubMed  Google Scholar 

  35. Nikolova V, Papacleovoulou G, Bellafante E et al (2017) Changes in LXR signaling influence early-pregnancy lipogenesis and protect against dysregulated fetoplacental lipid homeostasis. Am J Physiol Endocrinol Metab 313(4):E463–E472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sweeney TR, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR (2006) Decreased nuclear hormone receptor expression in the livers of mice in late pregnancy. Am J Physiol Metab 290(6):E1313–E1320

    CAS  Google Scholar 

  37. Bass J, Takahashi JS (2010) Circadian integration of metabolism and energetics. Science (80-) 330(6009):1349–1354

    Article  CAS  Google Scholar 

  38. Cho H, Zhao X, Hatori M et al (2012) Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 485(7396):123–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bugge A, Feng D, Everett LJ et al (2012) Rev-erba and Rev-erbb coordinately protect the circadian clock and normal metabolic function. Genes Dev 26(7):657–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Papacleovoulou G, Nikolova V, Oduwole O et al (2017) Gestational disruptions in metabolic rhythmicity of the liver, muscle, and placenta affect fetal size. FASEB J 31(4):1698–1708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shynlova O, Nadeem L, Zhang J, Dunk C, Lye S (2020) Myometrial activation: novel concepts underlying labor. Placenta 92:28–36

    Article  CAS  PubMed  Google Scholar 

  42. Hardy DB, Janowski BA, Corey DR, Mendelson CR (2006) Progesterone receptor plays a major Antiinflammatory role in human myometrial cells by antagonism of nuclear factor-κB activation of cyclooxygenase 2 expression. Mol Endocrinol 20(11):2724–2733

    Article  CAS  PubMed  Google Scholar 

  43. Kalkhoven E, Wissink S, van der Saag PT, van der Burg B (1996) Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor. J Biol Chem 271(11):6217–6224

    Article  CAS  PubMed  Google Scholar 

  44. Mendelson CR, Montalbano AP, Gao L, Steroid J, Mol B, Author B (2017) Fetal-to-maternal signaling in the timing of birth HHS public access Author manuscript. J Steroid Biochem Mol Biol 170:19–27

    Article  CAS  PubMed  Google Scholar 

  45. Hendrix EM, Myatt L, Sellers S, Russell PT, Larsen WJ (1995) Steroid hormone regulation of rat myometrial gap junction formation: effects on cx43 levels and trafficking. Biol Reprod 52(3):547–560

    Article  CAS  PubMed  Google Scholar 

  46. Renthal NE, Chen C-C, Williams KC, Gerard RD, Prange-Kiel J, Mendelson CR (2010) miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor. Proc Natl Acad Sci 107(48):20828–20833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chai SY, Smith R, Zakar T, Mitchell C, Madsen G (2012) Term myometrium is characterized by increased activating epigenetic modifications at the progesterone receptor-a promoter. Mol Hum Reprod 18(8):401–409

    Article  CAS  PubMed  Google Scholar 

  48. Nadeem L, Shynlova O, Matysiak-Zablocki E, Mesiano S, Dong X, Lye S (2016) Molecular evidence of functional progesterone withdrawal in human myometrium. Nat Commun 7:11565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Peavey MC, Wu SP, Li R et al (2021) Progesterone receptor isoform B regulates the Oxtr- Plcl2- Trpc3 pathway to suppress uterine contractility. Proc Natl Acad Sci U S A 118(11):e2011643118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Merlino AA, Welsh TN, Tan H et al (2007) Nuclear progesterone receptors in the human pregnancy myometrium: evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-a. J Clin Endocrinol Metab 92(5):1927–1933

    Article  CAS  PubMed  Google Scholar 

  51. Pieber D, Allport VC, Hills F, Johnson M, Bennett PR (2001) Interactions between progesterone receptor isoforms in myometrial cells in human labour. Mol Hum Reprod 7(9):875–879

    Article  CAS  PubMed  Google Scholar 

  52. Williams KC, Renthal NE, Condon JC, Gerard RD, Mendelson CR (2012) MicroRNA-200a serves a key role in the decline of progesterone receptor function leading to term and preterm labor. Proc Natl Acad Sci U S A 109(19):7529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nadeem L, Balendran R, Dorogin A, Mesiano S, Shynlova O, Lye SJ (2021) Pro-inflammatory signals induce 20α-HSD expression in myometrial cells: a key mechanism for local progesterone withdrawal. J Cell Mol Med 25(14):6773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nadeem L, Shynlova O, Mesiano S, Lye S (2017) Progesterone via its type-a receptor promotes myometrial gap junction coupling. Sci Rep 7(1):13357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Lee Y, Sooranna SR, Terzidou V et al (2012) Interactions between inflammatory signals and the progesterone receptor in regulating gene expression in pregnant human uterine myocytes. J Cell Mol Med 16(10):2487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Allport VC, Pieber D, Slater DM, Newton R, White JO, Bennett PR (2001) Human labour is associated with nuclear factor-kappaB activity which mediates cyclo-oxygenase-2 expression and is involved with the “functional progesterone withdrawal”. Mol Hum Reprod 7(6):581–586

    Article  CAS  PubMed  Google Scholar 

  57. Poomalar GK (2015) Changing trends in management of gestational diabetes mellitus. World J Diabetes 6(2):284

    Article  PubMed  PubMed Central  Google Scholar 

  58. Cho NH, Shaw JE, Karuranga S et al (2018) IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 138:271–281

    Article  CAS  PubMed  Google Scholar 

  59. David Mcintyre H, Kapur A, Divakar H, Hod M (2020) Gestational diabetes mellitus – innovative approach to prediction, diagnosis, management, and prevention of future NCD – mother and offspring. Front Endocrinol (Lausanne) 11:6145333

    Google Scholar 

  60. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP et al (2009) Hyperglycemia and Adverse Pregnancy Outcomes. MCN 358(19):1991–2002

    Google Scholar 

  61. Lee AJ, Hiscock RJ, Wein P, Walker SP, Permezel M (2007) Gestational diabetes mellitus: clinical predictors and long-term risk of developing type 2 diabetes: a retrospective cohort study using survival analysis. Diabetes Care 30(4):878–883

    Article  CAS  PubMed  Google Scholar 

  62. Retnakaran R, Shah BR (2009) Mild glucose intolerance in pregnancy and risk of cardiovascular disease: a population-based cohort study. CMAJ 181(6–7):371–376

    Article  PubMed  PubMed Central  Google Scholar 

  63. Ornoy A, Becker M, Weinstein-Fudim L, Ergaz Z (2021) Diabetes during pregnancy: a maternal disease complicating the course of pregnancy with long-term deleterious effects on the offspring. A clinical review. Int J Mol Sci 22(6):1–38

    Article  CAS  Google Scholar 

  64. Chu AH, Godfrey KM (2020) Gestational diabetes mellitus and developmental programming. Ann Nutr Metab 76(Suppl 3):4

    Article  CAS  PubMed  Google Scholar 

  65. Gregorio KCR, Laurindo CP, Machado UF (2021) Estrogen and glycemic homeostasis: the fundamental role of nuclear estrogen receptors ESR1/ESR2 in glucose transporter GLUT4 regulation. Cells 10(1):90

    Article  CAS  Google Scholar 

  66. Herrera-Lopez EE, Castelan-Martinez OD, Suarez Sanchez F et al (2018) The rs1256031 of estrogen receptor β gene is associated with type 2 diabetes. Diabetes Metab Syndr 12(5):631–633

    Article  PubMed  Google Scholar 

  67. Li X, Su J, Zheng K et al (2020) Assessment of the association between the polymorphism rs1256031 of the estrogen receptor β gene and GDM susceptibility. Nagoya J Med Sci 82(4):703

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Li C, Qiao B, Zhou Y, Qi W, Ma C, Zheng L (2020) Asociation of estrogen receptor α gene polymorphism and its expression with gestational diabetes mellitus. Gynecol Obstet Investig 85(1):26–33

    Article  CAS  Google Scholar 

  69. Hocking S, Samocha-Bonet D, Milner KL, Greenfield JR, Chisholm DJ (2013) Adiposity and insulin resistance in humans: the role of the different tissue and cellular lipid depots. Endocr Rev 34(4):463–500

    Article  CAS  PubMed  Google Scholar 

  70. Kitessa SM, Abeywardena MY (2016) Lipid-induced insulin resistance in skeletal muscle: the chase for the culprit Goes from total intramuscular fat to lipid intermediates, and finally to species of lipid intermediates. Nutrients 8(8):466

    Article  PubMed Central  CAS  Google Scholar 

  71. Wilding JP (2007) The importance of free fatty acids in the development of Type 2 diabetes. Diabet Med 24(9):934–945

    Article  CAS  PubMed  Google Scholar 

  72. Dong Y, Gao G, Fan H, Li S, Li X, Liu W (2015) Activation of the liver X receptor by Agonist TO901317 improves hepatic insulin resistance via suppressing reactive oxygen species and JNK pathway. PLoS ONE 10(4):e0124778

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Maczewsky J, Sikimic J, Bauer C et al (2017) The LXR ligand T0901317 acutely inhibits insulin secretion by affecting mitochondrial metabolism. Endocrinology 158(7):2145–2154

    Article  CAS  PubMed  Google Scholar 

  74. Ding L, Pang S, Sun Y, Tian Y, Yu L, Dang N (2014) Coordinated actions of FXR and LXR in metabolism: from pathogenesis to pharmacological targets for type 2 diabetes. Int J Endocrinol 2014:7518599

    Google Scholar 

  75. Lappas M (2014) Effect of pre-existing maternal obesity, gestational diabetes and adipokines on the expression of genes involved in lipid metabolism in adipose tissue. Metabolism 63(2):250–262

    Article  CAS  PubMed  Google Scholar 

  76. Ma K, Saha PK, Chan L, Moore DD (2006) Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 116(4):1102–1109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bellafante E, McIlvride S, Nikolova V et al (2020) Maternal glucose homeostasis is impaired in mouse models of gestational cholestasis. Sci Rep 10(1):11523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mudaliar S, Henry RR, Sanyal AJ et al (2013) Efficacy and safety of the farnesoid x receptor agonist Obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145(3):574

    Article  CAS  PubMed  Google Scholar 

  79. McIlvride S, Nikolova V, Fan HM et al (2019) Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes. Am J Physiol Endocrinol Metab 317(2):E399–E410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lee RH, Goodwin TM, Greenspoon J, Incerpi M (2006) The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol 26(9):527–532

    Article  CAS  PubMed  Google Scholar 

  81. Wood AM, Livingston EG, Hughes BL, Kuller JA (2018) Intrahepatic cholestasis of pregnancy: a review of diagnosis and management. Obstet Gynecol Surv 73(2):103–109

    Article  PubMed  Google Scholar 

  82. Geenes V, Chappell LC, Seed PT, Steer PJ, Knight M, Williamson C (2014) Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology 59(4):1482–1491

    Article  PubMed  Google Scholar 

  83. Ovadia C, Seed PT, Sklavounos A et al (2019) Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet 393(10174):899–909

    Article  PubMed  PubMed Central  Google Scholar 

  84. Turro E, Astle WJ, Megy K et al (2020) Whole-genome sequencing of patients with rare diseases in a national health system. Nature 583(7814):96–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dixon PH, Wadsworth CA, Chambers J et al (2014) A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. Am J Gastroenterol 109(1):76–84

    Article  CAS  PubMed  Google Scholar 

  86. Abu-Hayyeh S, Martinez-Becerra P, Abdul Kadir SHS et al (2010) Inhibition of Na+−taurocholate co-transporting polypeptide-mediated bile acid transport by cholestatic sulfated progesterone metabolites. J Biol Chem 285(22):16504–16512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sookoian S, Castaño G, Burgueño A, Gianotti TF, Pirola CJ (2008) Association of the multidrug-resistance-associated protein gene (ABCC2) variants with intrahepatic cholestasis of pregnancy. J Hepatol 48(1):125–132

    Article  CAS  PubMed  Google Scholar 

  88. Houten SM, Auwerx J (2004) The enterohepatic nuclear receptors are major regulators of the enterohepatic circulation of bile salts. Ann Med 36(7):482–491

    Article  CAS  PubMed  Google Scholar 

  89. Makishima M, Okamoto AY, Repa JJ et al (1999) Identification of a nuclear receptor for bite acids. Science (80-) 284(5418):1362–1365

    Article  CAS  Google Scholar 

  90. Parks DJ, Blanchard SG, Bledsoe RK et al (1999) Bile acids: Natural ligands for an orphan nuclear receptor. Science (80-) 284(5418):1365–1368

    Article  CAS  Google Scholar 

  91. Chiang JYL (2009) Bile acids: regulation of synthesis. J Lipid Res 50(10):1955–1966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Goodwin B, Jones SA, Price RR et al (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6(3):517–526

    Article  CAS  PubMed  Google Scholar 

  93. Denson LA, Sturm E, Echevarria W et al (2001) The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121(1):140–147

    Article  CAS  PubMed  Google Scholar 

  94. Müller M, Jansen PLM, Faber KN et al (2002) Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump. Hepatology 35(3):589–596

    Article  PubMed  CAS  Google Scholar 

  95. Milona A, Owen BM, Cobbold JFL et al (2010) Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function. Hepatology 52(4):1341–1349

    Article  CAS  PubMed  Google Scholar 

  96. Chen Y, Vasilenko A, Song X et al (2015) Estrogen and estrogen receptor-α-mediated Transrepression of bile salt export pump. Mol Endocrinol 29(4):613–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Song X, Vasilenko A, Chen Y et al (2014) Transcriptional dynamics of bile salt export pump during pregnancy: mechanisms and implications in intrahepatic cholestasis of pregnancy. Hepatology 60(6):1993–2007

    Article  CAS  PubMed  Google Scholar 

  98. Abu-Hayyeh S, Papacleovoulou G, Lövgren-Sandblom A et al (2013) Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype. Hepatology 57(2):716–726

    Article  CAS  PubMed  Google Scholar 

  99. Dann AT, Kenyon AP, Wierzbicki AS, Seed PT, Shennan AH, Tribe RM (2006) Plasma lipid profiles of women with intrahepatic cholestasis of pregnancy. Obstet Gynecol 107(1):106–114

    Article  CAS  PubMed  Google Scholar 

  100. Martineau M, Raker C, Powrie R, Williamson C (2014) Intrahepatic cholestasis of pregnancy is associated with an increased risk of gestational diabetes. Eur J Obstet Gynecol Reprod Biol 176(1):80–85

    Article  PubMed  Google Scholar 

  101. Martineau MG, Raker C, Dixon PH et al (2015) The metabolic profile of intrahepatic cholestasis of pregnancy is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth. Diabetes Care 38(2):243–248

    Article  PubMed  Google Scholar 

  102. Geenes V, Williamson C (2009) Intrahepatic cholestasis of pregnancy. World J Gastroenterol 15(17):2049

    Article  PubMed  PubMed Central  Google Scholar 

  103. Trauner M, Wagner M, Fickert P, Zollner G (2005) Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis. J Clin Gastroenterol 39(4 Suppl 2):S111–S124

    Article  PubMed  Google Scholar 

  104. Chappell LC, Bell JL, Smith A et al (2019) Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial. Lancet 394(10201):849–860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ovadia C, Sajous J, Seed PT et al (2021) Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis. Lancet Gastroenterol Hepatol 6(7):547–558

    Article  PubMed  PubMed Central  Google Scholar 

  106. Papacleovoulou G, Abu-Hayyeh S, Nikolopoulou E et al (2013) Maternal cholestasis during pregnancy programs metabolic disease in offspring. J Clin Invest 123(7):3172–3181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Borges Manna L, Papacleovoulou G, Flaviani F et al (2020) Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in hypercholanemic pregnancy. Sci Rep 10(1):10361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chappell LC, Cluver CA, Kingdom J, Tong S (2021) Pre-eclampsia. Lancet 3:341–354

    Article  Google Scholar 

  109. Duffy J, Cairns AE, Richards-Doran D et al (2020) A core outcome set for pre-eclampsia research: an international consensus development study. BJOG 127(12):1516–1526

    Article  PubMed  Google Scholar 

  110. WHO recommendations: Policy of interventionist versus expectant management of severe pre-eclampsia before term. WHO Recomm Policy Interv versus Expect Manag Sev pre-eclampsia before term. 2018. https://www.ncbi.nlm.nih.gov/books/NBK535829/. Accessed 15 July 2021

  111. Kwiatkowski S, Kwiatkowska E, Torbe A (2019) The role of disordered angiogenesis tissue markers (sflt-1, Plgf) in present day diagnosis of preeclampsia. Ginekol Pol 90(3):173–176

    Article  PubMed  Google Scholar 

  112. Melchiorre K, Giorgione V, Thilaganathan B (2021) The placenta and preeclampsia: villain or victim? Am J Obstet Gynecol 226:S954–S962

    Article  PubMed  CAS  Google Scholar 

  113. Magee LA, von Dadelszen P, Rey E et al (2015) Less-tight versus tight control of hypertension in pregnancy. N Engl J Med 372(5):407–417

    Article  CAS  PubMed  Google Scholar 

  114. Koopmans CM, Bijlenga D, Groen H et al (2009) Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicentre, open-label randomised controlled trial. Lancet 374(9694):979–988

    Article  PubMed  Google Scholar 

  115. Chappell LC, Brocklehurst P, Green ME et al (2019) Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet 394(10204):1181–1190

    Article  PubMed  PubMed Central  Google Scholar 

  116. Rodie VA, Young A, Jordan F, Sattar N, Greer IA, Freeman DJ (2005) Human placental peroxisome proliferator-activated receptor δ and γ expression in healthy pregnancy and in preeclampsia and intrauterine growth restriction. J Soc Gynecol Investig 12(5):320–329

    Article  CAS  PubMed  Google Scholar 

  117. Holdsworth-Carson SJ, Lim R, Mitton A et al (2010) Peroxisome proliferator-activated receptors are altered in pathologies of the human placenta: gestational diabetes mellitus, intrauterine growth restriction and preeclampsia. Placenta 31(3):222–229

    Article  CAS  PubMed  Google Scholar 

  118. Laasanen J, Heinonen S, Hiltunen M, Mannermaa A, Laakso M (2002) Polymorphism in the peroxisome proliferator-activated receptor-gamma gene in women with preeclampsia. Early Hum Dev 69(1–2):77–82

    Article  CAS  PubMed  Google Scholar 

  119. McCarthy FP, Drewlo S, English FA et al (2011) Evidence implicating peroxisome proliferator-activated receptor-? In the pathogenesis of preeclampsia. Hypertension 58(5):882–887

    Article  CAS  PubMed  Google Scholar 

  120. McCarthy FP, Drewlo S, Kingdom J, Johns EJ, Walsh SK, Kenny LC (2011) Peroxisome proliferator-activated receptor-γ as a potential therapeutic target in the treatment of preeclampsia. Hypertension 58(2):280–286

    Article  CAS  PubMed  Google Scholar 

  121. Ahham HIG, Masri AAA (2018) The potential therapeutic role of peroxisome ProliferatorActivated receptors agonist in Preeclamptic pregnant rats. J Coll Physicians Surg Pak 28(1):31–35

    Article  Google Scholar 

  122. Waite LL, Louie RE, Taylor RN (2005) Circulating activators of peroxisome proliferator-activated receptors are reduced in preeclamptic pregnancy. J Clin Endocrinol Metab 90(2):620–626

    Article  CAS  PubMed  Google Scholar 

  123. Plösch T, Gellhaus A, Van Straten EME et al (2010) The liver X receptor (LXR) and its target gene ABCA1 are regulated upon low oxygen in human trophoblast cells: a reason for alterations in preeclampsia? Placenta 31(10):910–918

    Article  PubMed  CAS  Google Scholar 

  124. Weedon-Fekjaer MS, Johnsen GM, Anthonisen EH et al (2010) Expression of liver X receptors in pregnancies complicated by preeclampsia. Placenta 31:818–824

    Article  CAS  PubMed  Google Scholar 

  125. Wang J, Dong X, Wu H-Y et al (2016) Relationship of liver X receptors α and Endoglin levels in serum and placenta with preeclampsia. PLoS One 11(10):e0163742

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Preterm birth. https://www.who.int/news-room/fact-sheets/detail/preterm-birth. Accessed 5 Aug 2021

  127. Newborns: improving survival and well-being. https://www.who.int/news-room/fact-sheets/detail/newborns-reducing-mortality. Accessed 5 Aug 2021

  128. Bayar E, Bennett PR, Chan D, Sykes L, MacIntyre DA (2020) The pregnancy microbiome and preterm birth. Semin Immunopathol 42(4):487–499

    Article  PubMed  PubMed Central  Google Scholar 

  129. Rood KM, Buhimschi CS (2017) Genetics, hormonal influences, and preterm birth. Semin Perinatol 41(7):401–408

    Article  PubMed  Google Scholar 

  130. Talati AN, Hackney DN, Mesiano S (2017) Pathophysiology of preterm labor with intact membranes. Semin Perinatol 41(7):420–426

    Article  PubMed  Google Scholar 

  131. Stewart LA, Simmonds M, Duley L et al (2021) Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet 397(10280):1183–1194

    Article  Google Scholar 

  132. Nold C, Maubert M, Anton L, Yellon S, Elovitz MA (2013) Prevention of preterm birth by progestational agents: what are the molecular mechanisms? Am J Obstet Gynecol 208(3):223.e1

    Article  CAS  Google Scholar 

  133. Furcron A-E, Romero R, Plazyo O et al (2015) Vaginal progesterone, but not 17α-hydroxyprogesterone caproate, has antiinflammatory effects at the murine maternal-fetal interface. Am J Obstet Gynecol 213(6):846.e1

    Article  CAS  Google Scholar 

  134. Kuon RJ, Shi S-Q, Maul H et al (2010) Pharmacological actions of progestins to inhibit cervical ripening and prevent delivery depend upon their properties, the route of administration and the vehicle. Am J Obstet Gynecol 202(5):455.e1

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Women and Children’s Health, King’s College London, London, UK

    Luiza Borges Manna & Catherine Williamson

Authors
  1. Luiza Borges Manna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catherine Williamson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Catherine Williamson .

Editor information

Editors and Affiliations

  1. College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Moray J. Campbell

  2. Department of Surgery & Cancer, Imperial College London, London, UK

    Charlotte L. Bevan

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Borges Manna, L., Williamson, C. (2022). Nuclear Receptors in Pregnancy and Outcomes: Clinical Perspective. In: Campbell, M.J., Bevan, C.L. (eds) Nuclear Receptors in Human Health and Disease. Advances in Experimental Medicine and Biology, vol 1390. Springer, Cham. https://doi.org/10.1007/978-3-031-11836-4_1

Download citation

Publish with us

Policies and ethics

Search

Navigation