Skip to main content

Advertisement

SpringerLink
Log in

Glucocorticoid receptors α and β are modulated sex specifically in human placentas of intrauterine growth restriction (IUGR)

  • Maternal-Fetal Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

The objective of this study was to analyze the expression of the glucocorticoid receptor (GR) subtypes GRα and GRβ in placentas affected by intrauterine growth restriction (IUGR).

Methods

We analyzed the sex-specific placental expression of GRα and GRβ in 23 IUGR and 40 control placentas using immunohistochemistry and immunofluorescence. The GR gene, also known as nuclear receptor subfamily 3 group C member 1 (NR3C1), mRNA production in trophoblast-like cell line BeWo after stimulation with prednisolone was analyzed using quantitative polymerase chain reaction (qPCR) and on the protein level using western blot analysis.

Results

GR subtypes showed a sex-specific upregulation in placentas from IUGR compared to control placentas. An increased expression of GRα was detectable in female placental tissue, whereas GRβ was increased in males.

Conclusion

Our data support previous findings suggesting that the glucocorticoid metabolism plays a role in the pathophysiology of IUGR. Furthermore, the data suggest that the underlying molecular mechanisms differ between male and female cases.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Nardozza LMM, Caetano ACR, Zamarian ACP, Mazzola JB, Silva CP, Marçal VMG, Lobo TF, Peixoto AB, Araujo Júnior E (2017) Fetal growth restriction: current knowledge. Arch Gynecol Obstet 295(5):1061–1077. https://doi.org/10.1007/s00404-017-4341-9

    Article  PubMed  Google Scholar 

  2. Longo S, Bollani L, Decembrino L, Di Comite A, Angelini M, Stronati M (2013) Short-term and long-term sequelae in intrauterine growth retardation (IUGR). J Matern Fetal Neonatal Med 26(3):222–225. https://doi.org/10.3109/14767058.2012.715006

    Article  CAS  PubMed  Google Scholar 

  3. Khong TY, De Wolf F, Robertson WB, Brosens I (1986) Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol 93(10):1049–1059

    Article  CAS  Google Scholar 

  4. Jackson MR, Walsh AJ, Morrow RJ, Mullen JB, Lye SJ, Ritchie JW (1995) Reduced placental villous tree elaboration in small-for-gestational-age pregnancies: relationship with umbilical artery Doppler waveforms. Am J Obstet Gynecol 172(2 Pt 1):518–525

    Article  CAS  Google Scholar 

  5. Schiessl B, Mylonas I, Hantschmann P, Kuhn C, Schulze S, Kunze S, Friese K, Jeschke U (2005) Expression of endothelial NO synthase, inducible NO synthase, and estrogen receptors alpha and beta in placental tissue of normal, preeclamptic, and intrauterine growth-restricted pregnancies. J Histochem Cytochem 53(12):1441–1449. https://doi.org/10.1369/jhc.4A6480.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wadhwa PD, Sandman CA, Porto M, Dunkel-Schetter C, Garite TJ (1993) The association between prenatal stress and infant birth weight and gestational age at birth: a prospective investigation. Am J Obstet Gynecol 169(4):858–865

    Article  CAS  Google Scholar 

  7. Lee BE, Ha M, Park H, Hong YC, Kim Y, Kim YJ, Ha EH (2011) Psychosocial work stress during pregnancy and birthweight. Paediatr Perinat Epidemiol 25(3):246–254. https://doi.org/10.1111/j.1365-3016.2010.01177.x

    Article  PubMed  Google Scholar 

  8. Economides DL, Nicolaides KH, Linton EA, Perry LA, Chard T (1988) Plasma cortisol and adrenocorticotropin in appropriate and small for gestational age fetuses. Fetal therapy 3(3):158–164

    Article  CAS  Google Scholar 

  9. Ho JT, Lewis JG, O'Loughlin P, Bagley CJ, Romero R, Dekker GA, Torpy DJ (2007) Reduced maternal corticosteroid-binding globulin and cortisol levels in pre-eclampsia and gamete recipient pregnancies. Clin Endocrinol 66(6):869–877. https://doi.org/10.1111/j.1365-2265.2007.02826.x

    Article  CAS  Google Scholar 

  10. McTernan CL, Draper N, Nicholson H, Chalder SM, Driver P, Hewison M, Kilby MD, Stewart PM (2001) Reduced placental 11beta-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms. J Clin Endocrinol Metab 86(10):4979–4983. https://doi.org/10.1210/jcem.86.10.7893

    Article  CAS  PubMed  Google Scholar 

  11. Shams M, Kilby MD, Somerset DA, Howie AJ, Gupta A, Wood PJ, Afnan M, Stewart PM (1998) 11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction. Hum Reprod 13(4):799–804

    Article  CAS  Google Scholar 

  12. Stewart PM, Rogerson FM, Mason JI (1995) Type 2 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal adrenal steroidogenesis. J Clin Endocrinol Metab 80(3):885–890. https://doi.org/10.1210/jcem.80.3.7883847

    Article  CAS  PubMed  Google Scholar 

  13. Oakley RH, Sar M, Cidlowski JA (1996) The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem 271(16):9550–9559

    Article  CAS  Google Scholar 

  14. Lu NZ, Cidlowski JA (2005) Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes. Mol Cell 18(3):331–342. https://doi.org/10.1016/j.molcel.2005.03.025

    Article  CAS  PubMed  Google Scholar 

  15. Oakley RH, Webster JC, Jewell CM, Sar M, Cidlowski JA (1999) Immunocytochemical analysis of the glucocorticoid receptor alpha isoform (GRalpha) using GRalpha-specific antibody. Steroids 64(10):742–751

    Article  CAS  Google Scholar 

  16. Oakley RH, Jewell CM, Yudt MR, Bofetiado DM, Cidlowski JA (1999) The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action. J Biol Chem 274(39):27857–27866

    Article  CAS  Google Scholar 

  17. Hamilos DL, Leung DY, Muro S, Kahn AM, Hamilos SS, Thawley SE, Hamid QA (2001) GRbeta expression in nasal polyp inflammatory cells and its relationship to the anti-inflammatory effects of intranasal fluticasone. J Allergy Clin Immunol 108(1):59–68. https://doi.org/10.1067/mai.2001.116428

    Article  CAS  PubMed  Google Scholar 

  18. Barnes PJ (2004) Corticosteroid resistance in airway disease. Proc Am Thorac Soc 1(3):264–268. https://doi.org/10.1513/pats.200402-014MS

    Article  CAS  PubMed  Google Scholar 

  19. Saif Z, Hodyl NA, Hobbs E, Tuck AR, Butler MS, Osei-Kumah A, Clifton VL (2014) The human placenta expresses multiple glucocorticoid receptor isoforms that are altered by fetal sex, growth restriction and maternal asthma. Placenta 35(4):260–268. https://doi.org/10.1016/j.placenta.2014.01.012

    Article  CAS  PubMed  Google Scholar 

  20. Cuffe JS, Dickinson H, Simmons DG, Moritz KM (2011) Sex specific changes in placental growth and MAPK following short term maternal dexamethasone exposure in the mouse. Placenta 32(12):981–989. https://doi.org/10.1016/j.placenta.2011.09.009

    Article  CAS  PubMed  Google Scholar 

  21. Hodyl NA, Wyper H, Osei-Kumah A, Scott N, Murphy VE, Gibson P, Smith R, Clifton VL (2010) Sex-specific associations between cortisol and birth weight in pregnancies complicated by asthma are not due to differential glucocorticoid receptor expression. Thorax 65(8):677–683. https://doi.org/10.1136/thx.2009.123091

    Article  PubMed  Google Scholar 

  22. Clifton VL, Cuffe J, Moritz KM, Cole TJ, Fuller PJ, Lu NZ, Kumar S, Chong S, Saif Z (2017) Review: The role of multiple placental glucocorticoid receptor isoforms in adapting to the maternal environment and regulating fetal growth. Placenta 54:24–29. https://doi.org/10.1016/j.placenta.2016.12.017

    Article  CAS  PubMed  Google Scholar 

  23. Knabl J, Hiden U, Huttenbrenner R, Riedel C, Hutter S, Kirn V, Gunthner-Biller M, Desoye G, Kainer F, Jeschke U (2015) GDM alters expression of placental estrogen receptor alpha in a cell type and gender-specific manner. Reprod Sci 22(12):1488–1495. https://doi.org/10.1177/1933719115585147

    Article  CAS  PubMed  Google Scholar 

  24. Hutter S, Knabl J, Andergassen U, Mayr D, Hofmann S, Kuhn C, Mahner S, Arck P, Jeschke U (2015) Fetal gender specific expression of tandem-repeat galectins in placental tissue from normally progressed human pregnancies and intrauterine growth restriction (IUGR). Placenta 36(12):1352–1361. https://doi.org/10.1016/j.placenta.2015.09.015

    Article  CAS  PubMed  Google Scholar 

  25. Challis J, Newnham J, Petraglia F, Yeganegi M, Bocking A (2013) Fetal sex and preterm birth. Placenta 34(2):95–99. https://doi.org/10.1016/j.placenta.2012.11.007

    Article  CAS  PubMed  Google Scholar 

  26. Saif Z, Hodyl NA, Stark MJ, Fuller PJ, Cole T, Lu N, Clifton VL (2015) Expression of eight glucocorticoid receptor isoforms in the human preterm placenta vary with fetal sex and birthweight. Placenta 36(7):723–730. https://doi.org/10.1016/j.placenta.2015.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee JY, Yun HJ, Kim CY, Cho YW, Lee Y, Kim MH (2017) Prenatal exposure to dexamethasone in the mouse induces sex-specific differences in placental gene expression. Dev Growth Differ 59(6):515–525. https://doi.org/10.1111/dgd.12376

    Article  CAS  PubMed  Google Scholar 

  28. Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8(3):138–140

    CAS  Google Scholar 

  29. Heublein S, Vrekoussis T, Kuhn C, Friese K, Makrigiannakis A, Mayr D, Lenhard M, Jeschke U (2013) Inducers of G-protein coupled estrogen receptor (GPER) in endometriosis: potential implications for macrophages and follicle maturation. J Reprod Immunol 97(1):95–103. https://doi.org/10.1016/j.jri.2012.10.013

    Article  CAS  PubMed  Google Scholar 

  30. Kisanga EP, Tang Z, Guller S, Whirledge S (2018) Glucocorticoid signaling regulates cell invasion and migration in the human first-trimester trophoblast cell line Sw7.1. Am J Reprod Immunol 80(1):12974. https://doi.org/10.1111/aji.12974

    Article  CAS  Google Scholar 

  31. Clifton VL (2010) Review: sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta 31(Suppl):S33–39. https://doi.org/10.1016/j.placenta.2009.11.010

    Article  CAS  PubMed  Google Scholar 

  32. Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJ (2010) Boys live dangerously in the womb. Am J Hum Biol 22(3):330–335. https://doi.org/10.1002/ajhb.20995

    Article  PubMed  PubMed Central  Google Scholar 

  33. Dodic M, May CN, Wintour EM, Coghlan JP (1998) An early prenatal exposure to excess glucocorticoid leads to hypertensive offspring in sheep. Clin Sci (Lond) 94(2):149–155

    Article  CAS  Google Scholar 

  34. Ozaki T, Nishina H, Hanson MA, Poston L (2001) Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. J Physiol 530(Pt 1):141–152

    Article  CAS  Google Scholar 

  35. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP (2000) Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 127(19):4195–4202

    CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the “Friedrich Baur Stiftung” for S.H. and by the Department of Obstetrics and Gynecology of the LMU Munich.

Author information

Author notes

  1. Stefan Hutter and Paula Hepp contributed equally to this work.

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, LMU Munich, Maistraße 11, 80337, Munich, Germany

    Stefan Hutter, Paula Hepp, Simone Hofmann, Christina Kuhn, Julia Messner, Ulrich Andergassen, Sven Mahner & Udo Jeschke

  2. Department of Pathology, LMU Munich, Thalkirchner Str. 142, 80337, Munich, Germany

    Doris Mayr

  3. Department of Gynecology and Obstetrics, University of Hamburg, Martinistr. 52, 20246, Hamburg, Germany

    Maria Emilia Solano & Petra Arck

  4. Institute of Social Pediatrics and Adolescent Medicine, LMU Munich, Haydnstr. 5, 80336, Munich, Germany

    Viola Obermeier

Authors
  1. Stefan Hutter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paula Hepp
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simone Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christina Kuhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Julia Messner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ulrich Andergassen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Doris Mayr
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maria Emilia Solano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Viola Obermeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sven Mahner
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Petra Arck
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Udo Jeschke
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

UA: data analysis. PA: protocol/project development. PH: data analysis, manuscript writing/editing. SH: data collection or management. SH: protocol/project development, manuscript writing/editing. UJ: protocol/project development, manuscript writing/editing. CK: data collection or management. SM: data analysis. DM: other (contributed reagents/materials/analysis tools). JM: data collection or management, data analysis, manuscript writing/editing. VO: data analysis. MES: data analysis.

Corresponding author

Correspondence to Udo Jeschke.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 12 kb)

Supplementary file2 (TIFF 4261 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hutter, S., Hepp, P., Hofmann, S. et al. Glucocorticoid receptors α and β are modulated sex specifically in human placentas of intrauterine growth restriction (IUGR). Arch Gynecol Obstet 300, 323–335 (2019). https://doi.org/10.1007/s00404-019-05189-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-019-05189-7

Keywords

Search

Navigation