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The Role of the Glucocorticoid Receptor Signalling Pathway within the Human Endometrium / Samantha Thomas

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DOI (Published version): 10.23889/Suthesis.50584

Abstract

Summary:The activation of the stress-responsive biological system, known as the hypothalamic-pituitary-adrenal axis leads to an increase in the synthesis of the glucocorticoids (GCs). The GCs regulate a number of diverse biological processes within the body by altering the transcription of an array...

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Published: 2019
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa50584
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2022-09-27T16:25:28.1054193</datestamp><bib-version>v2</bib-version><id>50584</id><entry>2019-05-31</entry><title>The Role of the Glucocorticoid Receptor Signalling Pathway within the Human Endometrium</title><swanseaauthors/><date>2019-05-31</date><abstract>Summary:The activation of the stress-responsive biological system, known as the hypothalamic-pituitary-adrenal axis leads to an increase in the synthesis of the glucocorticoids (GCs). The GCs regulate a number of diverse biological processes within the body by altering the transcription of an array of steroid responsive genes, mediated by the glucocorticoid receptor (GR). Along with the well-characterised sex steroid hormones, the human endometrium is also targeted by GCs due to the presence of GR within the healthy human endometrium Nevertheless, research is lacking in elucidating the role of stress and hence the GR signalling pathway on reproductive functions and fertility.Objectives:The principal aims were to present novel evidence for the expression of GCs and its nuclear receptor; GR in the endometrium of fertile and infertile patients and to relate these observations to key features of common reproductive endocrinological pathologies namely PCOS, endometriosis and unexplained infertility (UI). Secondary to this, was to establish the effect of GR signalling pathway activation in the process of endometrial decidual transformation in fertile and infertile patients.Methodology:This project employed the use of immunohistochemistry (IHC), cell culture, Real-time polymerase chain reaction (qPCR), immunoblotting, enzyme linked immunosorbant assays (ELISAs), chromatin immunoprecipitation (ChIP), cell morphology analysis and TRANSFAC promoter analysis.Results:Circulating cortisol levels and endometrial GR expression follow a distinct expression pattern throughout the normal menstrual cycle, with the lowest levels being observed during the secretory phase. Conversely, infertile patients exhibited significantly higher levels of both. In vitro analysis revealed that activation of the GR signalling pathway, although crucial for reproductive processes in the fertile patients, can result in delayed decidualization in the presence of the stress hormone cortisol. The effect of stress on the decidual response was able to be inhibited when a GR antagonist was used. ChIP analysis confirmed the presence of GR on the promoter regions of target genes in the presence of GCs during decidual transformation. An already hindered decidual response present in infertile patients was further exacerbated in the presence of the stress hormone. Moreover, a genetic switch from GR to mineralocorticoid receptor (MR) dominance, crucial for successful decidualization is inhibited in the infertile patients. Finally, a degree of crosstalk between GR and the sex steroid hormone signalling pathways also takes place during endometrial decidual transformation.Conclusion:In conclusion, it is apparent that the GR signalling pathway plays a crucial role in reproduction in the absence of the stress response. However, endometrial GR expression and circulating levels of the stress hormone cortisol is altered in infertile patients diagnosed with PCOS, endometriosis and UI. The activation of the GR signalling pathway due to the presence of the stress hormone cortisol is detrimental for crucial reproductive functions, including decidualization in both fertile and infertile patients.</abstract><type>E-Thesis</type><journal/><volume/><journalNumber/><paginationStart/><paginationEnd/><publisher/><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic/><keywords>Glucocorticoid receptor, decidualization, stress, infertility</keywords><publishedDay>31</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-12-31</publishedDate><doi>10.23889/Suthesis.50584</doi><url/><notes>A selection of third party content is redacted or is partially redacted from this thesis.</notes><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><degreelevel>Doctoral</degreelevel><degreename>Ph.D</degreename><degreesponsorsfunders>KESS</degreesponsorsfunders><apcterm/><funders/><projectreference/><lastEdited>2022-09-27T16:25:28.1054193</lastEdited><Created>2019-05-31T09:51:01.0186788</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Samantha</firstname><surname>Thomas</surname><order>1</order></author></authors><documents><document><filename>Under embargo</filename><originalFilename>Under embargo</originalFilename><uploaded>2019-05-31T13:52:21.4670000</uploaded><type>Output</type><contentLength>15188222</contentLength><contentType>application/pdf</contentType><version>Redacted version - open access</version><cronfaStatus>true</cronfaStatus><embargoDate>2024-05-22T00:00:00.0000000</embargoDate><copyrightCorrect>true</copyrightCorrect></document></documents><OutputDurs/></rfc1807>
spelling 2022-09-27T16:25:28.1054193 v2 50584 2019-05-31 The Role of the Glucocorticoid Receptor Signalling Pathway within the Human Endometrium 2019-05-31 Summary:The activation of the stress-responsive biological system, known as the hypothalamic-pituitary-adrenal axis leads to an increase in the synthesis of the glucocorticoids (GCs). The GCs regulate a number of diverse biological processes within the body by altering the transcription of an array of steroid responsive genes, mediated by the glucocorticoid receptor (GR). Along with the well-characterised sex steroid hormones, the human endometrium is also targeted by GCs due to the presence of GR within the healthy human endometrium Nevertheless, research is lacking in elucidating the role of stress and hence the GR signalling pathway on reproductive functions and fertility.Objectives:The principal aims were to present novel evidence for the expression of GCs and its nuclear receptor; GR in the endometrium of fertile and infertile patients and to relate these observations to key features of common reproductive endocrinological pathologies namely PCOS, endometriosis and unexplained infertility (UI). Secondary to this, was to establish the effect of GR signalling pathway activation in the process of endometrial decidual transformation in fertile and infertile patients.Methodology:This project employed the use of immunohistochemistry (IHC), cell culture, Real-time polymerase chain reaction (qPCR), immunoblotting, enzyme linked immunosorbant assays (ELISAs), chromatin immunoprecipitation (ChIP), cell morphology analysis and TRANSFAC promoter analysis.Results:Circulating cortisol levels and endometrial GR expression follow a distinct expression pattern throughout the normal menstrual cycle, with the lowest levels being observed during the secretory phase. Conversely, infertile patients exhibited significantly higher levels of both. In vitro analysis revealed that activation of the GR signalling pathway, although crucial for reproductive processes in the fertile patients, can result in delayed decidualization in the presence of the stress hormone cortisol. The effect of stress on the decidual response was able to be inhibited when a GR antagonist was used. ChIP analysis confirmed the presence of GR on the promoter regions of target genes in the presence of GCs during decidual transformation. An already hindered decidual response present in infertile patients was further exacerbated in the presence of the stress hormone. Moreover, a genetic switch from GR to mineralocorticoid receptor (MR) dominance, crucial for successful decidualization is inhibited in the infertile patients. Finally, a degree of crosstalk between GR and the sex steroid hormone signalling pathways also takes place during endometrial decidual transformation.Conclusion:In conclusion, it is apparent that the GR signalling pathway plays a crucial role in reproduction in the absence of the stress response. However, endometrial GR expression and circulating levels of the stress hormone cortisol is altered in infertile patients diagnosed with PCOS, endometriosis and UI. The activation of the GR signalling pathway due to the presence of the stress hormone cortisol is detrimental for crucial reproductive functions, including decidualization in both fertile and infertile patients. E-Thesis Glucocorticoid receptor, decidualization, stress, infertility 31 12 2019 2019-12-31 10.23889/Suthesis.50584 A selection of third party content is redacted or is partially redacted from this thesis. COLLEGE NANME COLLEGE CODE Swansea University Doctoral Ph.D KESS 2022-09-27T16:25:28.1054193 2019-05-31T09:51:01.0186788 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Samantha Thomas 1 Under embargo Under embargo 2019-05-31T13:52:21.4670000 Output 15188222 application/pdf Redacted version - open access true 2024-05-22T00:00:00.0000000 true
title The Role of the Glucocorticoid Receptor Signalling Pathway within the Human Endometrium
spellingShingle The Role of the Glucocorticoid Receptor Signalling Pathway within the Human Endometrium
,
title_short The Role of the Glucocorticoid Receptor Signalling Pathway within the Human Endometrium
title_full The Role of the Glucocorticoid Receptor Signalling Pathway within the Human Endometrium
title_fullStr The Role of the Glucocorticoid Receptor Signalling Pathway within the Human Endometrium
title_full_unstemmed The Role of the Glucocorticoid Receptor Signalling Pathway within the Human Endometrium
title_sort The Role of the Glucocorticoid Receptor Signalling Pathway within the Human Endometrium
author ,
author2 Samantha Thomas
format E-Thesis
publishDate 2019
institution Swansea University
doi_str_mv 10.23889/Suthesis.50584
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 0
active_str 0
description Summary:The activation of the stress-responsive biological system, known as the hypothalamic-pituitary-adrenal axis leads to an increase in the synthesis of the glucocorticoids (GCs). The GCs regulate a number of diverse biological processes within the body by altering the transcription of an array of steroid responsive genes, mediated by the glucocorticoid receptor (GR). Along with the well-characterised sex steroid hormones, the human endometrium is also targeted by GCs due to the presence of GR within the healthy human endometrium Nevertheless, research is lacking in elucidating the role of stress and hence the GR signalling pathway on reproductive functions and fertility.Objectives:The principal aims were to present novel evidence for the expression of GCs and its nuclear receptor; GR in the endometrium of fertile and infertile patients and to relate these observations to key features of common reproductive endocrinological pathologies namely PCOS, endometriosis and unexplained infertility (UI). Secondary to this, was to establish the effect of GR signalling pathway activation in the process of endometrial decidual transformation in fertile and infertile patients.Methodology:This project employed the use of immunohistochemistry (IHC), cell culture, Real-time polymerase chain reaction (qPCR), immunoblotting, enzyme linked immunosorbant assays (ELISAs), chromatin immunoprecipitation (ChIP), cell morphology analysis and TRANSFAC promoter analysis.Results:Circulating cortisol levels and endometrial GR expression follow a distinct expression pattern throughout the normal menstrual cycle, with the lowest levels being observed during the secretory phase. Conversely, infertile patients exhibited significantly higher levels of both. In vitro analysis revealed that activation of the GR signalling pathway, although crucial for reproductive processes in the fertile patients, can result in delayed decidualization in the presence of the stress hormone cortisol. The effect of stress on the decidual response was able to be inhibited when a GR antagonist was used. ChIP analysis confirmed the presence of GR on the promoter regions of target genes in the presence of GCs during decidual transformation. An already hindered decidual response present in infertile patients was further exacerbated in the presence of the stress hormone. Moreover, a genetic switch from GR to mineralocorticoid receptor (MR) dominance, crucial for successful decidualization is inhibited in the infertile patients. Finally, a degree of crosstalk between GR and the sex steroid hormone signalling pathways also takes place during endometrial decidual transformation.Conclusion:In conclusion, it is apparent that the GR signalling pathway plays a crucial role in reproduction in the absence of the stress response. However, endometrial GR expression and circulating levels of the stress hormone cortisol is altered in infertile patients diagnosed with PCOS, endometriosis and UI. The activation of the GR signalling pathway due to the presence of the stress hormone cortisol is detrimental for crucial reproductive functions, including decidualization in both fertile and infertile patients.
published_date 2019-12-31T04:02:05Z
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score 11.013731

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