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Title: The role of the glucocorticoid receptor signalling pathway within the human endometrium
Author: Thomas, Samantha J.
ISNI:       0000 0004 7967 4525
Awarding Body: Swansea University
Current Institution: Swansea University
Date of Award: 2019
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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.
Supervisor: Gonzalez, Deyarina ; Guy, Owen, J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral