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Title: Characterization of the endometrium of women with reproductive failure
Author: Salker, Madhuri Sonal
ISNI:       0000 0004 2735 4802
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Differentiation of human endometrial stromal cells (HESCs) into decidual cells represents a highly coordinated process essential for embryo implantation. Following the post-ovulatory rise in progesterone levels HESCs undergo biochemical and morphological transformation in a process known as decidualization. It heralds the end of the mid-secretory phase implantation window, defined as the limited period during which progesterone-driven changes in the luminal epithelium allow apposition, attachment and invasion of a developmentally competent blastocyst. Failure of the endometrium to acquire a receptive phenotype is widely viewed as a major cause of infertility and IVF treatment failure. Conversely, recurrent pregnancy loss (RPL) is associated with impaired decidualization. Firstly, analysis of mid-secretory endometrial biopsies from RPL patients demonstrated that there is a decreased expression of the decidual marker, Prolactin but increased levels of pro-inflammatory cytokine, Prokineticin-1. Secondly, HESCs were then identified to mount a highly coordinated but transient inflammatory response that renders the endometrium receptive, by rapidly releasing Interleukin-33, up-regulating its cognate transmembrane receptor-ST2L and other pro-inflammatory mediators before mounting an anti-inflammatory response that includes down-regulation of ST2L and increased secretion of the soluble decoy receptor sST2. In agreement, only during the transient pro-inflammatory phase of the decidual process did HESCs secrete factors conducive to implantation in mice. Failure of HESCs to constrain this pro-inflammatory response appeared to prolong the implantation window and was associated with RPL. Furthermore, deregulated Serum and Glucocorticoid Kinase 1 (SGK1) activity in the endometrium during the window of implantation either interfered with embryo implantation, leading to infertility, or compromised the integrity of the decidual-placental interface, resulting in pregnancy loss. A constitutively active SGK1 mutant was expressed in luminal epithelial cells of the mouse uterus; perturbing uterine fluid handling and abolished embryo implantation. However, implantation was not impaired in Sgk1-deficient mice, although there was evidence of fetal demise. RPL was also associated with lower SGK1 induction in decidualizing HESCs and impaired expression of oxidative stress defence genes. In summary, impaired decidualization or unfettered endometrial receptivity carries an obvious risk of implantation of developmentally delayed or compromised embryos thus triggering a spectrum of pathological events, leading to miscarriage or predisposing for obstetrical complications. Together, these findings provide fundamental insights of uterine receptivity and describe a novel paradigm of reproductive failure with potentially far-reaching clinical implications.
Supervisor: Brosens, Jan ; Christian, Mark Sponsor: Genesis Research Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available