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The human endometrium is a complex tissue that undergoes an idealised 28-day cycle, strictly controlled by the ovarian steroid hormones. Endometriosis is a common disease affecting 10% of all women of reproductive age. It is characterised by severe abdominal pain, and can result in infertility. Current treatment strategies for this disease are insufficient. In this study, I determine the transcript profiles of normal human endometrium and endometriosis, in the hope that they may lead to improved treatments for this debilitating disease. I use microarray technology to determine the levels of tens of thousands of transcripts in a range of endometrial samples. Through the application of a range of sophisticated statistical techniques, specifically designed for the analysis of extensive microarray data sets, I identify transcripts that are present at significantly different levels in eutopic endometrium, from women with and without endometriosis, and in peritoneal ectopic endometriotic lesions. I discover a number of transcripts that have not previously been identified in either the endometrium or endometriosis, and report three new factors that may be important in the correct cycling of the endometrium or in the pathology of endometriosis. I propose that glutathione peroxidase 3 is required in the endometrium during the secretory phase of the menstrual cycle to protect implanting blastocysts from free radical damage. I suggest that intestinal trefoil protein TFF3 may be required for the correct remodelling of the endometrium following menstruation, and I implicate the transcription factor four and a half LIM domains 1 in the establishment of endometriotic lesions at ectopic sites. These findings offer novel insights into the regulation of the endometrium and its potential pathologies. The identification of these new transcripts in the endometrial system are a step towards the development of improved treatments for endometriosis.

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Angiogenesis is highly regulated during reproduction, as vessel growth, maturation and regression are observed in cyclic endometrium. This thesis investigates the possible regulation of endothelial and endometrial function, mainly focused on Wnt signalling, in angiogenesis and the female reproductive tract. The transcript profiles in a murine model of menstruation were also studied using two independent microarray experiments and platforms, which provide a broader view of molecular processes during menstruation. The major findings of this thesis include: 1) mRNAs encoding many Wnt signalling-related molecules are present in human umbilical vein endothelial cells and female reproductive tissues. 2) Wnt signalling has a role in endothelial cell growth control and this is mediated through cell-cell contact. 3) Wnt signalling is tightly regulated in endothelial cells and endometrium through the balance of positive and negative regulators of Wnt signalling pathway. There is also a tight balance between the canonical pathway and the non-canonical pathway. 4) Transcript levels of genes involved in many molecular processes changed during the time-course of a murine model of menstruation, suggesting that these molecule processes, including immune response, cell growth and maintenance, metabolism, transport and cell-cell interaction, are regulated during menstruation and participate in regulating endometrial function. These results provide further insights into the complexity of endometrial function and offer new therapeutic possibilities for the treatment of gynaecological disease.

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No description available.

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Maternal vascular dysfunction may alter the feto-placental environment and be associated with aberrant placental vascular development. We therefore aimed to determine: (1) if pregnancy in the insulin dependent (type I) diabetic woman is associated with increased maternal endothelial dysfunction, and (2) if the ultrastructure of the terminal placental villus, the functional exchange unit, is altered in these pregnancies. As an index of maternal vascular function circulating concentrations of defined endothelial-derived cell adhesion molecules were assessed. An ELISA was used to quantify the concentrations of the cell adhesion molecules throughout diabetic and control pregnancies and in matched non-pregnant women. The circulating concentrations of the cell adhesion molecules: E-selectin and ICAM-1 were increased in non-pregnant diabetic subjects compared to non-pregnant controls. These cell adhesion molecules interact with neutrophils and provide evidence of endothelial dysfunction in our population of non-pregnant diabetic women. In contrast, during pregnancy there was no difference in the circulating concentrations of ICAM-1 between diabetic and control groups. The concentration of E-selectin was significantly reduced when measured in the pregnant compared to the non-pregnant diabetic cohorts. These findings suggest that pregnancy, in our population of diabetic women, may actually be a time of vascular well-being. We hypothesize that this is a reflection of the improved glycaemic control achieved by these women during pregnancy. The ultrastructure of the terminal placental villi from ten diabetic and control pregnancies was assessed by three techniques: transmission electron microscopic determination of cross-sectional architecture, scanning electron microscopy of specially prepared placental vascular casts and immunohistochemical assessment of villous stromal composition and cell turnover. The terminal villi of diabetic placentae were highly comparable to those of control placentae. Specifically we demonstrated no significant difference on comparison of villous diameter, villous capillary diameter, cytotrophoblast or syncytiotrophoblast nuclei number and turnover, or stromal matrix content.