The endometrial factor in human embryo implantation

The studies presented in this thesis aimed to explore the role of the endometrium in the implantation process. At present, embryo implantation is the major rate-limiting step for success in fertility treatment. Clinicians have sought to develop clinical interventions aimed at enhancing implantation rates from IVF. As reviewed in this thesis, there is no evidence supporting the empirical use of most pharmaceutical interventions, such as aspirin, nitric oxide, aromatase inhibitors, ascorbic acid, prolonged progesterone treatment, or insulin sensitizing drugs, in an unselected IVF population. A meta-analysis of RCTs on the effect of adjuvant glucocorticoids in the peri-implantation period was performed and showed higher pregnancy rates in women undergoing IVF (not ICSI) using adjuvant glucocorticoids of borderline significance. For ethical and practical reasons it is difficult to study human embryo implantation in vivo, since many approaches will risk disturbing the process itself. Endometrial secretion aspiration prior to embryo transfer and analysis by a multiplex immunoassay is non-invasive and has been shown to be safe and a clinically useful approach to study the endometrial factor in human embryo implantation. We have shown that endometrial secretion cytokine profiling identifies a profile conducive to clinical pregnancy, and the ability to predict clinical pregnancy by interleukin (IL)-1? and Tumor Necrosis Factor (TNF)-? levels in endometrial secretions was similar and additive to the predictive value of embryo quality. Supraphysiological sex steroid levels resulting from ovarian stimulation are considered to be detrimental to endometrial receptivity in IVF. Significantly higher concentrations of IL-1߬ IL-5, IL-10, IL-12, IL-17, TNF-?, Heparin-binding Epidermal Growth Factor (Hb-EGF), Eotaxin, and Dickkopf homolog (Dkk)-1 were present in endometrial secretions obtained in stimulated compared to natural cycles. There is evidence that embryo implantation rates may be impaired by the pathogenic effects of bacterial vaginosis. The intra-uterine cytokine profile of women with or without bacterial vaginosis was assessed and women with bacterial vaginosis showed cytokine concentrations which were within the normal range compared to controls, with a tendency to a more pro-inflammatory profile. Previous approaches to investigate implantation have generally relied on the analysis of individual candidate genes. To date no single marker has been identified that is specific and sensitive in identifying a receptive endometrium though. Microarray analysis enables an approach from a global genomic perspective. Results of the largest set of microarray data on the endometrial transcriptome in women with idiopathic recurrent implantation failure versus controls have been reported. Dysregulated pathways in the endometrium in women with recurrent implantation failure have been identified meriting further investigation. Concerning the endometrial factor in the human implantation process in the general IVF population, we believe that we can conclude from the studies presented in this thesis that the endometrium is an important determinant of success and is not simply facilitory. However, a diminished endometrial receptivity as the primary cause of recurrent implantation failure may only be present in a limited number of patients, who cannot be easily identified by known clinical parameters or an endometrial gene expression profile. A test for endometrial receptivity remains elusive.