Comparative study of molecular processes and factors affecting endometrial function in subfertile patients with uterine disorders

Resumen

The human endometrium is a highly dynamic and complex tissue that only becomes receptive to the embryo during a short period of time. Therefore, identifying pathologies and factors that prevent the endometrium from acquiring its receptive phenotype is crucial to prevent implantation failure and increase pregnancy rates. Uterine disorders are complex, polygenic, and multifactorial alterations that often compromise female fertility, although their effects on endometrial receptivity are poorly understood. In addition to many of them currently lacking effective treatments, they are often comorbid and their incidence increases with age. Transcriptomic technologies are powerful tools to provide some insight into these topics. However, remaining problems include the poor overlap of results of different transcriptomic studies evaluating the same uterine disorder, and the lack of gene expression studies comparing functional alterations in endometrium amongst uterine disorders or exploring the effect of age on endometrial gene expression and function and its relationship with an increased incidence of uterine disorders. To this end, the main aim of this PhD thesis dissertation was to identify and compare the molecular mechanisms underlying distinct uterine disorders and factors (e.g. age) and its comorbidities at a functional level, as well as determine how they may affect subfertility of endometrial origin. To achieve this, different functional genomic approaches were applied to case versus control transcriptomic data from studies evaluating the endometrium of patients of different ages and/or affected by uterine disorders. Dysregulated functions relevant to endometrial receptivity acquisition were identified in patients diagnosed with endometriosis, endometrial adenocarcinoma, recurrent implantation failure, recurrent pregnancy loss, and in the endometrium of women older than 35 years. These results revealed new molecules and functions altered in the endometrium of patients affected by uterine disorders and with age. Moreover, they gave rise to new guidelines for endometrial biomarker discovery, confirmed previous hypothesis and generated new hypotheses relevant for the reproductive medicine field, giving insight into how uterine disorders and age affect fertility and are related to one another through the dysregulation of ciliary processes and the cell cycle. Taken together, this work provides further knowledge of the molecular mechanisms by which uterine disorders and age affect endometrial gene function and fertility, and how these conditions are related to each other. The results obtained in this PhD thesis dissertation reinforce the need for endometrial evaluation of patients diagnosed with uterine disorders and/or older than 35 years during in vitro fertilization treatments to prevent implantation failure, being relevant for the future development of personalized diagnostic and treatment methods that will improve the reproductive outcomes of these patients.