Prostaglandin E2 and prostaglandin F2 alpha as endometrial receptivity biomarkers in successful embryo implantation

Resumen

Failure in the adhesion of the human blastocyst to the endometrium has been described as an important cause of infertility. Establishing the period of the so-called window of implantation and understanding the molecular mechanisms associated with embryo implantation has clinical and scientific implications. While over the last decades histological evaluation has been used to determine the phase of the menstrual cycle of the endometrium, the poor information obtained has made the case of using new technologies to identify specific markers, understand and characterize the receptive stage. This doctoral thesis investigates the existence, function and clinical impact of two specific lipids, the prostaglandins E(2) and F(2?), which are abundant in human endometrial fluid (EF) during the window of implantation in natural, IVF, and ovum recipient cycles, which is abrogated with the insertion of an IUD. Developments in endometrial receptivity diagnosis using lipidomics demonstrate the correlation between those prostaglandins (PGs) and the receptive stage of the endometrium. The mechanisms that influence the production of these individual PGs in the endometrium were studied with a clinical approach that sheds light on the sequence of events that leads to the development of endometrial receptivity. Our results indicate that PG synthases required for the production of PGE2 and PGF2? are located in the endometrial epithelium and EF for the regulation of PGs concentrations during the window of implantation. Most of the accumulated evidence, using an in vitro model of embryonic adhesion, indicates that inhibition of PGE2 and PGF2? or the PG receptors EP2 and FP prevents embryo adhesion, which can be reversed by adding back these molecules or by using EP2 and FP agonists. Finally, our pilot study demonstrates that PGE2 and PGF2? concentrations in EF aspirated 24 hours prior to embryo transfer showed to be predictive of a successful pregnancy outcome. In summary, our findings indicate that embryo implantation is associated with an active crosstalk of PGE2 and PGF2? via EP2 and FP receptors, respectively, that might serve to nurse the blastocyst at the time of embryo implantation. Likewise the levels of these PGs in EF could potentially serve as non-invasive biomarkers to define the receptive phase of the endometrium and, therefore, have a significant impact in clinical translation.