PGE2 and PGF2α Concentrations in Human Endometrial Fluid as Biomarkers for Embryonic Implantation

Background: Prostaglandin (PG) signaling has been implicated in embryonic implantation in several animal species including humans; however, this knowledge has not yet been clinically translated. The objective of this work is to investigate whether PGE(2) and PGF(2)alpha in endometrial fluid (EF) can be used as biomarkers of human embryonic implantation. Patients and Methods: Lipidomic profile of human EF (n = 173) obtained through natural cycles, hormonal replacement therapy, controlled ovarian stimulation, and refractory endometrium induced by the insertion of an intrauterine device was analyzed by liquid chromatography and tandem mass spectrometry. Immunohistochemistry, Western blotting, immunolocalization of PG receptors on mouse embryos, embryo adhesion assay, pharmacological interventions, and statistical analysis were conducted. Results: PGE(2) and PGF(2)alpha concentrations increased significantly in thehumanEF during the window of implantation in natural cycles and assisted reproductive technologies patients undergoing in vitro fertilization and ovum donation. This profile was abrogated in the refractory endometrium. We also demonstrated that PGE(2) and PGF(2)alpha synthases are located in the endometrial epithelium being hormonally regulated during the window of implantation, and PG receptors are expressed in the trophoectoderm and inner cell mass of mouse blastocysts. Using an in vitro model of embryo adhesion, we demonstrated that inhibition of PGE(2) and PGF(2)alpha or PG receptors (EP2 and FP) prevents embryo adhesion, which can be overcome by adding these molecules back or using their agonists. Finally, in a pilot study, we demonstrated that PGE(2) and PGF(2)alpha levels from EF 24 hours prior to embryo transfer could predict pregnancy outcome. Conclusions: Our results suggest that PGE(2) and PGF(2)alpha concentrations 24 hours prior to embryo transfer are potential noninvasive biomarkers of endometrial receptivity.