Uterine fluid proteins for minimally invasive assessment of endometrial receptivity

Context Clinically used endometrial (EM) receptivity assays are based on transcriptomic patterning of biopsies at mid-secretory endometrium (MSE) to identify the possible displacement or disruption of window of implantation (WOI) in patients with recurrent implantation failure (RIF). However, biopsies are invasive and cannot be performed in the same cycle with IVF embryo transfer, while uterine fluid (UF) analysis is considered minimally invasive and can immediately precede embryo transfer. Objective To determine whether UF proteome can be used for WOI monitoring and whether it would highlight the etiology of RIF. Patients Paired early secretory endometrial (ESE) and MSE UF samples from six fertile control women for discovery, and additional 11 paired ESE/MSE samples from controls and 29 MSE samples from RIF patients for validation. Results Using discovery mass spectrometry (MS) proteomics we detected 3,158 proteins from secretory phase UF of which 367 undergo significant (q < 0.05) proteomic changes while transitioning from ESE to MSE. 45 proteins were further validated with targeted MS, and 21 were found to display similar levels between control ESE and RIF MSE, indicating displacement of the WOI. Panel of PGR, NNMT, SLC26A2 and LCN2 demonstrated specificity and sensitivity of 91.7% for distinguishing MSE from ESE samples. The same panel distinguished control MSE samples from RIF MSE with a 91.7% specificity and 96.6% sensitivity. Conclusion UF proteins can be used for estimating uterine receptivity with minimal invasiveness. Women with RIF appear to have altered MSE UF profiles that may contribute to their low IVF success rate.