DISTINCT ENDOMETRIAL PROTEIN PROFILES IN SPONTANEOUS AND STIMULATED CYCLES IN WOMEN WITH POOR OVARIAN RESPONSE

The window of implantation is a critical period for embryo implantation. Ovarian stimulation can disrupt endometrial receptivity, potentially through altered gene expression and protein synthesis. However, the impact on the endometrial proteome remains underexplored. Identifying biomarkers of endometrial receptivity provides an opportunity to develop targeted interventions aimed at improving implantation outcomes. This prospective, case-crossover, open-label study was conducted by the Department of Human Reproduction, Division of Obstetrics and Gynecology of the University Medical Centre Ljubljana, Slovenia from September 2023 to June 2024. The study included 15 women under the age of 43 with primary infertility and poor ovarian response, classified per POSEIDON criteria. Endometrial samples were collected using a pipelle biopsy during the the window of implantation in spontaneous and stimulated cycles and analyzed using protein microarrays targeting 1,438 proteins. Differential protein expression was assessed using linear models for microarray data (LIMMA). Comparison of endometrial samples from spontaneous and stimulated cycles revealed 107 differentially abundant proteins (|logFC| > 0.5, adj. p < 0.05). Key proteins were associated with immune response (IL-8, proteins S100-A8 and S100-A9, CAMP) and extracellular matrix remodeling (MMP-9). KEGG analysis highlighted significant pathways, including cytokine-cytokine receptor interaction, IL-17 signaling pathway, and pathways in cancer. Cluster analysis demonstrated distinct protein expression patterns, with all stimulated cycles exhibiting pronounced changes. Additionally, in 40% of the stimulated cycle samples, ovarian stimulation induced more pronounced variations in protein concentrations. The findings highlight the need to refine ovarian stimulation protocols to minimize adverse effects on the endometrial environment. By tailoring treatments to individual patient profiles, it may be possible to enhance synchronization between the embryo and the endometrium, thereby improving clinical pregnancy rates.