The oocyte microenvironment is altered in adolescents compared to oocyte donors

Abstract STUDY QUESTION Do the molecular signatures of cumulus cells (CCs) and follicular fluid (FF) of adolescents undergoing fertility preservation differ from that of oocyte donors? SUMMARY ANSWER The microenvironment immediately surrounding the oocyte, including the CCs and FF, is altered in adolescents undergoing fertility preservation compared to oocyte donors. WHAT IS KNOWN ALREADY Adolescents experience a period of subfecundity following menarche. Recent evidence suggests that this may be at least partially due to increased oocyte aneuploidy. Reproductive juvenescence in mammals is associated with suboptimal oocyte quality. STUDY DESIGN, SIZE, DURATION This was a prospective cohort study. Adolescents (10–19 years old, n = 23) and oocyte donors (22–30 years old, n = 31) undergoing ovarian stimulation and oocyte retrieval at a single center between 1 November 2020 and 1 May 2023 were enrolled in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS Patient demographics, ovarian stimulation, and oocyte retrieval outcomes were collected for all participants. The transcriptome of CCs associated with mature oocytes was compared between adolescents (10–19 years old, n = 19) and oocyte donors (22–30 years old, n = 19) using bulk RNA-sequencing. FF cytokine profiles (10–19 years old, n = 18 vs 25–30 years old, n = 16) were compared using cytokine arrays. MAIN RESULTS AND THE ROLE OF CHANCE RNA-seq analysis revealed 581 differentially expressed genes in CCs of adolescents relative to oocyte donors, with 361 genes downregulated and 220 upregulated. Genes enriched in pathways involved in cell cycle and cell division (e.g. GO: 1903047, P = 3.5 × 10−43; GO: 0051983, P = 4.1 × 10−30; GO: 0000281, P = 7.7 × 10−15; GO: 0044839, P = 5.3 × 10−13) were significantly downregulated, while genes enriched in several pathways involved in cellular and vesicle organization (e.g. GO: 0010256, P = 1.2 × 10−8; GO: 0051129, P = 6.8 × 10−7; GO: 0016050, P = 7.4 × 10−7; GO: 0051640, P = 8.1 × 10−7) were upregulated in CCs of adolescents compared to oocyte donors. The levels of nine cytokines were significantly increased in FF of adolescents compared to oocyte donors: IL-1 alpha (2-fold), IL-1 beta (1.7-fold), I-309 (2-fold), IL-15 (1.6-fold), TARC (1.9-fold), TPO (2.1-fold), IGFBP-4 (2-fold), IL-12-p40 (1.7-fold), and ENA-78 (1.4-fold). Interestingly, seven of these cytokines have known pro-inflammatory roles. Importantly, neither the CC transcriptomes nor FF cytokine profiles were