DIFFERENCES IN FOLLICULAR FLUID CYTOKINE PROFILE IN WOMEN WITH DIMINISHED OVARIAN RESERVE

Abstract

To investigate the expression of cytokines in follicular fluid (FF) of women with diminished ovarian reserve (DOR) undergoing in vitro fertilization (IVF) and explore correlated functional pathways. Nested case-control study Women undergoing ovarian stimulation and planned oocyte retrieval were recruited from the Emory Reproductive Center. We included 51 women with DOR and 30 controls, defined as women undergoing IVF for male factor, tubal factor due to tubal ligation, or oocyte cryopreservation for planned fertility delay (non-oncologic). Follicular fluid samples were collected from each participant at the time of oocyte retrieval and stored for later use. The follicular fluid samples were then assessed using multiplexed sandwich ELISA-based quantitative array platform (RayBiotech). Quantile regression was used to assess the association of DOR diagnosis and cytokine concentrations. The false detection rate was controlled at 5%. A total of 357 cytokines were investigated in both women with DOR and controls. Expression of 26 cytokines was found to be significantly different in the follicular fluid between the DOR and the control group (FDR<0.05), following adjustment for age and BMI. Differentially expressed cytokines belong to diverse functional groups involved in follicular development and maturation including growth factor and related proteins, receptor signaling, apoptosis and inflammation. Among the most significant differentially expressed cytokines were sonic hedgehog ligand (SHH) and Amphiregulin (AR), both of which were lower in women with DOR. SHH is involved in granulosa and theca cell communication and promotes cellular proliferation in mouse ovary. AR has a significant role in oocyte maturation. We also detected a lower level of soluble Fas in women with DOR comparted to controls. The soluble form of Fas has anti-apoptotic activity, and our finding suggests down regulation of this pathway in women with DOR, We found 26 cytokines differentially expressed between women with DOR and controls with normal ovarian reserve. Our data suggest feasibility of identifying biomarkers that illuminate how the ovarian follicle microenvironment is altered in the DOR population and identification of pathways playing a role in pathophysiology of DOR.