A Case-Control Study of Follicular Fluid Cytokine Profiles in Women with Diminished Ovarian Reserve

• Authors: Sina Abhari, Emory University; Jingqiao Lu, RayBiotech Life, Inc; Heather Hipp, Emory University; Brianne Petritis, RayBiotech Life, Inc; Sabrina A. Gerkowicz, IVF MD; Quinton S. Katler, Emory University; Haw-Hen Yen, RayBiotech Life, Inc; Yingqing Mao, RayBiotech Life, Inc; Hao Tang, RayBiotech Life, Inc; Weirong Shang, Emory University; Laurie J. McKenzie, Baylor College of Medicine; Alicia K Smith, Emory University; Ruo-Pan Huang, RayBiotech Life, Inc; Anna Knight, Emory University
• Journal Title: Reproductive Sciences
• Volume: Volume 29, Number 9
• Publisher: Springer Link | 2021-11-04, Pages 2515-2524
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s43032-021-00757-2
• Subjects: Health Sciences, Obstetrics and Gynecology
• Keywords: Diminished ovarian reserve; Follicular fluid; Cytokines; In vitro fertilization

Abstract

Ovarian reserve is an important determinant of a woman’s reproductive potential, and women with diminished ovarian reserve (DOR) often seek in vitro fertilization (IVF). The underlying etiology of DOR is unknown, but follicular fluid cytokine concentrations likely play a role in follicular development and maturation. The present study seeks to investigate the expression of cytokines in follicular fluid (FF) of women with DOR undergoing IVF and explore correlated functional pathways. 194 women undergoing ovarian stimulation were recruited at the time of oocyte retrieval. Women were classified as having DOR if they met one or more of the following criteria: AMH <1 ng/ml, FSH >10 mIU/ml and/or AFC <10. Controls included women undergoing IVF for male factor, tubal factor due to tubal ligation, or planned oocyte cryopreservation (non-oncologic). The concentrations of 480 cytokines and related growth factors in follicular fluid were determined using a multiplex immunoassay. Fifty-nine (59) cytokines had significantly different concentrations (53 higher and 6 lower) in the DOR relative to the control group after adjusting for age and body mass index (BMI) (false discovery rate; FDR<0.1). Using the most informative 44 biomarkers as indicated by a random forest (RF) model, an area under the curve (AUC) of 0.78 was obtained. Thus, follicular microenvironment differs between women with DOR and normal ovarian reserve. The differentially expressed cytokines belong to diverse processes that are primarily involved in follicular maturation and ovulation. These changes may play an important role in treatment outcomes in women with DOR.