Ovarian stimulation with excessive FSH doses causes cumulus cell and oocyte dysfunction in small ovarian reserve heifers

Authors: KARL, KAITLIN - Michigan State University; SCHALL, PETER - Michigan State University; CLARK, ZARAMASINA - Michigan State University; Ruebel, Meghan; CIBELLI, JOSE - Michigan State University; TEMPELMAN, ROBERT - Michigan State University; LATHAM, KEITH - Michigan State University; IRELAND, JAMES - Michigan State University

Submitted to: Molecular Human Reproduction
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/12/2023
Publication Date: 9/15/2023
Citation: Karl, K.R., Schall, P.Z., Clark, Z.L., Ruebel, M., Cibelli, J., Tempelman, R., Latham, K.E., Ireland, J.J. 2023. Ovarian stimulation with excessive FSH doses causes cumulus cell and oocyte dysfunction in small ovarian reserve heifers. Molecular Human Reproduction. 29(10). Article gaad033. https://doi.org/10.1093/molehr/gaad033.
DOI: https://doi.org/10.1093/molehr/gaad033

Interpretive Summary: Excessive doses of follicle stimulating hormone (FSH) to stimulate ovulation during assisted reproduction is associated with a range of negative effects on reproduction and pregnancy outcome. Using a bovine (cow) model we discovered that excessive FSH doses elicit a phenomenon we have termed ovarian hyperstimulation dysgenesisis, in which ovarian functions are disrupted. This study sought to discover whether excessive FSH doses disrupt ovarian cell function and compromise the ability of oocytes to mature and be fertilized. We found that excessive FSH doses directed aberrant gene expression in ovarian cells of all ovulatory size follicles examined, as well as disrupting the correct regulation of oocyte maturation and ability of the oocytes to be fertilized. Importantly, excessive FSH doses result in the production of abnormal cumulus cell-oocyte complexes that are morphologically very similar to healthy complexes, thereby increasing the risk of oocyte wastage and fertilizing compromised oocytes.

Technical Abstract: Excessive FSH doses during ovarian stimulation in the small ovarian reserve heifer (SORH) cause premature cumulus expansion and follicular hyperstimulation dysgenesis (FHD) in nearly all ovulatory-size follicles with predicted disruptions in cell-signaling pathways in cumulus cells and oocytes (before ovulatory hCG stimulation). These observations support the hypothesis that excessive FSH dysregulates cumulus cell function and oocyte maturation. To test this hypothesis, we determined whether excessive FSH-induced differentially expressed genes (DEGs) in cumulus cells identified in our previously published transcriptome analysis were altered independent of extreme phenotypic differences observed amongst ovulatory-size follicles, and assessed predicted roles of these DEGs in cumulus and oocyte biology. We also determined if excessive FSH alters cumulus cell morphology, and oocyte nuclear maturation before (premature) or after an ovulatory hCG stimulus or during IVM. Excessive FSH doses increased expression of 17 cumulus DEGs with known roles in cumulus cell and oocyte functions (responsiveness to gonadotrophins, survival, expansion, and oocytematuration). Excessive FSH also inducedpremature cumulus expansion and oocytematuration but inhibited cumulus expansion and oocytematuration post-hCG and diminished the ability of oocytes with prematurely expanded cumulus cells to undergo IVF or nuclear maturation during IVM. Ovarian stimulation with excessive FSH is concluded to disrupt cumulus cell and oocyte functions by inducing premature cumulus expansion and dysregulating oocyte maturation without an ovulatory hCG stimulus yielding poor-quality cumulus–oocyte complexes that may be incorrectly judgedmorphologically as suitable for IVF during ART.