Excessive FSH doses during ART cause premature cumulus dysfunction and enhance the risk of recovering poor-quality oocytes for IVF

Authors: KARL, KAITLIN - Michigan State University; MARTINS, MARTINS ROGATTO - 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: N/A
Citation: N/A

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 doses of FSH during ovarian stimulation of the small ovarian reserve heifer (SORH) model cause premature (prior to an hCG ovulatory stimulus) cumulus expansion and follicular hyperstimulation dysgenesis (FHD) in nearly all ovulatory-size follicles. FHD results in severe abnormalities in multiple cell-signaling pathways in granulosa and cumulus cells and oocytes critical for ovulatory follicle function and oocyte quality. These observations support the hypothesis that excessive FSH action dysregulates cumulus cell function and oocyte maturation. To test this hypothesis, we used the SORH model to determine if excessive compared with the industry-standard FSH doses during ovarian stimulation alter expression of genes critical for cumulus function and oocyte maturation, cumulus morphology, and nuclear maturation of oocytes before (premature) or after an hCG ovulatory stimulus or during in vitro maturation (IVM). Results show that excessive FSH doses increased expression of 14 cumulus genes with well-established regulatory roles in cumulus cell and oocyte functions (responsiveness to gonadotropins, survival, expansion, and oocyte maturation) in all ovulatory-size follicles. Excessive FSH also induced premature cumulus expansion and oocyte maturation prior to hCG, inhibition of cumulus expansion and oocyte maturation post hCG, and inhibition of capacity of oocytes with prematurely expanded cumulus cells to undergo in vitro fertilization (IVF) or nuclear maturation during IVM. Ovarian stimulation with excessive FSH doses is concluded to dysregulate cumulus cell and oocyte functions by prematurely enhancing cumulus expansion and oocyte maturation without an ovulatory hCG stimulus, thereby risking recovery of poor-quality cumulus-oocyte complexes (COCs) morphologically like healthy COCs for IVF during ART.