Follicular hyperstimulation dysgenesis: new explanation for adverse effects of excessive FSH in ovarian stimulation

Authors: CLARK, ZARAMASINA - Victoria University Of Wellington; Ruebel, Meghan; SCHALL, PETER - University Of Michigan Medical School; KARL, KAITLIN - Michigan State University; IRELAND, JAMES - Michigan State University; LATHAM, KEITH - Michigan State University

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/3/2022
Publication Date: 8/1/2022
Citation: Clark, Z., Ruebel, M., Schall, P.Z., Karl, K.R., Ireland, J.J., Latham, K.E. 2022. Follicular hyperstimulation dysgenesis: new explanation for adverse effects of excessive FSH in ovarian stimulation. Endocrinology. 163(9):bqac106. https://doi.org/10.1210/endocr/bqac100.
DOI: https://doi.org/10.1210/endocr/bqac100

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, most follicles showed signs of premature luteinization and abnormalities. We looked at gene expression profiles of the different cell types within an individual follicle, including granulosa cells (GCs), cumulus cells(CCs), and oocytes from animals given standard or excessive doses of FSH. Our results showed changes in GCs and CCs gene expression that reflected an overall loss of cell–cell communication within the follicle and dysregulation of maturational processes. In the oocyte, we identified different signaling pathways and functions association with changes in cell survival, phagocytosis, EIF2 signaling, leading to poor oocyte quality. Combined, these results provide a compelling argument against the use of excessive FSH doses during ovarian stimulation in SORH cattle and in small ovarian reserve patients seeking ART.

Technical Abstract: High follicle-stimulating hormone (FSH) doses during ovarian stimulation protocols for assisted reproductive technologies (ART) are detrimental to ovulatory follicle function and oocyte quality. However, the mechanisms are unclear. In a small ovarian reserve heifer model, excessive FSH doses lead to phenotypic heterogeneity of ovulatory size follicles, with most follicles displaying signs of premature luteinization and a range in severity of abnormalities. By performing whole transcriptome analyses of granulosa cells, cumulus cells, and oocytes from individual follicles of animals given standard or excessive FSH doses, we identified progressive changes in the transcriptomes of the 3 cell types, with increasing severity of follicular abnormality with the excessive doses. The granulosa and cumulus cells each diverged progressively from their normal phenotypes and became highly similar to each other in the more severely affected follicles. Pathway analysis indicates a possible dysregulation of the final stages of folliculogenesis, with processes characteristic of ovulation and luteinization occurring concurrently rather than sequentially in the most severely affected follicles. These changes were associated with disruptions in key pathways in granulosa and cumulus cells, which may account for previously reported reduced estradiol production, enhanced progesterone and oxytocin production and diminished ovulation rates. Predicted deficiencies in oocyte survival, stress response, and fertilization suggest likely reductions in oocyte health, which could further compromise oocyte quality and ART outcomes.