High gonadotropin doses used during assisted reproductive technology (ART) cycles cause ovulatory follicle dysfunction, oocyte and embryo wastage, and decrease live birth rate. We used the small ovarian reserve heifer model to investigate the hypothesis that excessive FSH doses during ovarian stimulation induce premature luteinization and ovulatory follicle dysfunction.
Compared to heifers treated with an industry standard FSH (70 IU Folltropin-V) dose, we observed heterogeneity in follicular fluid (FF) estradiol:progesterone ratios and cumulus cell-oocyte complex (COC) morphology in follicles from excessive (210 IU) dose treated heifers. Overall, >70% of follicles from 210 IU treated heifers contained expanded COC with the majority also exhibiting increased FF concentrations of key endocrine markers of luteinization (progesterone and/or oxytocin; P<0.05). Subsequent RNA-seq analysis identified increasing transcriptome alterations in the oocyte, granulosa and cumulus cells as the severity of follicle phenotypic heterogeneity increased. Ingenuity pathway analysis indicated processes associated with ovulation and luteinization occurred concurrently and that oocyte quality is likely reduced in these follicles.
Thus, excessive FSH doses during ovarian stimulation induced follicular hyperstimulation dysgenesis, characterised by ovulatory follicle dysfunction. These changes result in predicted deficiencies in the oocyte, potentially explaining the negative relationship between excessive FSH doses and ART outcomes.
This project was supported by the NIH-USDA Dual Purpose Program by Agriculture and Food Research Initiative Competitive Grant no 2017-67015-26084 from the USDA National Institute of Food and Agriculture awarded to JJI and KL, and in part by the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD087166).