Unraveling the Clinical FSH Conundrum: Insights From the Small Ovarian Reserve Heifer Model

High doses of follicle stimulating hormone (FSH) are used during ovarian stimulation to maximize the number of oocytes recovered for in vitro fertilization (IVF) during assisted reproductive technology (ART) in women. Whether high FSH doses are detrimental to embryo viability remains controversial. Evidence from many clinical studies revealed that FSH dose is inversely correlated with live birth rate in women. The mechanistic basis for this effect has been elusive. This review summarizes over 20 years of work using a unique biomedical model, the small ovarian reserve heifer (SORH). Those studies revealed that excessive FSH doses can disrupt gene expression via multiple cell-signaling pathways in ovarian cells, resulting in follicular hyperstimulation dysgenesis (FHD). This compromises the capacity of ovulatory-size follicles to respond to gonadotropins, produce estradiol and ovulate, causes premature cumulus expansion and oocyte maturation, and impairs the fertilizability of oocytes. The SORH model has thus provided new insights into the nature and mechanisms of the deleterious effects of excessive FSH doses during ovarian stimulation. The SORH model has been and remains valuable for basic research and for the discovery of ways to optimize FSH dosing clinically to improve IVF success and ART outcomes.