GnRH Antagonist Pre-treatment in the Early Follicular Phase for the Prevention of Asynchronous Follicular Growth - A Proof-of-concept Pilot Study

During the late luteal phase, parallel to the corpus luteum demise, FSH levels gradually increase in order to preserve antral follicles from atresia. Early antral follicles show different sensitivity to FSH possibly contributing to the establishment of the dominant follicle by starting their development earlier than others. Previous studies indicated larger follicles are more sensitive to FSH then smaller ones, thus respond to lower levels of FSH. The premature gradual exposure to FSH may accelerate the development of the larger follicle and accentuate size discrepancies observed during controlled ovarian hyperstimulation (COH).

During COH exogenous gonadotropins are expected to influence early antral follicle growth to simultaneously reach functional and morphological maturation. Significant size discrepancy at the time of HCG administration may result in a larger fraction of immature oocytes, reducing the number of embryos and the pregnancy rate.

Since baseline FSH levels are higher in older and poor responder patients, early antral follicles are exposed to higher levels of FSH thus size discrepancies are observed more frequently, contributing to higher cancellation rates and reducing furthermore pregnancy rates.

Several protocols have been established to overcome early antral follicle exposure to FSH. Estradiol priming for 7 days in the late luteal phase prior to GT stimulation achieved FSH suppression and resulted in size discrepancy reduction and better cycle outcome (higher number of mature oocytes, embryos and pregnancy rates). A meta-analysis demonstrated reduced cycle cancellation rate and higher clinical pregnancy rate. GnRH antagonist priming, also by reducing FSH levels in the late luteal phase, resulted in coordination of early antral follicular size. These priming protocols require preplanning and a relatively predictable menstrual cycle in order to start the priming supply in the late luteal phase. Poor responder patients and those in-between IVF treatment cycles may not have regular menses or may be waiting for pregnancy test results, thus do not represent optimal potential candidates for a priming protocol.

Several studies have investigated the outcome of GnRH antagonist supplementation at the beginning of the menstrual cycle prior to GT stimulation. The delayed start protocol which combines estradiol priming followed by GnRH antagonist for 7 days at the beginning of menses prior to GT administration to further synchronize antral follicles improved ovarian response in poor responders and reduced cycle cancellation rate with no significant effect on pregnancy rates. A preliminary study investigated the effect of three day administration of GnRH antagonist at the beginning of the follicular phase prior to GT stimulation in normal responders regardless of baseline hormonal levels and found a trend towards increase in clinical pregnancy rate, and similar profiles of early embryo development, compared to standard fixed GnRH antagonist protocol.