Abstract Study question Could Medroxyprogesterone Acetate (MPA) be a good alternative to gonadotropin-realeasing hormone (GnRH) antagonist in vitrified oocyte donation cycles? Summary answer MPA is a good alternative to GnRH antagonist in vitrified oocyte donation cycles, ensuring comparable embryo quality and clinical outcome. What is known already Progestin-primed ovarian stimulation (PPOS), such as oral administration MPA in the follicular phase appears to be an effective alternative to conventional protocols, as it prevents premature LH surge and ovarian hyperstimulation syndrome. The drawback of these treatments is that it requires vitrification of oocytes or embryos because the endometrium is out of phase when embryo transfer is performed. Our previous studies have shown similar oocyte retrieval rates in fertility preservation cycles and comparable clinical outcomes in fresh donation cycles. Our objective is to expand evidence on PPOS, extending its success to new populations like vitrified donation cycles. Study design, size, duration This retrospective cohort study performed at IVI Valencia compared the effect of the MPA (10 mg/day) versus ganirelix (0.25 mg/day) on egg donors undergoing ovarian stimulation whose eggs were vitrified after retrieval. Donor cycles were divided intro groups, with 495 cycles in the MPA group and 307 in the ganirelix group. After oocyte donations and warming, the artificial intelligence based embryo assessment and clinical outcome were compared and analyzed for the two study populations Participants/materials, setting, methods 497 recipients using oocytes from the MPA group and 307 from the ganirelix group were included in the study. Post-oocyte donation and warming, a follow-up of 10,108 oocytes was performed, analyzing survival, fertilization, and blastocyst development. The embryo score obtained with the deep learning based model iDAScore v2, and the ASEBIR evaluation performed by embryologists were compared between both study populations. Finally, comprehensive clinical outcome comparisons were conducted between the two study populations. Main results and the role of chance The mean number of thawed oocytes was significantly different* between the two groups (12.80±3.54 in the MPA group vs. 12.20±3.58 in the antagonist group). Survival, fertilization, and blastocyst development rates showed no significant differences (89.83%, 76.38% and 66.22% respectively in the MPA group and 88.67%, 76.75% and 64.29% in the antagonist group). However, ASEBIR embryo assessment showed a significantly higher percentage of embryos classified as A and B in MPA group* (10.5% and 58.0% respectively vs. 7.2% and 53.6%), and more C embryos* in the antagonist group (34.3% vs. 39.2%). Artificial intelligence-based embryo assessment revealed no significant differences between the two groups*, with mean evaluations being 4.97±2.60 in the MPA group and 5.07±2.68 in the antagonist group. Regarding clinical outcomes, the MPA group had significantly higher number of frozen embryos per cycle* (4.08±2.07 in the MPA group vs. 3.65±2.00 in the antagonist group) but no disparities in implantation, clinical pregnancy, ongoing pregnancy, live birth and cumulative live birth rates. A generalized estimation equation highlighted that the study group (MPA or antagonist) did not significantly impact the live birth rate, but was significantly influenced instead by the number of thawed oocytes, recipient BMI, and transferred embryo quality assessed with iDAScore*. (*p<.05) Limitations, reasons for caution This project is limited by its retrospective and single-center nature. Despite being the largest sample size ever reported for PPOS in vitrified donation cycles, the number of patients included could be considered low. Consequently, it would be advisable to conduct a multicenter RCT to confirm the conclusions of this study. Wider implications of the findings The administration of MPA as a gonadotropin adjuvant demonstrates clinical outcomes comparable to those achieved with ganirelix in vitrified oocyte donation cycles. Its user-friendly application encourages the wider adoption of this protocols. These promising results promote the widespread use of MPA-based protocols in vitrified oocyte donation cycles. Trial registration number not applicable
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