Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis

Does progestin-primed ovarian stimulation (PPOS) have a negative effect on reproductive outcomes compared with a gonadotrophin-releasing hormone (GnRH) antagonist protocol?

This retrospective cohort study included 907 patients aged <40 years with normal ovarian reserves undergoing either PPOS (n = 299) or a GnRH-antagonist protocol (n = 608) in their first IVF cycle between 2018 and 2020. An additional genetic analysis, single-cell RNA sequencing (scRNA-seq), was performed on the mural granulosa cells (mGC) of metaphase II oocyte follicles retrieved from 16 patients, with the above inclusion criteria, undergoing PPOS (n = 8) or a GnRH-antagonist protocol (n = 8) between 2021 and 2022. Inverse probability of treatment weighting (IPTW) was performed on the clinical data. Predetermined primary outcomes were the premature LH surge rate and the live birth rate of the first frozen embryo transfer cycle for the first and second IPTW analyses, respectively.

The premature LH surge rate was lower in the PPOS group compared with the GnRH-antagonist group (3.1% versus 20.1%, OR 0.13, 95% CI 0.07-0.23; P < 0.001) in the first IPTW analysis. The good-quality cleavage embryo rate was lower in the PPOS group compared with the GnRH-antagonist group (37.2% versus 49.1%; P < 0.001). The live birth rate was lower in the PPOS group compared with the GnRH-antagonist group (31.5% versus 42.3%, OR 0.63, 95% CI 0.46-0.86; P = 0.004) in the second IPTW analysis. The scRNA-seq analysis demonstrated higher expression of 12 mitochondrial DNA (mtDNA) genes in the PPOS group compared with the GnRH-antagonist group.

PPOS suppressed the premature LH surge rate but was associated with a lower live birth rate compared with the GnRH-antagonist protocol. The elevated expression of mtDNA genes in mGC may also indicate a decline in oocyte quality with PPOS.