PGR-mediated transcriptome identifies SOX9 as a critical regulator of progesterone production in human ovulatory follicles

Despite the widespread use of progesterone or progesterone receptor (PGR) blockers as contraceptives, the complete set of PGR-regulated genes and their roles in human ovulatory follicles remain unidentified. Here, we identified the PGR-regulated transcriptome, revealing numerous genes involved in metabolism, steroidogenesis, signaling activation, cell cycle regulation, and transcriptional control during ovulation using integrative omics and a primary human granulosa cell model that recapitulates the <i>in vivo</i> ovulatory phenomenon. These results led us to discover SRY-box transcription factor 9 (<i>SOX9</i>) as a human-specific, PGR-target gene during ovulation. Further functional studies showed that SOX9 regulates the expression of steroidogenesis-related genes, impacting progesterone production. In summary, we mapped the full spectrum of PGR-responsive genes in human ovulatory follicles and identified SOX9 as a human-specific mediator of the ovulatory process. These data provide critical insights into PGR-regulated ovulatory pathways, laying the foundation for developing targeted therapeutic strategies for infertility treatment and contraception.