OXTR Overexpression Induces Polycystic Ovary Syndrome-like Phenotype via prolactin/p-STAT3 Signaling in Mice. [RNA-seq]

While the oxytocin receptor (OXTR) is well-characterized in parturition and lactation, its role in follicular development remains undefined. In this study, we establish that global OXTR overexpression in female mice (++Oxtr) recapitulates cardinal PCOS features, including hyperandrogenism, oligo-ovulation, and fertility impairment. ++Oxtr females exhibited distinct ovarian pathology marked by follicular atresia, cystic changes, hemorrhage, and deficient corpus luteum formation.

These morphological alterations coincided with profound endocrine dysregulation, featuring hyperprolactinemia, suppressed LH secretion, and progesterone deficiency - contrasting with preserved fertility in ++Oxtr males. Mechanistically, we identified an OXTR-PRL-p-STAT3 axis as central to PCOS pathogenesis. Corresponding to hyperprolactinemia, persistent activation of nuclear p-STAT3 (Tyr705) in ++Oxtr granulosa cells - absent in WT controls at pregnancy - epigenetically upregulated folliculogenesis genes (Lhcgr, Pgr, Leptin, CYP17A1) while impairing ovulation.