OXTR Overexpression Induces Polycystic Ovary Syndrome-like Phenotype via prolactin/p-STAT3 Signaling in Mice [CUT&Tag]

Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder, represents the most common cause of anovulatory infertility. 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. Therapeutic intervention with bromocriptine normalized prolactin and progesterone levels, partially restoring ovarian function. Notably, ++Oxtr females developed metabolic dysfunction characterized by insulin resistance and gonadal adiposity despite maintaining lean phenotypes. Our findings position OXTR as a novel upstream regulator of PCOS pathogenesis with hyperprolactinemia, suggesting bromocriptine may have therapeutic value in hyperprolactinemic PCOS cases. These insights open new avenues for targeted PCOS interventions.