Unveiling the mysteries in the pathogenesis of endometriosis and adenomyosis.

Recent advances in understanding endometriosis and adenomyosis pathogenesis have re- vealed crucial molecular mechanisms underlying these debilitating gynecological conditions. This thesis demonstrates the pivotal role of sphingosine-1-phosphate (S1P) signaling in dis- ease progression, particularly through S1P receptor 3 (S1PR3) in endometriosis-associated fibrosis. The study establishes that Neuropeptide S (NPS) induces an invasive phenotype in endometriotic cells through S1P1/S1P3 signaling, mediated by sphingosine kinase (SK) acti- vation. This process involves the RhoA/ROCK pathway, contributing to cellular invasion and cytoskeletal remodeling. In examining adenomyosis, the research presents novel findings regarding its persistence in postmenopausal women, with imaging techniques revealing characteristic features corre- lating with molecular markers of fibrosis. Notably, the study introduces an innovative in vitro model utilizing primary epithelial-stromal assembloids generated from endometrial biop- sies. These assembloids successfully replicate secretory phase-specific characteristics and demonstrate reduced progesterone responsiveness in adenomyosis patients, characterized by decreased expression of crucial implantation markers including LIF and HOXA10, and im- paired pinopodes formation. Further optimization of the assembloid model through hanging drop methodology has en- hanced structural integrity and viability, providing a more physiologically relevant platform for studying endometrial biology and pathology. These findings collectively advance our un- derstanding of disease mechanisms and suggest potential non-hormonal therapeutic tar- gets, particularly within the S1P signaling pathway, while establishing a robust preclinical model for investigating endometrial disorders and testing therapeutic interventions.