SUN-110 - The Ovulatory Follicular Fluid IGF Axis Drives Endometriosis Pathogenesis by Promoting Stemness and Suppressing Necroptosis

Background:
Endometriosis, a common gynecological disorder, is estrogen-dependent and associated with ovulation. However, the direct role of the ovulatory microenvironment, specifically follicular fluid (FF), in disease pathogenesis remains unknown. We hypothesized that growth factors within FF promote the survival and implantation of retrograde endometrial tissue.

Methods:
Utilizing murine allograft models of endometriosis, we assessed lesion establishment after pharmacological superovulation or in genetic models of anovulation (Pgr knock-out). The functional impact of human FF versus peritoneal fluid (PF) was tested in vivo via co-administration with endometrial grafts or cells, with or without the IGF-1R inhibitor PPP. Molecular mechanisms were analyzed in ex vivo endometrial cultures and primary endometrial cells using immunohistochemistry, western blot, and colony-forming assays.

Results:
Superovulation significantly increased endometriotic lesion burden in vivo, whereas genetic ablation of follicle rupture dramatically reduced it. We identified IGF2 and its activating protease PAPP-A as key components enriched specifically in human ovulatory FF. This FF-IGF axis activated IGF-1R signaling in endometrial cells, inducing a stem-like state (OCT4/NANOG upregulation) and concomitantly suppressing the expression of the necroptosis kinase RIP3. FF enhanced the stemness, survival, clonogenicity, and growth of endometrium and endometrial cells, effects abrogated by IGF-1R inhibition. Critically, pharmacological blockade of IGF-1R in vivo reversed FF-driven lesion establishment, inducing lesion atrophy and concomitant activation of apoptotic and necroptotic cell death pathways.

Conclusion:
Our findings establish a direct pathogenic link between ovulation and endometriosis. We identify the IGF axis within FF as a critical molecular signal that fuels disease progression by reprogramming endometrial cells toward a stem-like, survival-prone state while inhibiting necroptosis. Targeting this pathway presents a promising, ovulation-specific therapeutic strategy.

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