Ex vivo removal of pro-fibrotic collagen and rescue of metabolic function in human ovarian fibrosis

Tissue fibrosis, with the excessive accumulation of extracellular matrix, leads to organ dysfunction. The ovary shows signs of fibrosis from an early age, creating a permissive environment for ovarian cancer. A robust culture-platform to study human ovarian fibrosis would enable screens for antifibrotic drugs to prevent or even reverse this process. Based on previous results showing that androgen therapy can induce ovarian fibrosis, we characterized the fibrotic state of ovaries from transmasculine donors of reproductive age. Anti-inflammatory and antioxidant drugs, such as Pirfenidone, Metformin, and Mitoquinone, could reduce and revert the excess collagen content of the ovarian cortical tissue during culture. We demonstrated that Metformin exerts an antioxidant role and prevents a glycolytic metabolic shift in non-immune ovarian stromal cells in the human ovary, while promoting early folliculogenesis during culture. These results may contribute to develop strategies to manage pro-tumorigenic fibrotic ovarian stroma in advanced age and metabolic disorders.