Ovarian fibrosis as a common mechanism of infertility

Abstract Female fertility has long been explained through observation of the ovarian follicle: the number of residing follicles and the quality of the oocyte. This review argues that the tissue surrounding those follicles involved in regulating cyclical ovarian remodelling is an additional contributor to female subfertility. Ovarian fibrosis, the accumulation of extracellular matrix with stromal stiffening and inflammation, was historically viewed as a passive consequence of aging or injury. Here, we present evidence that this phenomenon may be an active constraint on fertility, altering the biomechanical environment that manages follicle activation, ovulation, and oocyte quality. Although reproductive aging, premature ovarian insufficiency, polyendocrine metabolic ovarian syndrome, obesity, endometriosis, chronic psychological stress, and treatment/environment-induced ovarian injury have different underlying causes, all reach a similar fibrotic state. Strong causal evidence comes from in vitro hydrogel studies isolating stiffness from all other variables, where stiff matrices inhibit follicle growth, survival and quality. Despite this highly fibrotic morphology impacting maturation of follicles, pre-clinical and human studies have shown the efficacy of antifibrotic drugs in restoring follicular growth. Further, in early human trials, antifibrotic finerenone yields mature oocytes and embryos in women with premature ovarian insufficiency. While the current focus in standard infertility treatment aims to improve follicle and hormone health, fibrosis may be reversible and preventable, making it a candidate therapeutic target that could complement existing treatments. However, key gaps remain: no standardized measure of ovarian fibrosis, uncertain rodent-to-human translation, and no study linking fibrosis measurement to a fertility outcome in human patients.