Endometriosis-Associated Infertility: Multi-Omics Insights into Pathogenesis and Precision Therapeutics

Yuyi Ou^*

• Department of Gynecology,Foshan Women and Children Hospital, Foshan, Guangdong, 528000, China, Foshan, China

Endometriosis is a prevalent gynecological disorder marked by ectopic growth of endometrial-like tissue, causing chronic inflammation and severe reproductive sequelae, including infertility. This review synthesizes current knowledge on the multifactorial pathophysiological mechanisms underlying endometriosis-associated infertility, highlighting the intricate interplay of hormonal dysregulation, immune dysfunction, oxidative stress, ferroptosis, genetic and epigenetic alterations, and microbiome imbalance. Estrogen dominance combined with progesterone resistance impairs endometrial receptivity and decidualization, while immune cell imbalances and chronic inflammation contribute to a hostile pelvic environment detrimental to gamete quality, fertilization, and implantation. Iron overload-induced oxidative stress promotes ferroptosis selectively damaging granulosa cells yet sparing endometriotic lesions, thereby exacerbating infertility. Genetic polymorphisms and epigenetic modifications further disrupt hormonal and immune pathways, whereas emerging roles of reproductive tract and gut microbiota emphasize novel etiological and therapeutic perspectives. Clinically, endometriosis detrimentally affects ovarian reserve, oocyte competence, endometrial receptivity, and pelvic anatomy through adhesions and fibrosis, cumulatively impairing fertility potential. Current therapeutic strategies encompass surgical excision, hormonal suppression, and assisted reproductive technologies tailored to disease severity and reproductive goals. Adjunctive therapies targeting oxidative stress and immune modulation show potential but require robust clinical validation. Advances in biomarker discovery—including epigenetic regulators, immune-inflammatory mediators, coagulation factors, and microbiome signatures—offer promise for earlier diagnosis and personalized treatment approaches. Innovative interventions such as immunotherapy targeting nociceptor-immune crosstalk, ferroptosis modulation, microbiota manipulation, and dietary-based metabolic regulation constitute emerging frontiers. The integration of multidisciplinary, patient-centered, and precision medicine frameworks is vital to improving outcomes across the lifespan of women affected by endometriosis-associated infertility.