Endometrial organoids to model benign disorders affecting the endometrium

The endometrium is a highly dynamic and complex tissue lining the uterus, playing a central role in reproductive health. Despite its importance, the pathogenesis of many benign endometrial disorders remains poorly understood, largely due to limitations in current experimental models. Traditional in vivo models like murine and primate models fail to replicate key human-specific features like menstruation or spontaneous disease development. Similarly, conventional 2-dimensional in vitro cultures using cell lines or primary cells lack the structural and functional complexity of native endometrium, often losing physiological relevance over time. To address these challenges, endometrial epithelial organoids (EEOs), 3-dimensional self-organizing epithelial structures derived from endometrial biopsies, have emerged as a promising in vitro model. EEOs mimic many aspects of in vivo endometrial glands, including apical-basal polarity, hormone responsiveness, long-term preservation of epithelial identity, and retention of patient-specific genetic and molecular signatures. Their ability to reproduce cellular interactions and tissue architecture makes them an invaluable tool for studying endometrial physiology and disease. This review explores the application of EEOs in modeling various benign conditions affecting the endometrium, including endometriosis, adenomyosis, uterine fibroids, implantation failure, endometrial aging, endometritis, and endometrial hypoplasia, as well as systemic diseases and exposure to environmental or pharmacological agents. While EEOs do not yet fully replicate functional human endometrium, they represent a significant step forward in bridging the gap between basic research and clinical understanding of endometrial disorders.