Variation in endometriosis aetiology, potential impact on lesion heterogeneity and the consequences for research and treatment

• Endometriotic lesion development occurs through multiple routes. • Routes of lesion development drives endometriosis heterogeneity. • Genetic risks predispose individuals to various routes of lesion development. • Clinically relevant endometrial models are required for functional genomics. Endometriosis is the extra-uterine development of endometrial-like tissue that affects 1 in 7 women of reproductive age. Endometriosis is associated with intense pain and suffering, sub-fertility, and reduction in the overall quality of life. It is significantly heterogeneous with variation in symptom presentation, lesion appearance and disease progression. Delayed diagnosis (7 to 12 years between disease onset and diagnosis) is a major problem for both clinical management and research. Laparoscopy remains the gold standard for diagnosis and treatment. Non-invasive methods are limited, and the natural progress of the disease is not understood. Current theories of pathogenesis can explain some form of lesions, but none can describe the entire spectrum. Here, we discuss a more subtle and nuanced version of endometriosis pathophysiology that incorporates multiple aetiologies. We explore the possibility that various aetiologies could explain different routes of lesion initiation where the underlying genetic architecture is the background that create a susceptibility to different routes. We propose this could contribute to lesion heterogeneity and finally outline approaches to investigate these possibilities using molecular profiling and high-fidelity in vitro models. A better understanding of both the complexity of disease aetiology and the subsequent presentation will lead to advances in understanding endometriosis heterogeneity, assist early detection, and improve treatments outcomes.