A Proposed Platform for Phenotyping Endometriosis-Associated Pain: Unifying Peripheral and Central Pain Mechanisms

Endometriosis is defined by a finding of ectopic endometrial glands/stroma, and is characterized by a wide variability in pain symptoms. The goal of this review is to identify peripheral to central factors that can modulate pain output in a given patient with endometriosis. Based on this constellation of factors, we propose a pain classification for endometriosis. The development and persistence of endometriosis-associated pain is influenced by a complex interplay between local factors that then interact with central variables. Starting peripherally, endometriosis anatomic characteristics include anatomic sub-type (superficial, deep, ovarian) and location/depth/amount of disease. Other peripheral factors involve local inflammation, neurogenesis, and sensitization of peripheral nerve cells around endometriosis glands/stroma. Uterine factors are eutopic endometrial neuroinflammation and concurrent adenomyosis. Other anatomic factors include risk factors for pain such as a history of PID or previous surgeries. Beyond the gynecologic organs, adjacent pelvic structures such as musculoskeletal, gastrointestinal, and urological can serve as pain generators. Finally, centrally, there is central nervous system and/or cross-organ sensitization, presence of systemic pain conditions such as fibromyalgia, and psychosocial comorbidities. Pain can be modulated by a combination of peripheral and central mechanisms, resulting in varied clinical presentations, even in those with the same endometriosis anatomic characteristics. Based on this complex interplay of features with peripheral and central factors, we propose four sub-types of endometriosis pain: type I (pain primarily due to endometriosis lesions and associated inflammation/neurogenesis), type II (pain primarily due to comorbid condition), type III (central pain), and type IV (combination of types I–III). Clinically, this classification could help identify which patients may not respond to conventional gynecologic management alone. In research studies, the classification could allow for patient sample stratification, since diagnostic markers or treatments may only be effective in certain sub-types. This phenotypic classification of endometriosis-associated pain requires further study and validation.