Beyond staging: Potentially divergent trajectories of pain, quality of life, and fertility in endometriosis - prospective observational cohort study.

BackgroundEndometriosis is a heterogeneous disease in which anatomical lesion burden often shows poor correlation with pain severity and quality-of-life impairment. While classification systems such as the revised American Society for Reproductive Medicine (r-ASRM) and Enzian score accurately describe anatomical disease extent, their relationship to symptom burden and reproductive outcomes remains incompletely understood. Objective(s)This study aimed to investigate the relationships between anatomical disease extent, pain severity, quality-of-life impairment, and fertility outcomes across ovarian, deep, and peritoneal endometriosis in a prospective cohort of women undergoing surgical treatment. Study DesignThis prospective observational cohort study included women aged 18-45 years undergoing laparoscopic surgery between 2023 and 2025 at a tertiary endometriosis center. Participants were categorized into ovarian (OE), deep (DE), or peritoneal (PE) endometriosis based on imaging and intraoperative findings. Pain severity was assessed using numeric rating scales across multiple domains, and quality of life was evaluated using the Endometriosis Health Profile (EHP-30+23). Anatomical disease burden was determined using r-ASRM and Enzian classifications. Patients were followed for 12 months after surgery to assess symptom trajectories, pregnancy outcomes, and surgical complications. A subset of lesion samples underwent RNA sequencing to explore molecular signatures associated with pain severity. ResultsA total of 145 women were included (OE n=33, DE n=55, PE n=25, controls n=32). Pain severity showed limited correlation with anatomical staging across subtypes. In contrast, infertility and the need for ureter surgery were strongly associated with higher Enzian scores and structural disease burden. Quality-of-life impairment closely paralleled pain intensity rather than anatomical stage. Transcriptomic analysis identified a molecular signature associated with high pain burden characterized by increased expression of inflammatory mediators (IL6, CCL8, SPP1), endocannabinoid system components (PENK, CNR1) and nociceptive transcription factors (NR4A3, EGR3). Longitudinal follow-up demonstrated substantial postoperative improvement in pain and quality of life independent of pregnancy outcomes. ConclusionsPain severity, quality-of-life impairment, and reproductive dysfunction in endometriosis represent partially independent dimensions of disease activity. While neuroinflammatory mechanisms appear to drive pain and quality-of-life impairment, fertility outcomes and organ-threatening complications are primarily determined by structural disease burden. Integrating anatomical staging with multidimensional symptom assessment and molecular profiling may enable more personalized management strategies for women with endometriosis.