Abnormal uterine bleeding (AUB) is not a single clinical entity: different clinical causes are associated with distinct cellular and molecular endometrial characteristics

Background: Abnormal uterine bleeding (AUB) is commonly managed as a single clinical entity with standardised pathways. However, high therapeutic failure and subsequent hysterectomy rates indicate AUB is not a single symptom. AUB affects over a billion individuals worldwide representing a substantial global health burden. While the symptom of AUB has multiple causes, the underlying endometrial mechanisms remain largely unexplored. To determine why standardised, medical management consistently fails, we directly compared the endometrium associated with two distinct aetiologies of AUB: uterine fibroids (AUB-L), and a primary endometrial disorder (AUB-E). Methods: We investigated menstrual cycle-staged endometrium from women with AUB-L (n=32) and AUB-E (n=41). Endometrial tissue underwent quantitative RT-PCR (n=73), bulk RNA sequencing (n=35), and quantitative immunohistochemistry (n=18) to assess transcriptomic signatures and spatial immunolocalisation of sex steroid receptors across menstrual cycle phases. Findings: Deep tissue interrogation confirmed menstrual cycle stage remains the major determinant of gene expression in endometrium of women with AUB and regular menstrual cycles. The global endometrial transcriptome was determined by clinical cause of AUB, with 81 differentially expressed genes (FDR <0.05) identified when comparing AUB-L and AUB-E. Aetiology of AUB dictated endometrial spatial immunolocalisation of sex steroid receptors, with glandular persistence of epithelial progesterone receptor expression (PR, PR-B) in mid-secretory phase endometrium in subjects with AUB-L versus AUB-E. Interpretation: AUB should not be conceptualised as a single endometrial phenotype simply because the clinical bleeding symptom is shared by several aetiologies. These findings demand a paradigm shift in clinical care: to improve patient outcomes, management of AUB must evolve from empirically treating a shared symptom to delivering precision therapeutics guided by distinct molecular endometrial phenotypes. Funding: UK Charity Wellbeing of Women (RTF902), BBSRC-NC3R ageing project grant BB/S002995/1; Wellcome Trust (225021/Z/22/Z); MRC Centre for Reproductive Health Centre grants: G1002033, MR/N022556/1; MRC research grants G0000066, G0500047, G0600048, and MR/J003611/1.