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).

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. Evidence before this study We searched PubMed from inception to July 1, 2026, using terms including “abnormal uterine bleeding”, “endometrium”, “leiomyoma”, and “fibroid” finding a paucity of studies researching the endometrium in women with AUB. Published studies have predominantly focused on the clinical causes of AUB rather than the endometrium, i.e., the tissue that bleeds. Furthermore, when the endometrium has been studied, menstrual cycle phases have frequently been inadequately characterised particularly in the secretory phase, limiting accurate mechanistic inferences. Consequently, the underlying tissue-level mechanistic drivers of AUB remain unknown, and likely contributing to the high failure rates of medical management. It is timely that the biological causes of AUB have been identified recently as the second research priority in the James Lind Alliance Priority Setting Partnership for Problematic Menstrual Bleeding. Added value of this study We directly compared rigorously phenotyped and menstrual cycle-staged endometrium from women with different clinical causes of AUB (uterine fibroids: AUB-L versus primary endometrial disorder: AUB-E). We demonstrate that the global endometrial transcriptome is determined by the underlying clinical cause of AUB rather than the shared bleeding symptom. Furthermore, we identified that endometrium from women with AUB-L is uniquely characterised by an altered spatial immunolocalisation of sex steroid receptors (PR, PR-B, ERα) during the mid-secretory phase. Implications of all the available evidence The presence of distinct transcriptomic profiles and altered sex steroid receptor immunolocalisation in the endometrium, provides insights into a biological rationale for why uniform, non-targeted progestin therapies may frequently fail to manage the symptom of AUB. Advancing patient care now necessitates a fundamental conceptual shift. We must cease treating AUB as a singular biological entity, we need to move away from empirical symptom control, and instead move toward precision therapy for AUB guided by exact clinical phenotyping. Competing Interest Statement H.O.D.C. has received clinical research support for laboratory consumables and staff from Bayer AG, and provided consultancy/advisory board advice (all paid to institution; no personal remuneration) to Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc., Myovant Sciences GmbH, Pharmacosmos and BioInnovations Institute (BII, Copenhagen). H.O.D.C. has received royalties from UpToDate for an article on abnormal uterine bleeding. H.O.D.C. is the current Chair of the Wellbeing of Women's Research Advisory Committee and a previous Chair (2021 - 2023) of the International Federation of Gyneology and Obstetrics (FIGO) Committee for Menstrual Disorders and Related Health Impacts (MDRHI). V.J. is a current associate member of the FIGO Committee for MDHRI and has received salary and research support from Wellbeing of Women (Clinical Research Training Fellowship). F.P. was a consultant for SOTIO Biotech and Immunocore. The transcriptomic analysis method described in this study is the subject of a patent titled "Methods for determining menstrual cycle time point" (WO/2023/245243, PCT/AU2023/050559), by the University of Melbourne and includes J.C. and P.A.W.R. as inventors. A.O.T., P.W-S. and A.R.W. do not have any competing interests to declare. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: National Health Service (NHS) Health Research Authority's Research Ethics Committees (References 19/SS/0102 and 20/ES/0119) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes