The endometriosis-adenomyosis spectrum: shared pathophysiology and microenvironment-driven disease divergence

Endometriosis and adenomyosis are common gynecologic disorders associated with dysmenorrhea, chronic pelvic pain, and infertility. Although they share several molecular features, the mechanisms by which endometrium-derived tissues develop distinct pathological phenotypes in different tissue environments remain incompletely understood. This review summarizes shared and divergent pathogenic mechanisms, focusing on lesion-specific microenvironments. This narrative review was based on a PubMed literature search from the year of the first publication through December 2025 using terms related to endometriosis, adenomyosis, mitochondrial function, oxidative stress, fibrosis, mechanical stress, and calcium signaling. Both disorders develop in the context of repetitive tissue injury, estrogen-dependent repair responses, chronic inflammation, oxidative stress, and mitochondrial dysfunction. However, differences in lesion location and microenvironment appear to drive distinct pathological phenotypes. In superficial peritoneal endometriosis and ovarian endometrioma, mitochondrial adaptation primarily supports hypoxia tolerance, oxidative stress responses, angiogenesis, cellular survival, and metabolic reprogramming. In contrast, deep infiltrating endometriosis and adenomyosis are characterized by fibrosis, extracellular matrix remodeling, tissue stiffening, and adaptation to mechanical stress. In adenomyosis, mitochondrial regulation of calcium homeostasis, smooth muscle contractility, reactive oxygen species production, and TGF-β–related fibrotic signaling may play important roles in disease progression. We propose a proliferation–fibrosis divergence model in which common pathogenic stimuli are integrated through mitochondria-dependent responses to distinct local microenvironments. Mitochondria may act as central regulators linking hypoxic adaptation, inflammation, metabolism, fibrosis, and mechanotransduction, thereby influencing whether disease progression favors proliferative expansion or fibrotic remodeling. This framework may provide a basis for future mechanism-based precision therapeutic strategies. Similar content being viewed by others Abbreviations - AKT: - Protein kinase B - AMPK: - AMP-Activated Protein Kinase - ARID1A: - AT-Rich Interaction Domain 1A - Bax: - Bcl-2-associated X protein - Bcl-2: - B-cell lymphoma 2 - CTNNB1: - Catenin Beta 1 - DIE: - Deep infiltrating endometriosis - EMT: - Epithelial–mesenchymal transition - ER: - Endoplasmic reticulum - FMT: - Fibroblast-to-myofibroblast transdifferentiation - GLUT1: - Glucose Transporter 1 - GRIM-19: - Gene associated with Retinoid-IFN-induced Mortality 19 - HIF-1α: - Hypoxia-Inducible Factor-1 alpha - HK2: - Hexokinase 2 - IP3: - Inositol 1,4,5-trisphosphate - KRAS: - Kirsten Rat Sarcoma Viral Oncogene Homolog - LDHA: - Lactate Dehydrogenase A - MAPK: - Mitogen-Activated Protein Kinase - MCU: - Mitochondrial calcium uniporter - MLCK: - Myosin light chain kinase - MRI: - Magnetic resonance imaging - mTOR: - Mechanistic target of rapamycin - NF-κB: - Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells - OMA: - Ovarian endometrioma - PDK1: - Pyruvate Dehydrogenase Kinase 1 - PI3K: - Phosphatidylinositol 3-kinas - PIK3CA: - Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha - PINK1: - PTEN-induced putative kinase 1 - PLC: - Phospholipase C - PTEN: - Phosphatase and Tensin Homolog - ROS: - Reactive oxygen species - S1P: - Sphingosine-1-phosphate - SANRA: - Scale for the Assessment of Narrative Review Articles - SIRT3: - Sirtuin 3 - SMM: - Smooth muscle metaplasia - SOD2: - Superoxide Dismutase 2 - SUP: - Superficial peritoneal endometriosis - TAZ: - Transcriptional Co-Activator with PDZ-Binding Motif - TGF-β: - Transforming Growth Factor-β - TIAR: - Tissue Injury and Repair - VEGF: - Vascular Endothelial Growth Factor - YAP: - Yes-Associated Protein

The figures were created by Toyomi Kobayashi (Ms.Clinic MayOne, Nara, Japan) using vector graphics software (Adobe Illustrator, Adobe). Funding No funding was received for this study. Author information Authors and Affiliations Corresponding author Ethics declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Kobayashi, H. The endometriosis–adenomyosis spectrum: shared pathophysiology and microenvironment-driven disease divergence. Reprod Biol Endocrinol (2026). https://doi.org/10.1186/s12958-026-01588-z Received: Accepted: Published: DOI: https://doi.org/10.1186/s12958-026-01588-z