{"paper_id":"3054537d-4075-46b7-9825-aed035c256c0","body_text":"Abstract\nEndometriosis 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.\nSimilar content being viewed by others\nAbbreviations\n- AKT:\n-\nProtein kinase B\n- AMPK:\n-\nAMP-Activated Protein Kinase\n- ARID1A:\n-\nAT-Rich Interaction Domain 1A\n- Bax:\n-\nBcl-2-associated X protein\n- Bcl-2:\n-\nB-cell lymphoma 2\n- CTNNB1:\n-\nCatenin Beta 1\n- DIE:\n-\nDeep infiltrating endometriosis\n- EMT:\n-\nEpithelial–mesenchymal transition\n- ER:\n-\nEndoplasmic reticulum\n- FMT:\n-\nFibroblast-to-myofibroblast transdifferentiation\n- GLUT1:\n-\nGlucose Transporter 1\n- GRIM-19:\n-\nGene associated with Retinoid-IFN-induced Mortality 19\n- HIF-1α:\n-\nHypoxia-Inducible Factor-1 alpha\n- HK2:\n-\nHexokinase 2\n- IP3:\n-\nInositol 1,4,5-trisphosphate\n- KRAS:\n-\nKirsten Rat Sarcoma Viral Oncogene Homolog\n- LDHA:\n-\nLactate Dehydrogenase A\n- MAPK:\n-\nMitogen-Activated Protein Kinase\n- MCU:\n-\nMitochondrial calcium uniporter\n- MLCK:\n-\nMyosin light chain kinase\n- MRI:\n-\nMagnetic resonance imaging\n- mTOR:\n-\nMechanistic target of rapamycin\n- NF-κB:\n-\nNuclear Factor Kappa-light-chain-enhancer of Activated B Cells\n- OMA:\n-\nOvarian endometrioma\n- PDK1:\n-\nPyruvate Dehydrogenase Kinase 1\n- PI3K:\n-\nPhosphatidylinositol 3-kinas\n- PIK3CA:\n-\nPhosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha\n- PINK1:\n-\nPTEN-induced putative kinase 1\n- PLC:\n-\nPhospholipase C\n- PTEN:\n-\nPhosphatase and Tensin Homolog\n- ROS:\n-\nReactive oxygen species\n- S1P:\n-\nSphingosine-1-phosphate\n- SANRA:\n-\nScale for the Assessment of Narrative Review Articles\n- SIRT3:\n-\nSirtuin 3\n- SMM:\n-\nSmooth muscle metaplasia\n- SOD2:\n-\nSuperoxide Dismutase 2\n- SUP:\n-\nSuperficial peritoneal endometriosis\n- TAZ:\n-\nTranscriptional Co-Activator with PDZ-Binding Motif\n- TGF-β:\n-\nTransforming Growth Factor-β\n- TIAR:\n-\nTissue Injury and Repair\n- VEGF:\n-\nVascular Endothelial Growth Factor\n- YAP:\n-\nYes-Associated Protein\nAcknowledgements\nThe figures were created by Toyomi Kobayashi (Ms.Clinic MayOne, Nara, Japan) using vector graphics software (Adobe Illustrator, Adobe).\nFunding\nNo funding was received for this study.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nEthics declarations\nEthics approval and consent to participate\nNot applicable.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nAdditional information\nPublisher’s note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nRights and permissions\nOpen 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/.\nAbout this article\nCite this article\nKobayashi, 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\nReceived:\nAccepted:\nPublished:\nDOI: https://doi.org/10.1186/s12958-026-01588-z","source_license":"CC0","license_restricted":false}