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.