ABSTRACT Adenomyosis is a prevalent disorder of the archimetra, historically conflated with endometriosis but possessing a unique pathobiological trajectory. This review synthesises current molecular evidence to propose a unified mechanistic framework initiated by tissue injury and repair (TIAR), aberrant stem cell activation, or de novo metaplasia, all of which converge to disrupt the endometrial–myometrial interface disruption (EMID). Following this structural breach, a self‐perpetuating ‘vicious cycle’ is triggered, driven by four interconnected axes: (1) Hormonal Dysregulation, characterised by local hyper‐estrogenism, progesterone resistance, and a specific paracrine prolactin loop that drives reactive myometrial hypertrophy; (2) Immune‐Hemostatic Crosstalk, where activated platelets and M2‐polarised macrophages establish a pro‐fibrotic niche via TGF‐β1 signalling; (3) Hypoxia and Neuroangiogenesis, where HIF‐1α stabilisation orchestrates metabolic reprogramming (Warburg effect) and the pathological sprouting of sensory nerves, underpinning chronic pain; and (4) Epigenetic Fibrosis, driven by the oestrogen–slug–VEGF axis and HDAC‐mediated chromatin remodelling leading to epithelial–mesenchymal transition (EMT). Furthermore, we clarify the genetic distinction between adenomyosis and uterine leiomyomas, highlighting their divergent responses to androgen receptor signalling. By elucidating these molecular targets, we discuss emerging non‐hormonal therapeutics—including anti‐platelet agents and dopamine agonists—offering mechanism‐based strategies for fertility preservation.
Yang et al. (2026) studied this question.