The Histamine-Associated Inflammatory Landscape of Endometriosis: Molecular Profiling of HDC, HRH1-HRH4, and Cytokines Across Lesion Subtypes

Pain in endometriosis involves not only nociceptive but also neuropathic and neurogenic components, reflecting its complex nature. Histamine, a biogenic amine, has emerged as a critical mediator connecting inflammation and nerve sensitization. This study aimed to characterize histamine receptor (HRH1-HRH4) expression, localization, and related inflammatory mediators in peritoneal, deep infiltrating, and ovarian endometriosis. Gene expression datasets were analyzed, and immunofluorescence staining of endometriotic lesions was performed using immune and neuronal markers. Histamine and its metabolite methylhistamine were quantified in serum, peritoneal fluid, and urine samples. <i>HDC</i> expression was significantly elevated in all endometriotic lesions compared with controls (all <i>p</i> < 0.01), paralleling increased <i>IL-6</i>, <i>COX-2</i>, <i>NGF</i>, and <i>NGFR</i> levels (<i>p</i> < 0.0001). In contrast, <i>HRH1-HRH4</i> transcript levels showed no significant differences between groups. Immunofluorescence demonstrated robust HRH1-HRH4 protein expression in epithelial, immune, and nerve fibers, with subtype-specific colocalization patterns. Serum histamine concentrations were significantly higher in endometriosis patients than controls (0.484 vs. 0.153 ng/mg protein; <i>p</i> = 0.0014), whereas peritoneal histamine and urinary methylhistamine showed no group differences. Overall, these findings highlight histamine signaling as a potentially important component of endometriosis pathophysiology and point toward new directions for mechanistic studies and therapeutic exploration.