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Volume 27
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10.3390/ijms27010212
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

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

by
Renata Voltolini Velho
1,
Julia Hannah Freitag
1,
Arie Maeve Brueckner
1,
Laura Thalmeier
1,
Jonathan Pohl
2 and
Sylvia Mechsner
1,*
1
Department of Gynecology Charité with Centre of Oncological Surgery, Endometriosis Research Centre Charité, Charité University Hospital, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
2
Institute for Pathology, Charité University Hospital, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(1), 212; https://doi.org/10.3390/ijms27010212
Submission received: 21 November 2025 / Revised: 16 December 2025 / Accepted: 21 December 2025 / Published: 24 December 2025
(This article belongs to the Special Issue Endometriosis: Current Trends and Research Developments)
Versions Notes

Abstract

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. HDC expression was significantly elevated in all endometriotic lesions compared with controls (all p < 0.01), paralleling increased IL-6, COX-2, NGF, and NGFR levels (p < 0.0001). In contrast, HRH1–HRH4 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; p = 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.
Keywords: endometriosis; histamine; histamine receptors; neuroimmune signaling; mast cells; nociception; inflammation endometriosis; histamine; histamine receptors; neuroimmune signaling; mast cells; nociception; inflammation

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MDPI and ACS Style

Velho, R.V.; Freitag, J.H.; Brueckner, A.M.; Thalmeier, L.; Pohl, J.; Mechsner, S. The Histamine-Associated Inflammatory Landscape of Endometriosis: Molecular Profiling of HDC, HRH1-HRH4, and Cytokines Across Lesion Subtypes. Int. J. Mol. Sci. 2026, 27, 212. https://doi.org/10.3390/ijms27010212

AMA Style

Velho RV, Freitag JH, Brueckner AM, Thalmeier L, Pohl J, Mechsner S. The Histamine-Associated Inflammatory Landscape of Endometriosis: Molecular Profiling of HDC, HRH1-HRH4, and Cytokines Across Lesion Subtypes. International Journal of Molecular Sciences. 2026; 27(1):212. https://doi.org/10.3390/ijms27010212

Chicago/Turabian Style

Velho, Renata Voltolini, Julia Hannah Freitag, Arie Maeve Brueckner, Laura Thalmeier, Jonathan Pohl, and Sylvia Mechsner. 2026. "The Histamine-Associated Inflammatory Landscape of Endometriosis: Molecular Profiling of HDC, HRH1-HRH4, and Cytokines Across Lesion Subtypes" International Journal of Molecular Sciences 27, no. 1: 212. https://doi.org/10.3390/ijms27010212

APA Style

Velho, R. V., Freitag, J. H., Brueckner, A. M., Thalmeier, L., Pohl, J., & Mechsner, S. (2026). The Histamine-Associated Inflammatory Landscape of Endometriosis: Molecular Profiling of HDC, HRH1-HRH4, and Cytokines Across Lesion Subtypes. International Journal of Molecular Sciences, 27(1), 212. https://doi.org/10.3390/ijms27010212

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