Altered Histamine Pathways in Endometriosis

Histamine Signaling Emerges as a Neuroimmune Feature of Endometriosis

Key Points

Highlights: 

• Systemic histamine levels were higher in women with endometriosis, while local peritoneal and urinary concentrations did not differ significantly from controls.
• Histamine pathway components, including histidine decarboxylase expression and histamine receptor protein localization, were enriched in endometriotic tissues, supporting a neuroimmune inflammatory signature.

Importance: 

• Characterizing histamine-related neuroimmune signaling may expand understanding of inflammatory mechanisms in endometriosis and inform future exploration of pathway-targeted interventions.

What’s done here:

• This translational study combined systemic biomarker analysis with molecular tissue profiling across endometriosis phenotypes.
• Histamine concentrations were measured in serum, peritoneal fluid, and urine samples from women with peritoneal, deep infiltrating, and ovarian endometriosis and from controls.
• Gene expression and protein localization of histamine pathway components—including histidine decarboxylase and histamine receptors—were assessed in endometriotic lesions and matched control tissues using molecular and immunohistochemical techniques.
• Expression of inflammatory and neurotrophic mediators was evaluated to explore potential neuroimmune interactions within lesions.

Key results:

• The expression of the histidine decarboxylase (HDC) gene was significantly higher in all three types of endometriosis compared to controls.
• Histamine receptor messenger RNA levels were similar between groups, but receptor proteins were more abundant in epithelial, immune, and nerve cells within lesions.
• Elevated levels of interleukin-6, cyclooxygenase-2, nerve growth factor, and its receptor were observed, consistent with an inflammatory and neurotrophic microenvironment.
• Distinct receptor co-localization patterns suggested cell-type–specific histamine signaling within lesions.

Strengths and Limitations:

• The integration of systemic biomarker measurements with tissue-level molecular and cellular analyses; and the inclusion of multiple endometriosis phenotypes enables comparison across lesion types are the strengths of the study.
• Limitations are: sample sizes within lesion subgroups were modest, receptor protein assessment was semi-quantitative, functional signaling studies were not performed, limiting mechanistic interpretation and the cross-sectional design precludes inference about symptom correlations or longitudinal effects.

From the Editor-in-Chief – EndoNews

"Interest in the neuroimmune dimension of endometriosis has intensified as accumulating evidence points to complex interactions between inflammatory mediators, peripheral nerves, and lesion microenvironments. Histamine, a multifunctional mediator with roles in immune regulation, nociception, and vascular signaling, represents a biologically plausible candidate within this network. By integrating systemic biomarker measurements with molecular and cellular analyses, this study contributes valuable data to the evolving understanding of inflammatory signaling in endometriosis.

The observation of elevated circulating histamine alongside increased histidine decarboxylase expression and upregulation of inflammatory and neurotrophic mediators supports the concept of an altered neuroimmune milieu in affected individuals. Notably, the absence of differences in receptor messenger RNA levels highlights the complexity of histamine signaling, suggesting that post-transcriptional regulation, receptor distribution, or local microenvironmental factors may be more relevant than gene expression alone.

Importantly, these findings should be interpreted within the exploratory framework typical of translational molecular studies. The cross-sectional design precludes conclusions regarding causality, and the lack of functional assays limits insight into downstream signaling dynamics or clinical correlates such as pain severity. Nevertheless, the integration of systemic and tissue-level analyses represents a methodological strength and provides a foundation for future mechanistic investigations.

From a broader perspective, the study reinforces the importance of examining endometriosis through a neuroimmune lens, where inflammatory mediators may interact with neural pathways to shape symptom expression and disease behavior. Whether histamine signaling represents a driver of pathophysiology, a secondary consequence of chronic inflammation, or a marker of immune activation remains to be determined. Prospective studies incorporating functional assays and clinical phenotyping will be essential to clarify these relationships.

In sum, this work advances the field by situating histamine within the molecular landscape of endometriosis, offering a nuanced contribution that highlights potential pathways for further investigation while underscoring the need for cautious interpretation and rigorous validation."

Lay Summary

Histamine, a key mediator of immune and inflammatory responses, is increasingly being investigated in the context of endometriosis.

In a study recently published in the International Journal of Molecular Sciences, researchers found that women with endometriosis had significantly higher histamine levels in their blood compared with women without the disease, while histamine concentrations in peritoneal fluid and methylhistamine levels in urine did not differ between groups.

To explore histamine-related mechanisms in more detail, Dr. Sylvia Mechsner and colleagues at Charité – Universitätsmedizin Berlin analyzed tissue and biological samples from women with peritoneal, deep infiltrating, and ovarian endometriosis as well as controls.

The investigators combined systemic measurements with molecular profiling, including analysis of gene expression datasets and immunohistochemical staining of endometriotic lesions using immune and neuronal markers.

They observed increased expression of the histidine decarboxylase gene, which encodes the enzyme responsible for histamine synthesis, across all endometriosis subtypes.

In addition, levels of inflammatory and neurotrophic mediators—including interleukin-6, cyclooxygenase-2, nerve growth factor, and its receptor—were elevated in endometriosis samples. Messenger RNA levels of histamine receptors H1 through H4, however, were not significantly different between groups.

Taken together, the findings suggest that histamine-related pathways may contribute to the inflammatory and neuroimmune environment of endometriosis.

While the study does not establish causal relationships, it provides a foundation for further research into the role of histamine signaling in disease mechanisms and potential therapeutic exploration.

Research Source: https://pubmed.ncbi.nlm.nih.gov/41516088/