Exploring the therapeutic potential of H1-antihistamines in endometriosis-A gene regulation-based perspective

Abstract

Introduction: Recent studies emphasize the role of immune dysregulation and inflammation in endometriosis (ES). While hormonal therapy remains the primary treatment, emerging research is exploring synergistic approaches that target inflammation. In this study, we investigate the potential of H1-antihistamines (H1-As) in ES management from a gene-regulation viewpoint.

Methods: We perform differential gene expression analysis on two gene-sequencing datasets from ES patients, with a primar focus on inflammatory signaling [nuclear factor-kappa B (NF-κB), tumor necrosis factor (TNF), and cytokine-cytokine receptor] and histamine synthesis and metabolism (HSM) pathways, considering disease severity and hormonal therapy usage.

Results & discussion: Consistent with the literature, our findings highlight the dysregulation of several genes involved in pro-inflammatory pathways, including interleukins (ILs), cyclooxygenase-2 (COX-2), chemokine ligands, cellular adhesionmolecules, and neuroangiogenesis. We also note dysregulation of genes in the HSM pathway, indicative of a microenvironment that favors histamine availability and inflammatory persistence through enhanced histamine synthesis and reduced breakdown, as well as a reduced potential to clear reactive aldehyde species. We also find that hormonal therapy minimally affects the dysregulation of the majority of pro-inflammatory and histaminic pathway genes, and their amplified dysregulation is noted in early stage disease. By placing our findings in the context of existing evidence on histamine-mediated modulation of inflammatory pathways via the H1 histamine receptor (HRH1), we present a comprehensive discussion on the potential therapeutic value of H1-As in ES management due to their anti-inflammatory and mast-cellstabilizing properties.

Keywords: H1-antihistamines; endometriosis; endometrium; gene expression; inflammation.

Figure 1

Top row: fold change (FC) of differentially expressed genes [adjusted p-value (p_adj) < 0.05 in black] between control endometrium (CE) vs. patient (eutopic) endometrium (PE) samples participating in the NF-κB (left), TNF-signaling (middle), and cytokine–cytokine receptor signaling (right) pathways sorted in decreasing order of FC from top to bottom. Genes that have a non-adjusted, native p-value < 0.05 are shown in red text. Bottom row: Same as in top row, but for the control peritoneum (CP) vs. patient peritoneum (PP) case.

Figure 2

Fold change (FC) of differentially expressed genes [adjusted p-value (p_adj) < 0.05 in black] between control endometrium (CE) vs. deep infiltrating endometriosis (DiE) samples participating in the NF-κB (left), TNF-signaling (middle), and cytokine–cytokine receptor signaling (right) pathways sorted in decreasing order of FC from top to bottom. Genes that have a non-adjusted, native p-value < 0.05 are shown in red text.

Figure 3

Fold change (FC) of differentially expressed genes [adjusted p-value (p_adj) < 0.05 in black] between control endometrium (CE) vs. peritoneal lesions (PeL; see Section 2 for more details) samples participating in the NF-κB (left), TNF-signaling (middle), and cytokine–cytokine receptor signaling (right) pathways sorted in decreasing order of FC from top to bottom. Genes that have a non-adjusted, native p-value < 0.05 are shown in red text.

Figure 4

Fold change for genes participating in the histamine synthesis and metabolism pathway based on DGE analysis performed on the GSE141549 (CE vs. PeL and CE vs. DiE cases) and GSE51981 (non-ES vs. ES cases) datasets.

Figure 5

Fold change (FC) of differentially expressed genes (adjusted p-value; p_adj < 0.05 in black) for the non-ES controls vs. ES samples (inclusive of all disease stages, that is, mild to severe) among three pathways: NF-κB (left), TNF signaling (middle), and cytokine–cytokine receptor signaling (right).

Figure 6

Difference in the differential expression Log₂ (fold change) of genes within NF-κB, TNF, and CC pathways for the case of control endometrium (CE) vs. deep infiltrating endometriosis (DiE) in patients who are reported to be not using vs. using hormonal therapy. A difference of zero indicates no change in the level of gene up- or downregulation when using (or not) hormonal therapy, whereas a deviation to positive (negative) values indicates relative downregulation (upregulation) when on hormonal therapy.

Figure 7

Difference in the differential expression Log₂ (fold change) of genes within NF-κB, TNF, and CC pathways for the case of control endometrium (CE) vs. peritoneal lesions (PeL) case between those patients that are reported to be not using vs. using hormonal therapy. A difference of zero indicates no change in the level of gene up- or downregulation when using (or not) hormonal therapy, whereas a deviation to positive (negative) values indicates relative downregulation (upregulation) when on hormonal therapy.

Figure 8

Difference in the Log₂ (fold change) without and with use of hormonal therapy (in the case of GSE141549) and between moderate-to-severe disease stage vs. minimal-to-mild disease stage (in the case of GSE51981).

Figure 9

Difference in the differential expression Log₂ (fold change) of genes within the NF-κB, TNF, and CC pathways for the non-ES vs. ES case between those patients that are reported to have minimal-to-mild ES vs. moderate-to-severe ES.