Fulvestrant, an estrogen receptor inhibitor, relieves postoperative hemorrhoid edema via up-regulation of miR- 424-5p

Abstract

Purpose: To investigate estrogen receptor (ER) expression in postoperative hemorrhoid edema tissues, and the likely mechanism involved in fulvestrant-mediated reduction of postoperative hemorrhoid edema.Methods: One hundred and eighty-five patients admitted to Jinshan Hospital of Fudan University, Shanghai who accepted hemorrhoidectomy were enrolled in this study. Primary cells were extracted from the anal margin tissues of patients for the determination of changes in ERα and vascular endothelial growth factor (VEGF). In vitro cellular experiments were performed in primary vascular endothelial cells to verify whether ER promoted postoperative perianal edema via the miR-424-5p estrogen receptor α gene (ESR1) axis. The cells were exposed to Fulvestrant, estradiol, and miR-424-5p mimic. Changes in expressions of ERα and VEGF were determined.Results: Fourteen patients (7.57 %), comprising 2 males (2.60 %) and 12 females (11.1 %), developedpostoperative anal margin edema. There was a significant difference in the incidence of postoperative anal edema between males and females (p < 0.05). Both immunohistochemistry and immunoblotting revealed markedly higher ERα levels in postoperative anal edema tissues than in preoperative tissues (p < 0.05). Moreover, ERα level was regulated by estradiol, and miR-424-5p targeted the estrogen receptor α gene (ESR1).Conclusion: Estradiol inhibits miR-424-5p through ERα in perianal tissues after hemorrhoid surgery. It increases VEGF and promotes perianal edema. However, fulvestrant inhibits ERα, thereby reducing VEGF expression and mitigating postoperative hemorrhoid edema, and therefore, has potential application for the management of postoperative hemorrhoid edema.

Integrated genomic network analysis revealed potential of a druggable target for hemorrhoid treatment

“…Within this range of 87 drugs, a diverse landscape emerged: ketamine (NCT04248205) was under active clinical investigation for hemorrhoids, fulvestrant was supported by preclinical in vitro models demonstrating potential efficacy for hemorrhoids ( Fanyu Meng et al, 2022 ), and methylene blue was supported by case series evidence for hemorrhoids ( Baldiwala and Trivedi, 2022 , Long et al, 2023 ), as shown in Fig. 4 .…”

“…It offers superior analgesia compared to placebo without affecting cognitive function, hence relieving post-hemorrhoidectomy pain. Fulvestrant, an estrogen receptor antagonist, has shown promise in preclinical in vitro models by inhibiting ERα, thereby reducing VEGF expression and mitigating postoperative hemorrhoid edema ( Fanyu Meng et al, 2022 ). Methylene blue, supported by case series evidence, demonstrates anti-inflammatory effects by suppressing nitric oxide production, ultimately alleviating post-hemorrhoidectomy pain ( Baldiwala and Trivedi, 2022 , Long et al, 2023 ).…”