The Efficacy of Polyphenolic Compounds in the Treatment of Endometriosis: A Preclinical Systematic Review and Meta-Analysis

Background: Natural polyphenols are plant secondary metabolites with a broad spectrum of biological activities. Extensive preclinical studies have demonstrated the significant therapeutic efficacy of polyphenolic compounds in animal models of endometriosis (EMs). Methods: A comprehensive literature search was conducted in PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Chongqing VIP Information Co., Ltd. (or VIP Database) (VIP) Database, and the Wanfang Database from their inception to December 2024. After screening titles, abstracts, and full texts, 43 studies were included. The risk of bias in the included studies was assessed with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias tool for animal studies. Meta-analysis of outcome measures was performed using STATA 17.0 software. Results: Polyphenolic compounds reduced lesion size, histopathological scores, and adhesion scores in ectopic lesions in animal models of EMs. They also decreased peripheral levels of estradiol (E2), tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), interleukin-1β (IL-1β), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and prostaglandin E2 (PGE2). Furthermore, they inhibited the expression of vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA), B-cell lymphoma 2 (BCL-2), and hypoxia-inducible factor-1α (HIF-1α). The underlying mechanisms include anti-inflammatory effects, immune regulation, anti-angiogenesis, antioxidant stress, and alleviation of tissue hypoxia. Conclusions: The therapeutic effects of polyphenolic compounds in animal models of EMs involve multiple mechanisms, including anti-inflammatory, immunomodulatory, anti-angiogenic, antioxidant stress, and hypoxia-alleviating effects. These findings provide preclinical evidence that supports the potential use of polyphenolic compounds for the treatment of EMs. Registration: The study has been registered on https://www.crd.york.ac.uk/prospero/ (registration number: CRD42024570708; registration link: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024570708).