Berberine and Berberine-Containing Alkaloid Preparations in Preclinical Models of Endometriosis and Adenomyosis: A Systematic Review

Background/Objectives: Berberine is increasingly promoted through social media and endometriosis-related websites as a non-hormonal supplement, although its disease-specific evidence remains unclear. This PRISMA-compliant systematic review evaluated experimental and clinical evidence for berberine in endometriosis and adenomyosis. Methods: PubMed/MEDLINE, EBSCOhost, BASE, CNKI Overseas, CENTRAL, and Google Scholar were searched from inception to 3 August 2026, supplemented by targeted manual searches. Clinical studies and experimental studies using endometriosis- or adenomyosis-related cellular or animal models were eligible. Purified berberine formed the primary evidence set. Chemically characterized multi-alkaloid preparations containing berberine were analyzed separately. Risk of bias was assessed with SYRCLE for animal studies and a predefined domain-based appraisal for in vitro studies. A structured qualitative assessment examined confidence in the synthesized findings. Contextual evidence from outside endometriosis and adenomyosis concerning steroid signaling, gut microbiota, microbial metabolites, and GLP-1 was discussed separately. Results: Six preclinical studies were included: three on endometriosis and three on adenomyosis, comprising four in vitro and two animal studies. Five investigated purified berberine and one a protoberberine-rich multi-alkaloid fraction. No clinical study was identified. Berberine reduced cell proliferation or viability and, where directly assessed, migration and invasion. It also reduced inflammatory and angiogenesis-related signaling, and, in an adenomyosis mouse model, myometrial infiltration and hyperalgesia. Reduced proliferation or viability recurred in all four cellular studies, with lower IL-6 and VEGF reported across cellular and animal adenomyosis models. Reported molecular effects involved NF-κB, STAT3, TLR4-associated signaling, VEGF, MMPs, TRPV1, COX-2, miR-429, and lncRNA H19. Gut microbiota modulation, short-chain fatty acids, intestinal barrier function, estrogen metabolism, GPER1, and GLP-1/GLP1R signaling remain plausible indirect routes that have not been demonstrated in disease-specific berberine studies. Conclusions: Berberine shows disease-relevant activity across a small and heterogeneous preclinical evidence base. Clinical efficacy, clinically achievable exposure, reproductive safety, and microbiota- or hormone-mediated effects remain unestablished.