A review of immunometabolic crosstalk in PCOS-related pregnancy loss: mechanisms and emerging therapeutic strategies

Abstract

Background: Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder affecting up to 18% of reproductive-aged women globally. Women with PCOS exhibit a significantly increased risk of miscarriage, independent of obesity and assisted reproduction variables. The etiology of PCOS-related pregnancy loss is multifactorial. Nevertheless, current clinical interventions target isolated mechanisms and demonstrate limited efficacy in reducing miscarriage rates. Objective: This review synthesize recent evidence connecting metabolic and immune dysregulation to pregnancy loss in PCOS and evaluate novel therapeutic strategies targeting immunometabolic pathways. Content: This review first presents an overview of the mechanistic pathways implicated in PCOS-related miscarriage, including endocrine-metabolic dysfunction, immune-inflammatory imbalance, oxidative stress and ferroptosis, vascular and coagulation defects, and uterine–placental abnormalities. Both translational and clinical for interventions with dual metabolic–immune effects are highlighted, such as metformin, antioxidants likeN-acetylcysteine, anti-androgens, and combination regimens including aspirin with low-molecular-weight heparin (LMWH). Agents with mechanistic promise but limited exploration, such as glucagon-like peptide-1 (GLP-1) receptor agonists, selenium nanoparticles, and stem cell–based therapies, are also discussed. Future directions for PCOS pregnancy care are outlined, emphasizing the integration of immunometabolic biomarkers, advanced animal models, and mechanism-informed combination trials. Conclusion: PCOS-related miscarriage is increasingly recognized as resulting from dysregulation of immune–metabolic crosstalk. Mechanism-based, multidimensional strategies targeting this dual pathology represent a promising paradigm for preventing and managing pregnancy loss in women with PCOS.