Interconnection between polycystic ovary syndrome, immune disorders, and reproductive outcomes

Abstract: Polycystic ovary syndrome (PCOS) is a multifactorial disorder traditionally recognized for its endocrine and metabolic disturbances. However, accumulating evidence indicates that chronic low-grade inflammation and immune dysregulation play a central role in its pathophysiology. This narrative review explores the immunological mechanisms underlying PCOS and their repercussions for reproductive outcomes. Women with PCOS exhibit increased circulating levels of inflammatory cytokines - including interleukin (IL)-6, IL-1β, IL-18, and tumor necrosis factor-alpha (TNF-α) - alongside macrophage and lymphocyte infiltration within ovarian and endometrial tissues. These alterations promote oxidative stress, granulosa cell apoptosis, impaired steroidogenesis, and diminished endometrial receptivity. The adaptive immune response is similarly altered, characterized by imbalances between Th1/Th2 and Th17/regulatory T lymphocyte subsets and the presence of autoantibodies, including antinuclear, antithyroid, and antiphospholipid antibodies. These immune abnormalities have been associated with implantation failure and recurrent pregnancy loss. Furthermore, autoimmune diseases, including Hashimoto's thyroiditis and type 1 diabetes mellitus, occur more frequently among women with PCOS, reinforcing the concept of an underlying systemic immunometabolic imbalance. Unlike prior reviews, this work offers a novel integrative framework that connects systemic inflammation with localized immune dysregulation in reproductive tissues, providing a more comprehensive understanding of PCOS pathophysiology from an immunological standpoint. This review also discusses the immunological implications of metabolic therapies - including metformin and glucagon-like peptide-1 receptor agonists - and the prospective role of targeted immunomodulation in selected immune-phenotypic PCOS subgroups. Understanding PCOS through an immunological lens provides a new framework for integrating metabolic, hormonal, and immune pathways, guiding future personalized interventions to improve reproductive outcomes. Lay summary: Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women and involves not only hormonal and metabolic problems but also immune system dysregulation. Women with PCOS often experience chronic low-grade inflammation involving the ovaries and uterus, which can impair egg quality and hinder successful embryo implantation. They are also more prone to autoimmune diseases, including thyroid disorders, which can contribute to pregnancy complications and miscarriages. This review synthesizes recent studies showing how immune cells and inflammatory molecules interfere with fertility in PCOS and how certain existing treatments - such as metformin and glucagon-like peptide-1 receptor agonists - may also help by improving immune balance. Understanding these immune mechanisms will help researchers and clinicians develop more targeted and effective therapies, supporting women with PCOS in achieving healthier pregnancies.