Metabolic–reproductive Crosstalk in Polycystic Ovary Syndrome: Therapeutic Implications of Dual Incretin Agonism with Tirzepatide

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine–metabolic disorder characterised by varying constellations of ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology alongside cardiometabolic risk factors including insulin resistance, adiposity, dysglycemia, and metabolic dysfunction–associated steatotic liver disease. This review synthesises contemporary evidence on metabolic–reproductive coupling in PCOS, examines the physiological basis of incretin signalling at the metabolism–reproduction interface, and discusses therapeutic implications, safety considerations, and research priorities for tirzepatide and related dual agonist strategies in PCOS. A focused narrative review was conducted, searching PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar for articles published between 2010-2025, combining keywords like "polycystic ovary syndrome", "insulin resistance", and "tirzepatide" to assess metabolic and reproductive outcomes. Increasingly, PCOS is conceptualised not as an isolated reproductive condition but as a systems-level disorder in which metabolic and reproductive axes interact bidirectionally across the lifespan. Hyperinsulinemia amplifies ovarian androgen production and suppresses hepatic sex hormone–binding globulin, while androgen excess and neuroendocrine dysregulation can worsen adipose dysfunction, appetite regulation, and insulin sensitivity. This metabolic–reproductive crosstalk helps explain the persistence of both subfertility and long-term cardiometabolic sequelae, but it also provides a mechanistic foundation for therapies that target metabolic drivers to improve reproductive outcomes. Incretin-based pharmacotherapy has emerged as a potent metabolic strategy for weight reduction and glycemic improvement. Among incretin approaches, dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonism with tirzepatide produces robust and sustained weight loss and improves insulin sensitivity and cardiometabolic parameters in populations with obesity and type 2 diabetes. Although direct clinical trials of tirzepatide in PCOS are limited or absent at present, the magnitude of its metabolic effects, along with established evidence that GLP-1 receptor agonists improve weight and metabolic parameters in women with PCOS, supports a strong translational rationale for evaluating dual incretin agonism as a disease-modifying adjunct in selected PCOS phenotypes.