Emerging Therapeutic Strategies Targeting Insulin Resistance in PCOS to Improve Fertility

Abstract

Background: Polycystic ovary syndrome is a major cause of anovulatory infertility, and insulin resistance contributes to compensatory hyperinsulinaemia, androgen excess, impaired follicular development, and adverse reproductive outcomes in many affected women. Metabolic treatment may improve the physiological environment required for ovulation and pregnancy, but its role must be distinguished from that of established fertility-directed therapy. Objective: To map the available evidence on lifestyle, pharmacological, nutritional, and other metabolic strategies targeting insulin resistance or related pathways and to examine their reported effects on fertility outcomes in women with polycystic ovary syndrome. Methods: A rapid structured scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews and Joanna Briggs Institute guidance. PubMed/MEDLINE, Google Scholar, international guideline repositories, and reference lists were searched through 8 June 2026. Eligible publications included clinical practice guidelines, randomised controlled trials, systematic reviews, meta-analyses, and major clinical reviews evaluating metabolic or fertility-directed interventions in women with polycystic ovary syndrome and reporting menstrual, ovulatory, pregnancy, live-birth, miscarriage, or assisted reproductive outcomes. Data were charted by study design, intervention, metabolic effect, reproductive outcome, and evidence limitation. Findings were synthesised descriptively without formal certainty grading or meta-analysis. Results: Nine publications met the eligibility criteria, comprising two clinical practice guidelines, two randomised controlled trials, four systematic reviews or meta-analyses, and one major clinical review. Lifestyle management was consistently recommended as the foundation of metabolic and preconception care, although direct evidence for live birth was limited within the audited evidence set. Metformin improved metabolic parameters, menstrual cyclicity, and ovulation in selected women but had a principally supportive role when conception was the immediate objective. Letrozole provided the clearest direct evidence for ovulation and live birth but did not directly treat insulin resistance. Inositol and exenatide-based glucagon-like peptide-1 receptor agonist therapy showed possible metabolic and intermediate reproductive benefits, whereas evidence for live birth and pregnancy safety remained insufficient. Berberine did not demonstrate a clear additional fecundity benefit when combined with letrozole. Conclusion: Fertility management in women with insulin-resistant polycystic ovary syndrome should combine metabolic assessment and optimisation with established fertility-directed treatment. Lifestyle management remains foundational, letrozole is the preferred first-line ovulation-induction treatment, and metformin may provide additional benefit in selected women with metabolic dysfunction. Evidence for inositol, glucagon-like peptide-1 receptor agonists, and berberine remains limited by heterogeneous methods and inadequate reporting of live birth, miscarriage, assisted reproduction, and pregnancy safety