Pharmacological Management of Benign Thyroid Nodules: A Comprehensive Systematic Review of Repurposed Therapeutics and Molecular-Targeted Strategies

Abstract

Background: Benign thyroid nodules are highly prevalent, affecting approximately 50–60% of adults on high-resolution ultrasonography. Despite their frequency, management remains limited to surveillance, minimally invasive ablative techniques, or surgery. Earlier levothyroxine-based thyroid-stimulating hormone (TSH) suppression showed inconsistent efficacy and adverse metabolic effects, limiting its role in current clinical practice. Objective: This systematic review synthesizes evidence from clinical trials, preclinical studies, and epidemiological data to evaluate emerging pharmacological therapies for benign thyroid nodules. It focuses on TSH-modulating agents, selective THR-β agonists, mTOR pathway modulators, antifibrotic and vascular-targeted therapies, and mutation-specific agents, with particular emphasis on drug repurposing. Methods: A comprehensive search of PubMed, Scopus, Web of Science, and Embase (January 2000–December 2025) identified relevant clinical, preclinical, and observational studies. Data extraction focused on nodule volume reduction, safety profiles, and mechanistic insights from thyroid cell cultures, organoid models, and murine experiments. Study quality was assessed using standardized tools. Results: Levothyroxine achieved a 10–20% mean volume reduction in 1,245 patients, but caused hyperthyroidism in 14–19% of patients. Selective THR-β agonists produced a 21% reduction with improved safety over 24 weeks (n=48). Mutation-directed therapies targeting RET, BRAF, and NTRK yielded 25–32% reductions in preliminary cohorts. mTOR inhibitors achieved an 18% reduction with acceptable tolerability (n=12). Repurposed agents such as metformin (16% reduction, n=67) and statins (22% reduced prevalence in observational studies) showed moderate efficacy and favorable safety. Antifibrotic therapies demonstrated promising preclinical results, reducing fibrotic markers by 35–45%. Conclusion: Evidence supports a shift from observation-only strategies toward precision pharmacotherapy for selected benign thyroid nodules. Repurposing established drugs with known safety profiles offers the most feasible near-term approach, while molecular stratification may improve targeted treatment effectiveness and address an unmet need in endocrinology practice.