Nonhormonal Pharmacological Interventions in Adolescent Polycystic Ovary Syndrome (PCOS): A Systematic Review

BACKGROUND: Adolescents with polycystic ovary syndrome (PCOS) experience metabolic dysfunction, reproductive disturbance, and psychosocial burden. While combined hormonal contraceptives (CHC) are first-line pharmacologic treatment, concerns regarding side effects and long-term safety have spurred interest in nonhormonal alternatives. However, most evidence is derived from adult cohorts, leaving guidance specific to adolescents limited. STUDY OBJECTIVES: To systematically review the efficacy of nonhormonal pharmacotherapies including metformin, glucagon-like peptide-1 receptor agonists (GLP-1RAs), anti-androgens, and combination regimens in adolescents with PCOS. METHODS: We searched Medline, EMBASE, Cochrane Library, and CINAHL (1990-June 2025) for RCTs, cohort, and case-control studies enrolling PCOS teenagers aged 12-19 years. Two reviewers independently screened, extracted data, and assessed study quality. Outcomes included clinical signs (hirsutism, menstrual regularity), metabolic indices (BMI, insulin resistance, lipids), hormonal markers (testosterone, AMH), and patient-reported quality of life. This is the first systematic review on this topic. RESULTS: Nineteen studies (744 adolescents) met the inclusion criteria: Eleven on metformin monotherapy, seven on SPIOMET (spironolactone, pioglitazone and metformin), and one on flutamide + metformin. Metformin alone modestly reduced BMI (1-2 kg/m² reduction), improved HOMA-IR (25% reduction), and restored menses in up to 91% of participants. SPIOMET improved ovulatory function and halved Ferriman-Gallwey scores, decreased visceral and hepatic fat, normalised inflammatory markers (CRP, GDF15), and sustained benefits up to one-year post-treatment, without significant weight change. Flutamide plus metformin yielded substantial anti-androgenic and metabolic improvements compared to CHCs. No full-text trials of GLP-1 receptor agonist monotherapy in adolescents were identified. CONCLUSION: Metformin appears to have some benefits for adolescents with PCOS, offering some metabolic and menstrual benefits based on a small number of observational studies and small RCTs. SPIOMET and flutamide & metformin show superior, multi-domain efficacy but should be studied in larger RCTs. Critical gaps include adolescent-specific GLP-1RA data and standardized outcome measures to guide optimal nonhormonal strategies.