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 non-hormonal alternatives. However, most evidence is derived from adult cohorts, leaving guidance specific to adolescents limited.

To systematically review the efficacy of non-hormonal pharmacotherapies including metformin, glucagon-like peptide-1 receptor agonists (GLP-1RAs), anti-androgens, and combination regimens in adolescents with PCOS.

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.

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.

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 standardised outcome measures to guide optimal non-hormonal strategies.