Metabolic Phenotype Predicts Biochemical Response to Inositol Supplementation in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

Objective: To evaluate the effect of inositol supplementation on biochemical hyperandrogenism in women with polycystic ovary syndrome (PCOS) and to explore whether metabolic phenotype modifies the endocrine response. Design: Systematic review and meta-analysis of randomized controlled trials conducted in accordance with PRISMA guidelines. Patients: Women diagnosed with PCOS according to established criteria (NIH, Rotterdam, or AE-PCOS). Nine eligible trials comprising a total of 440 participants were included. Measurements: Primary outcomes were serum total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI), and sex hormone–binding globulin (SHBG). Prespecified subgroup analyses explored differences according to body mass index (BMI) and insulin resistance (HOMA-IR). Results: Inositol supplementation was associated with significant reductions in TT (SMD –1.30; 95% CI –2.17 to –0.42), cFT, and FAI, together with an increase in SHBG. Substantial heterogeneity was observed for several outcomes. In subgroup analyses, the largest and most consistent reduction in TT was observed among normal-weight women (BMI < 25 kg/m²) (SMD –2.97; 95% CI –3.78 to –2.16), with minimal heterogeneity (I² = 9%). No significant improvements were detected in overweight or obese women, nor in women with insulin resistance when considered independently of BMI. These subgroup findings should be interpreted as exploratory. Conclusions: Inositol supplementation is associated with improvements in biochemical hyperandrogenism in women with PCOS, with evidence of phenotype-dependent variability. The most consistent biochemical response was observed in normal-weight individuals. These findings support a metabolically informed, hypothesis-generating framework and highlight the need for adequately powered, phenotype-stratified trials incorporating clinically meaningful outcomes, including standardized measures of hirsutism, ovulatory function, and patient-reported endpoints.