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

Daniele Tienforti; Gennaro Puocci; Claudia Venditti; Valentina Gizzi; Carlo Pisanò; Elisa Cocci; Elisabetta Perfetto; Francesco D'Alessandro; Luca Spagnolo; Marco Giorgio Baroni; Arcangelo Barbonetti

doi:10.1111/cen.70140

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

Tienforti D, Puocci G, Venditti C, Gizzi V, Pisanò C, Cocci E, Perfetto E, D'Alessandro F, Spagnolo L, Baroni MG, Barbonetti A

Published August 2026 Clinical endocrinology

DOI 10.1111/cen.70140 PMID 41947399 PMC PMC13326987

RRM Academy Synopsis

Inositol linked to lower testosterone in normal-weight PCOS

Across nine randomized trials in 440 women with PCOS, inositol was linked to lower testosterone and higher binding protein for sex hormones. The drop was largest in normal-weight women. In two studies of women with insulin resistance, testosterone did not change significantly.

Key Findings

Total testosterone fell more with inositol than with the comparator (SMD –1.30; 95% CI –2.17 to –0.42), with considerable heterogeneity (I² = 93%).
Calculated free testosterone fell (SMD –1.32; 95% CI –1.75 to –0.90), as did the free androgen index (SMD –2.65; 95% CI –4.27 to –1.03).
Sex hormone-binding globulin rose after inositol (SMD + 0.70; 95% CI 0.30 to 1.10; I² = 29%).
In normal-weight women (BMI < 25 kg/m²), two RCTs with 62 participants showed total testosterone falling (SMD –2.97; 95% CI –3.78 to –2.16; I² = 9%).
In women with insulin resistance (HOMA-IR > 4), two studies with 176 participants found no significant reduction (SMD –0.21; 95% CI –0.57 to 0.16; p = 0.26).

Interpretation

This meta-analysis pooled nine randomized trials in women with PCOS. Women took inositol for 6 to 24 weeks and were compared with a metabolically neutral comparator (placebo or folic acid). Response varied by phenotype, with the most consistent response in normal-weight women. The authors read this as support for a phenotype-oriented view of inositol responsiveness. They call the findings hypothesis-generating and ask for larger trials sorted by phenotype that track hirsutism, ovulation and patient-reported outcomes.

RRM Context

PCOS is now also called PMOS (Polyendocrine Metabolic Ovarian Syndrome). It has several metabolic patterns. Restorative reproductive medicine asks which pattern drives the excess androgens in each woman. A response that varies with weight and insulin status fits that cause-based approach.

Our editorial summary of this paper, not the article's abstract.

Abstract

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.

Daniele Tienforti, Gennaro Puocci, Claudia Venditti, Valentina Gizzi, Carlo Pisanò, Elisa Cocci, Elisabetta Perfetto, Francesco D'Alessandro, Luca Spagnolo, Marco Giorgio Baroni, Arcangelo Barbonetti

D Tienforti, G Puocci, C Venditti, V Gizzi, C Pisanò, E Cocci, E Perfetto, F D'Alessandro, L Spagnolo, M Baroni, A Barbonetti

PMID 41947399 41947399 DOI 10.1111/cen.70140 10.1111/cen.70140 Tienforti et al. 2026, Tienforti 2026

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

Inositol linked to lower testosterone in normal-weight PCOS

Key Findings

Interpretation

RRM Context

Abstract

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