Clinical and multiomics changes with or without metformin during an 8-week very-low-carbohydrate intervention in PMOS patients: an exploratory randomized controlled trial

Dietary interventions, particularly carbohydrate-restricted approaches, improve metabolic and endocrine abnormalities in patients with polyendocrine metabolic ovarian syndrome (PMOS). However, whether metformin (MET) provides additional benefits when combined with intensive dietary intervention and how host metabolism and the gut microbiota respond at the molecular level remain unclear. In this pilot randomized controlled trial, overweight or obese women with PMOS (BMI 26–32 kg/m², aged 25–35 years) underwent an 8-week very-low-carbohydrate, low-calorie, high-protein dietary intervention (VLCD), with or without MET. Clinical parameters, plasma lipoproteins, untargeted serum metabolomics, and fecal metagenomics were assessed before and after the intervention. Between-group differences were evaluated using ANCOVA adjusted for baseline values. Among 38 randomized participants (20 VLCD, 18 VLCD + MET), 32 completed the 8-week assessment. Within-group reductions were observed in body weight, BMI, fasting insulin, HOMA-IR, and triglycerides, with no significant between-group differences in any outcome after adjustment. Both groups showed substantial lipoprotein remodeling, dominated by reductions in very low-density lipoprotein levels. The sets of metabolites meeting the within-group significance criteria partially overlapped between groups (the overlapped metabolites accounted for 48.1% and 56.9% in VLCD group and VLCD + MET group, respectively), with convergent alterations in bile acid-, lipid-, and amino acid-related pathways. The gut microbiota composition, diversity, and functional profiles changed minimally under both interventions. In this small, exploratory pilot trial, no statistically significant baseline-adjusted clinical differences between the interventions were detected. Within-group clinical and molecular changes provide hypotheses for further investigation but do not establish equivalent efficacy or metformin-specific effects. Larger trials with longer follow-up periods are needed to clarify the incremental benefit of adjunctive metformin.