The Effect of Umbilical Cord-Derived Mesenchymal Stem Cells and Secretome on Metabolomic Profiles (C-Peptide, Adiponectin, Fasting Insulin, and Fasting Glucose): A Randomized Controlled Trial

<b>Background:</b> Polycystic ovary syndrome (PCOS) is a prevalent endocrine-metabolic disorder with chronic low-grade inflammation and insulin resistance (IR). Elevated C-peptide, a marker of compensatory hyperinsulinemia and reduced adiponectin, an insulin-sensitizing adipokine, contribute to the metabolic dysregulation observed in PCOS. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) and their secretome have immunomodulatory properties via paracrine and epigenetic mechanisms, yet longitudinal evidence in PCOS is limited. <b>Methods:</b> This randomized controlled trial (RCT) involved 40 women with PCOS (Rotterdam criteria) who were randomly assigned to four treatment groups: (1) metformin 750 mg/day, (2) UC-MSC infusion (0.3 million cells/kg body weight), (3) secretome (nasal drops, 2 mL), and (4) a combination of UC-MSC (0.3 million cells/kg body weight) and secretome (nasal drops, 2 mL). Parameters measured included fasting glucose, fasting insulin, HOMA-IR, C-peptide, and adiponectin at baseline and at months 1, 3, and 6. Analysis was performed using repeated-measures ANOVA or Friedman test, and ROC curves were used to evaluate the predictive value of biomarkers on therapy response. <b>Results:</b> All participants completed the 6-months of follow-up. The secretome group demonstrated a significant increase in fasting glucose (month 1: <i>p</i> = 0.013; month 3: <i>p</i> = 0.007; month 6: <i>p</i> = 0.032), as well as an increase in adiponectin in the UC-MSC group (month 6: <i>p</i> = 0.016). The combination of UC-MSC and secretome induced early metabolic modulation, characterized by transient reductions in adiponectin at months 1 and 3 (<i>p</i> = 0.022 and <i>p</i> = 0.013, respectively) and early increases in insulin-related parameters; however, these effects were not sustained at month 6. ROC analysis showed that glucose, insulin, and C-peptide variables had low discriminatory ability (AUC < 0.5), while adiponectin showed a trend of increasing predictive value for improving insulin sensitivity. <b>Conclusions:</b> Combination therapy with UC-MSCs and secretome may have potential to improve metabolic profiles through increasing adiponectin and improving insulin sensitivity in PCOS patients, especially in the group with insulin resistance. MSC-based approaches are not only symptomatic but also have the potential to restore ovarian function through immunomodulatory and epigenetic mechanisms.