Phenotype-Specific Profiles of Isthmin-1, Trimethylamine N-Oxide, and Nitric Oxide in Polyendocrine Metabolic Ovarian...

Background: This study aimed to evaluate the phenotype-specific profiles of serum Isthmin-1 (ISM-1), Trimethylamine N-Oxide (TMAO) and Nitric Oxide (NO) levels in women diagnosed with Polyendocrine Metabolic Ovarian Syndrome (PMOS, formerly known as Polycystic Ovary Syndrome-PCOS) according to the Rotterdam criteria. Methods: This cross-sectional study enrolled 90 reproductive-aged women, divided equally into five groups (n = 18 per group) with similar baseline metabolic parameters: healthy controls and PMOS Phenotypes A, B, C, and D. To minimize confounding effects, individuals with recent use of specific medications were excluded, and 24 h dietary recalls were obtained. Fasting blood samples were collected during the early follicular phase. Serum ISM-1, TMAO, and NO levels were quantified via ELISA, and insulin resistance was determined using the HOMA-IR index. Data were adjusted for potential confounders, including age, BMI, and smoking status, using multivariate linear regression models. Results: No statistically significant differences were observed between the groups in key parameters such as BMI and HOMA-IR. Serum ISM-1 levels did not show a significant difference between the groups (p = 0.501). In contrast, NO levels were found to be significantly lower in all PMOS phenotypes compared to the control group (p < 0.001), and this reduction remained independent in regression models. TMAO levels, however, exhibited a phenotype-specific distribution; in the non-hyperandrogenic Phenotype D, they were found to be significantly lower than in the control group and hyperandrogenic phenotypes A and B. In the multivariate regression analysis, it was confirmed that Phenotype D was independently associated with low TMAO levels (B = -0.131, p = 0.027). Conclusions: Although PMOS patients share a similar profile of obesity and insulin resistance, they exhibit marked biochemical heterogeneity. Whilst the reduction in NO levels may indicate a generalised vascular change affecting all phenotypes, the observation of low TMAO levels specifically in the non-hyperandrogenic Phenotype D highlights a distinct biochemical signature associated with this subgroup, observed in the absence of hyperandrogenism. Our findings support the notion that adopting phenotype-specific, individualised approaches in the management of PMOS may be beneficial.