Serum Metabolomic Profiling Reveals Potential Biomarkers in Assessing the Management of Women with Polycystic Ovary Syndrome: A Randomized Controlled Trial
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of childbearing age. It is characterized by a combination of symptoms, including oligo- or anovulation, hyperandrogenism, and polycystic ovarian morphology (PCOM). The heterogeneity of PCOS symptoms and the lack of a unified diagnostic criteria among international health organizations have made its diagnosis and management evaluation challenging. The prevalence of PCOS varies widely, ranging from 8% to 13%, depending on the diagnostic criteria used. The syndrome is also associated with long-term metabolic complications, such as insulin resistance, obesity, type 2 diabetes, and cardiovascular diseases. Given the complexity of PCOS, there is a pressing need for more efficient biomarkers to monitor its progression and the efficacy of therapeutic interventions.
Metabolomics, the study of small molecules within cells, tissues, and biofluids, has emerged as a powerful tool for understanding the metabolic changes associated with various diseases. As the end product of genetic and environmental interactions, metabolites provide a direct reflection of the physiological state of an individual. Advances in liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) have enabled the non-invasive and hypothesis-free profiling of metabolites with high accuracy and efficiency. This approach has been successfully applied to study metabolic disorders such as insulin resistance and type 2 diabetes. However, the metabolomic profile of PCOS remains underexplored, and further research is needed to identify potential biomarkers for its diagnosis and management.
This study aimed to characterize the serum metabolomic profile of women with PCOS and identify potential biomarkers for assessing the efficacy of medical interventions. A randomized controlled trial was conducted, enrolling 117 PCOS patients who were randomly assigned to one of three treatment groups: Group A received Dingkundan, a traditional Chinese herbal medicine; Group B received Diane-35, a combined oral contraceptive pill; and Group C received a combination of Dingkundan and Diane-35. The interventions lasted for three months, and serum samples were collected at baseline, two months, and three months for metabolomic analysis. Classical clinical parameters, such as blood glucose, insulin levels, and lipid profiles, were also measured to evaluate the patients’ metabolic status.
At baseline, the demographic and clinical characteristics of the three groups were comparable, with no significant differences in age, body mass index (BMI), total testosterone levels, fasting glucose, or lipid profiles. After three months of treatment, significant improvements were observed in several clinical parameters. In Group B (Diane-35), there was a notable decrease in total testosterone levels, indicating an improvement in hyperandrogenism. Group C (combination therapy) showed an additional reduction in BMI compared to Group B. However, both Group B and Group C exhibited increases in total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels, which diverged from the trend observed in Group A.
Metabolomic analysis revealed significant changes in the serum metabolome of PCOS patients following treatment. Over 600 small molecules were detected using LC-MS/MS, and multivariate statistical analysis, including partial least squares discriminant analysis (PLS-DA), was performed to identify metabolites associated with treatment efficacy. A total of 93 metabolites were found to be significantly altered, with variable importance in projection (VIP) scores greater than 1 and false discovery rate (FDR) adjustments below 0.05. Pathway enrichment analysis highlighted that the most significantly affected pathways were related to amino acid metabolism, particularly aspartate metabolism.
Among the identified metabolites, six were selected as potential biomarkers for assessing the management of PCOS: glutamic acid, aspartic acid, 1-methylnicotinamide, acetylcarnitine, glycerophosphocholine, and oleamide. These metabolites were chosen based on their high sensitivity and specificity in receiver operating characteristic (ROC) curve analysis, with area under the curve (AUC) values exceeding 0.96. The relative abundance of these metabolites was plotted to illustrate their changes over the course of treatment. Aspartic acid, glycerophosphocholine, and oleamide showed a gradual increase during treatment, while 1-methylnicotinamide, acetylcarnitine, and glutamic acid decreased.
The performance of these six metabolites in assessing treatment efficacy was validated using serum samples from all three treatment groups. The AUC values for the ROC curves constructed using these biomarkers were consistently high, indicating their reliability in monitoring the progression of PCOS management. Additionally, the biomarkers were applied to evaluate the efficacy of treatment at the two-month mark. The results showed that the combination therapy (Group C) was more effective in treating PCOS than Diane-35 alone, as evidenced by the higher predicted class probabilities for improvement in Group C compared to Group B.
The selected metabolites provide insights into the metabolic changes associated with PCOS and its management. Aspartic acid and glutamic acid, both non-essential amino acids, play crucial roles in the tricarboxylic acid (TCA) cycle and neurotransmitter synthesis. The changes in their levels suggest alterations in amino acid metabolism in PCOS patients. 1-Methylnicotinamide, a metabolite involved in nicotinamide metabolism, has anti-inflammatory properties and is associated with cardiovascular health. Its decrease during treatment aligns with the goal of reducing long-term cardiovascular risks in PCOS patients.
Acetylcarnitine and glycerophosphocholine are involved in lipid metabolism. The decrease in acetylcarnitine levels indicates reduced lipid synthesis, while the increase in glycerophosphocholine suggests enhanced hydrolysis of phosphatidylcholine. Oleamide, a fatty acid amide, was found to increase significantly during treatment, particularly in the combination therapy group. Oleamide is known to induce sleep in animals, which may be a side effect of the treatment.
The findings of this study highlight the potential of metabolomics in identifying biomarkers for the assessment of PCOS management. The six selected metabolites—glutamic acid, aspartic acid, 1-methylnicotinamide, acetylcarnitine, glycerophosphocholine, and oleamide—demonstrated high sensitivity and specificity in evaluating the efficacy of medical interventions. These biomarkers offer a more comprehensive understanding of the metabolic changes associated with PCOS and provide a valuable tool for monitoring treatment outcomes.
In conclusion, this study underscores the importance of metabolomics in advancing our understanding of PCOS and its management. The identified biomarkers represent a significant step toward personalized medicine for PCOS patients, enabling more accurate assessment of treatment efficacy and progression. Future research with larger sample sizes is needed to further validate these findings and explore their clinical applications.
doi.org/10.1097/CM9.0000000000001705
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