Facing the diagnosis of hyperandrogenic polycystic ovary syndrome by a novel combination of circulating biomarkers

The work-up of diagnosing a woman with polycystic ovary syndrome (PCOS) is still challenged by the lack of standardization of methods and threshold values used to establish the presence of its individual diagnostic criteria. This study aimed to address if a combination of circulating biomarkers suitable for clinical practice accurately discriminated among patients with polycystic ovary syndrome (PCOS) and non-hyperandrogenic women. The study included 253 premenopausal patients diagnosed with PCOS by state-of-the-art methodology and 71 non-hyperandrogenic controls with regular menses paired by body mass-index. We analyzed two circulating micro ribonucleic acids (miR-142-3p and miR-598-3p) that showed a strong association with PCOS in a previous validation study, and proton nuclear magnetic resonance spectroscopy metabolomic profiling of serum. Diagnostic accuracy was assessed by logistic regression models and receiver operating characteristics (ROC) curve analyses. Circulating miR-142-3p was under-expressed in patients with PCOS compared to controls. However, miR-598-3p expression was similar between patients with PCOS and non-hyperandrogenic controls. Patients with PCOS showed higher fasting circulating concentrations of alanine, leucine, isoleucine, glutamic acid, threonine, acetate, and lactate, and lower concentrations of glutamine and acetone, compared to controls. A binomial logistic regression [χ2(10): 94.2, P < 0.001] correctly classified patients with PCOS or non- hyperandrogenic individuals in 81% of cases. Only four biomarkers reached statistical significance in that model: miR-142-3p, isoleucine, acetate, and anti-müllerian hormone. The overall discriminatory ability of these variables was further addressed by ROC curve analyses. The model’s area under the ROC curve had a confidence interval from 0.826 to 0.917. However, the model’s performance was worse in identifying the subset of patients with non-hyperandrogenic PCOS. Patients with PCOS a particular pattern of circulating biomarkers comprised of miRNAs and low-molecular weight metabolites: compared to control women, PCOS patients consistently underexpressed circulating miR-142-3p and presented with higher circulating concentrations of isoleucine and acetate. When added to follicular-phase anti-müllerian hormone levels, this circulating biomarkers combination showed an excellent diagnostic performance in identifying hyperandrogenic PCOS, although its performance to detect normoandrogenic phenotypes was lower.