Background: Polycystic ovarian syndrome (PCOS) is common, affecting up to one-fifth of females. PCOS is associated with significant comorbidity including metabolic dysfunction, pro-inflammation and mood disorders. Despite this, it is poorly understood, and diagnosis and management remain challenging in adolescents. Proteomics enables the better understanding of disease mechanisms and facilitates the identification of novel biomarkers.
Objectives: To describe the clinical phenotype of PCOS in adolescents and undertake discovery proteomic urine profiling using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) to identify novel non-invasive biomarkers of PCOS.
Method: This prospective longitudinal study recruited females meeting NIH diagnostic criteria for PCOS from adolescent endocrinology and gynaecology clinics. The following were measured at baseline and annual follow-up: pituitary, adrenal and ovarian hormones, metabolic markers including an oral glucose tolerance test, psychological, menstrual, pubertal and anthropometric parameters, and pelvic ultrasounds. We have undertaken UPLC-MS/MS and developed new methods for discovery proteomic profiling of urine in an attempt to identify new disease mechanisms, drug targets and potential biomarkers.
Results: We have recruited 40 participants (median age 15.0 years, range 12.5-18.3), with two-thirds completing annual follow-up to date. Clinical signs at presentation included acne (89%), hirsutism (78%) and acanthosis nigricans (49%). Two-thirds of participants had depressive or anxiety symptoms yet only one-third were known to mental health services. Metabolic dysfunction was common at baseline; overweight/obesity (86%), elevated body fat (88%) and dyslipidaemia (35%). These parameters did not alter significantly at follow-up. Insulin resistance was almost universal at baseline and follow-up (91%). Impaired glucose metabolism was common but improved from baseline (29%) to follow-up (10%; p=0.11). Over two-thirds of participants had an elevated anti-Müllerian hormone, three-quarters had an elevated free androgen index. Elevated inflammatory markers (CRP/ESR) were present in 40% participants. Only three participants had definitive ultrasonographic evidence of PCOS. Interventions included lifestyle advice (27%), combined oral contraceptive pill (COCP) ± anti-androgen (16%), metformin (30%) or metformin + COCP ± anti-androgen (27%).
Conclusion and Future Directions: We have demonstrated that adolescents with PCOS are at high risk of metabolic dysfunction, inflammation and mental health disorders. As such, early diagnosis and intervention are imperative. However, current diagnostic and surveillance methods are suboptimal. We describe the use of urinary proteomics to study metabolic pathways affected in PCOS and the potential identification of novel non-invasive biomarkers. Subsequently, we will use this hypothesis-generating data-set to create a non-invasive and clinically translatable assay to aid diagnosis and stratify management of this common adolescent condition.
19 Sep 2019 - 21 Sep 2019