OR15-4 Heterogeneity of Clinical Presentation of Adolescent PCOS Is Attributable to Distinct Subtypes

Abstract Objective Adolescent polycystic ovary syndrome (PCOS) is a heterogenous clinical syndrome characterized by hyperandrogenism and irregular menses. Heterogeneous features of the syndrome include the presence/absence of obesity, degree of insulin resistance, and clinical and/or biochemical hyperandrogenism. In adult women with PCOS, discrete metabolic and reproductive subgroups can be identified. A recent study described distinct phenotypes using unsupervised hierarchical cluster analysis: a metabolic subgroup characterized by higher BMI, glucose, and insulin levels, and a reproductive subgroup demonstrating higher LH and SHBG levels. We hypothesized that non-obese and obese adolescent girls with PCOS would exhibit similar distinct phenotypes at the time of diagnosis. Methods Data were extracted from a multi-site PCOS registry including seven academic centers in the US with the following inclusion criteria: PCOS confirmed per 2018 international guidelines, diagnosis before age 18 years, and at least one follow-up visit. Data collected included demographics, medical and family history, physical characteristics including hirsutism, acanthosis nigricans, and laboratory measures such as HbA1c, ALT, lipid profiles and reproductive hormones (androgens, LH, FSH, SHBG). Hormone levels were normalized to the upper limit provided by the measuring laboratory. Patients were divided by obesity status, defined as obese (OB) with BMI ≥ 95th percentile for age and sex and non-obese (NO) < 85th percentile for age and sex. Differences in continuous variables were assessed with unpaired t-tests using GraphPad Prism. Results Complete diagnostic data from 390 patients from 7 different sites were included for analysis, with 284 OB (Age 15.3±1.5 years, BMI 36.1±5.6 kg/m2) and 68 NO (Age 15.8±1.3 years, BMI 22.6±3.4 kg/m2). OB presented with more severe acanthosis (p<0.0001) and higher HbA1c (OB 5.5±0.5, NO 5.2±0.3; %, p<0.0001), ALT (OB 35±30, NO 22±17; IU/L, p=0.0006), and triglycerides (OB 145±90, NO 110,±88; mg/dL, p=0.002). OB also presented with higher free testosterone (OB 219±188% vs NO 158±125% above upper limit of normal; p=0.003), while NO presented with higher total testosterone (OB 121±68%, NO 152±88% above upper limit of normal; p=0.003), androstenedione (OB 87±37%, NO 125±62 above upper limit of normal; p=0.002), and LH (OB 9.7±4.9, NO 15.2±10.4; mIU/mL, p=0.0001). No differences in Ferriman Gallwey score or number of menses in the 6 months prior to diagnosis were detected. Conclusions Metabolic and reproductive phenotypes differed in OB and NO adolescent girls at the time of PCOS diagnosis. The reproductive phenotype in NO was characterized by increased LH, total testosterone and androstenedione levels. In contrast, OB girls had a phenotype characterized by insulin resistance-driven hyperandrogenemia established by lower SHBG and higher free testosterone levels. Our data are consistent with findings reported for adult women with two divergent phenotypes: an insulin resistance-driven metabolic subtype and a primarily reproductive subtype, potentially driven by neuroendocrine mechanisms. Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.