OR15-01 Overweight/Obese Pubertal Girls Have Higher Androgen Levels - Can Metabolomics Tell Us Why?

Abstract

Abstract Disclosure: M. Calvert: None. S. Molsberry: None. A.K. Jarmusch: None. K.E. Overdahl: None. N. Shaw: None. Introduction: The Body Weight and Puberty Study (BWPS) was a 4-year longitudinal study of 90 healthy pubertal, pre-menarchal girls consisting of dual-energy x-ray absorptiometry to calculate total body fat (TBF), Tanner staging, breast ultrasound, and hormone tests. We observed that with time, girls with higher TBF demonstrated higher serum total and free testosterone and androstenedione levels. The cause of this association is unknown but is hypothesized to relate to greater insulin resistance. Methods: To investigate the association between higher androgens and higher TBF in late pubertal girls, we conducted an untargeted metabolomics study using our BWPS collection of 158 blood and 178 urine samples. Samples were run on an ultra-high performance liquid chromatograph (Vanquish, Thermo Scientific) coupled to a high-resolution mass spectrometer (Orbitrap Fusion Tribrid, Thermo Scientific) and analyzed in positive and negative ionization modes. We investigated the association between TBF or BMI Z-score and metabolites and the association between metabolites and serum androgen levels. All associations were examined cross-sectionally and lagged by one visit using linear generalized estimating equation models, adjusting for breast morphological stage and age at baseline, race, and time between visits. Benjamini-Hochberg false discovery rate (FDR) adjusted p-values were calculated to account for multiple testing. RaMP DB (Relational database of Metabolomic Pathways) was used to conduct enriched pathway analyses among metabolites nominally associated with body composition or hormone levels. Results: 70 participants (aged 10.9 ± 1.39 SD years; 60% White, 24% Black, 16% Other; 63% normal weight, 37% overweight/obese) contributed an average of 2.39 blood and 2.54 urine samples over the course of 1.15 ± 0.47 SD years of follow-up. While few metabolites were significantly associated with body composition or androgen levels after strict multiple testing correction, RaMP DB enriched pathway analyses identified several pathways linking TBF and androgen levels: 1) in lagged analyses of urinary metabolites, overall amino acid metabolism, arginine and proline metabolism, and the urea cycle linked TBF with androstenedione; 2) in cross-sectional analyses of serum metabolites, bile acid synthesis and metabolism, VEGF or extra-nuclear estrogen signaling (related to the metabolite, sphingosine-1-phosphate), and tryptophan metabolism linked TBF with androstenedione. Conclusions: Metabolomic analyses of samples from pubertal girls did not uncover signatures of insulin resistance (e.g., branched chain amino acids or C3- and C5-acyclcarnitines) to explain the association between higher androgens and TBF. Instead, we identified potential novel signaling pathways that may involve amino acid, bile acid, or sphingosine-1-phosphate action at the ovary and/or adrenal gland. Presentation: Friday, June 16, 2023