Identifying potential small molecule [ldquo]metabolites[rdquo] as biomarkers for growth hormone deficiency (GHD): Insights from a novel mouse model

Sarmed Al-Samerria; Huiting Xu; Joseph Phelan; Rubio Maria Elena Diaz; Sayaka Yamada; Ariel Negron; Fredric Wondisford; Sally Radovick

doi:10.1530/endoabs.99.RC9.3

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Endocrine Abstracts (2024) 99 RC9.3 | DOI: 10.1530/endoabs.99.RC9.3

ECE2024 Rapid Communications Rapid Communications 9: Pituitary and Neuroendocrinology | Part II (7 abstracts)

Identifying potential small molecule “metabolites” as biomarkers for growth hormone deficiency (GHD): Insights from a novel mouse model

Sarmed Al-Samerria ^1,2 , Huiting Xu ³ , Joseph Phelan ³ , Maria Elena Diaz Rubio ³ , Sayaka Yamada ¹ , Ariel Negron ¹ , Fredric Wondisford ⁴ & Sally Radovick ¹

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¹The University of Arizona Medical School, Department of Pediatrics, Phoenix, United States; ²The University of Arizona College of Medicine - Phoenix, Phoenix, United States; ³Rutgers University, Department of Medicine, New Brunswick, United States; ⁴The University of Arizona Medical School, Department of Medicine, Phoenix, United States

Growth hormone deficiency (GHD) diagnosis poses a significant challenge since no test definitively diagnoses GHD. The current diagnostic approach for GHD relies on a determination of auxologic parameters followed by determining Growth Hormone (GH) levels and Insulin-like Growth Factor-I (IGF-I) in serum. However, clinical assessment and interpretation of GH and IGF-1 levels lack sensitivity. Further provocative studies of GH secretion do not have a precise cutoff level that discriminates a normal response from a deficient response; second, they have poor specificity. With the goal of determining biomarkers for GHD, our laboratory developed a unique mouse model, inspired by a severe GHD patient due to a mutation in the PIT-1 gene, which provides a controlled setting for probing GHD intricacies, overcoming some challenges encountered in human studies. In this study, we utilized a metabolomic approach to analyze serum samples from both wild-type and mutant mice, both with and without GH treatment, aiming to identify potential biomarkers. Metabolomic analysis unveiled several impacted metabolic pathways associated with GHD in the developed mouse model. Among these pathways, the Purine metabolism pathway and Arginine and proline metabolism exhibited the most pronounced alterations, indicating their crucial involvement in GHD-related metabolic changes. Upon closer analysis, 3-hydroxy butyric acid, Glucose, and Hydroxyproline displayed distinctive patterns in male and female mutant mice, smggesting their potential as GHD biomarkers. Furthermore, we established a correlation between metabolomic changes and treatment response, enabling the monitoring of GH therapy effects. This research highlights the pivotal role of metabolomic analysis in identifying a unique biomarker for GHD and evaluating treatment response. Incorporating a novel mouse model with a PIT-1 gene mutation enriches GHD research, contributing to enhanced diagnostic accuracy and improved monitoring of treatment outcomes in individuals with GHD.