SAT-049 - Sex-Specific Metabolic Signatures in Growth Hormone Deficiency Reveal Distinct GH-Responsive and GH-Independent Biomarkers

Growth hormone deficiency (GHD) is associated with metabolic dysfunction, yet biological sex is rarely considered in therapeutic monitoring or biomarker discovery. Given the known sexual dimorphism in growth hormone (GH) secretion and signaling, we investigated how sex influences circulating metabolic profiles in GHD and the sex-specific response to GH replacement.
We performed untargeted serum metabolomic profiling in male and female Pit-1^K216E mice, a model of congenital GHD, across three conditions: GH-deficient, GH-treated, and GH-sufficient wild-type (WT). Sex-stratified multivariate analyses and receiver operating characteristic (ROC) based biomarker discovery identified metabolites distinguishing males from females. Metabolites were classified as GH-responsive or GH-independent based on their behavior across conditions, and pathway enrichment analyses were performed on GH-responsive features.
Pronounced sexual dimorphism was observed in serum metabolomic profiles across all groups, with clear separation between males and females in GHD, GH-treated, and WT mice. GH treatment modified, but did not eliminate these sex-specific metabolic differences. Two distinct classes of sex-dimorphic metabolites were identified. GH-responsive metabolites displayed marked sex differences in GH-deficiency and showed partial or complete normalization with GH treatment. These metabolites were enriched in pathways related to central energy metabolism, including glycolysis, the tricarboxylic acid cycle, and pyruvate metabolism. In contrast, GH-independent metabolites remained consistently distinct between sexes regardless of GH status, primarily reflecting amino acid and nitrogen-related metabolic pathways, consistent with intrinsic sex-based metabolic programming.
Collectively, these findings demonstrate that sex is a major determinant of circulating metabolic signatures in GHD and that GH replacement selectively modulates only a subset of sex-dimorphic biomarkers. Differentiating GH-responsive from GH-independent metabolites provides a framework for interpreting metabolic outcomes of GH therapy and underscores the need for sex-aware biomarker strategies beyond conventional monitoring.

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