Creatine Metabolism and Carnitine Shuttle System as Potential Diagnostic and Prognostic Biomarkers of Gonadotropin Replacement Therapy in Young Males With Panhypopituitarism

Background: Panhypopituitarism (Hypo-Pit) is characterized by a complete deficiency of anterior pituitary hormones. Besides hormone metabolism, the serum metabolomics in Hypo-Pit are largely unknown. We aimed to identify metabolic changes in Hypo-Pit to explain its clinical phenotype and to ultimately explore potential biomarkers to aid in diagnosis and personalized treatment. Methods: Metabolic profiles were collected in 134 males with Hypo-Pit and 90 same-aged healthy controls by non-targeted metabolomics in serum. Prognostic marker for human chorionic gonadotropin (hCG) therapy was validated in another cohort including 95 males with congenital Hypo-Pit. Results: 59 metabolites altered significantly in Hypo-Pit. The most discriminating pathways included steroid metabolism, arginine and proline metabolism, β-fatty acid and glycerophospholipid metabolism. Hypo-Pit shows significantly higher creatine and its precursors, but a relative lower creatinine, indicates creatine metabolism disorder, conform to decreased muscle mass and muscle strength; Hypo-Pit also shows a significantly lower long-chain acyl-carnitines, but a higher free carnitine, indicates carnitine shuttle disorder, consistent with the symptom of decreased fatty acid oxidation. In addition, the creatine/creatinine and Decanoyl-L-carnitine/L-carnitine ratio could serve as promising diagnostic biomarkers for Hypo-Pit, which showed an area under the ROC curve (AUC) of 0.976 and 0.988, respectively. Moreover, the serum creatinine and acyl-carnitines/L-carnitine were shown as promising predictors of hCG therapy, with AUC of 0.746 and 0.713 in discriminating the hCG-sensitive and resistant patients. Conclusions: This is the first study to link a framework of metabolic perturbations with the pathophysiology, diagnostic and prognostic biomarkers of Hypo-Pit. Funding Statement: The present study was supported by scientific research project of Shanghai Health and Family Planning Commission (grant no. 201840160), Natural Science Foundation of Shanghai (20ZR1434100; Shanghai, China), the Science and Technology Commission of Jiading District (JDKW‐2017‐W09 and JDKW‐2017‐W11; Shanghai, China), and the Interdisciplinary funding of Shanghai Jiao Tong University (YG2017QN57; Shanghai, China), Ruijin Hospital North for Young Talents (grant no. 2017RCPY-A01, 2017RCPY-B10 and 2017RCPY-C01; Shanghai, China). Declaration of Interests: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Ethics Approval Statement: The study was approved by the ethics committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. All participants or their legal guardians provided written informed consent.