Purpose: Polyethylene glycol-recombinant human growth hormone (PEG-rhGH) is the first commercial long-acting rhGH preparation approved in China. This study was designed to assess the efficacy and safety of PEG-rhGH in treating growth hormone deficiency (GHD) during the transition period. Methods: A prospective, multicenter and single-arm study was performed. The entire study duration spanned 66 weeks, comprising a 2-week trial screening phase, a 12week dose-adjustment period, and a 52-week PEG-rhGH treatment phase. A total of 10 interviews were conducted over the course of the study. The primary endpoint was change in body composition; secondary endpoints were changes in lumbar bone mineral density (BMD, L1-4) and lean body mass (LBM). Sex- and age-specific equations were developed to adjust body composition z-scores. Results: : A total of 31 subjects were included in this study. Throughout the 64-week therapy with PEG-rhGH, the insulin-like growth factor-1 (IGF-1) standard deviation score (SDS) demonstrated progressive elevation from baseline (-3.07 to -1.38; P<0.001). Significant alterations in body composition parameters were observed throughout the study. Body weight increased 3.96 kg (P<0.001), and the body weight SDS exhibited significant elevation from baseline (0.67) to 64 weeks (1.14; P=0.005). LBM significantly increased (4.54 kg; P<0.001), but there was a statistically significant reduction in fat percentage (Fat%) from 37.40% to 33.94% (P=0.008) and Fat% SDS from 1.91 to 1.47 (P= 0.009). The lumbar BMDz-score improved from-1.54 at baseline to-1.12 postintervention, but did not reach statistical significance (P>0.05). The triglyceride (TG) levels of the subjects decreased significantly at week 64 (P=0.018). There was no statistically significant difference in the changes of other lipid profile indicators. In this study, no adverse events attributable to direct drug-related causes were identified. Conclusion: Based on our study, PEG-rhGH can improve IGF-1 levels and alter body composition parameters by increasing LBM and decreasing body fat and TG levels in patients with GHD during the transition period, and it has a comparable safety profile and helps improve therapeutic adherence.

ABSTRACT Background Metabolic disorders, particularly insulin resistance (IR), represent important complications in adults with 21‐hydroxylase deficiency (21OHD). Glucocorticoid (GC) therapy is a known risk factor, yet evidence from longitudinal analyses remains scarce. Methods In this study, based on a large, genetically characterized, single‐center cohort of Chinese adults with 21OHD, we performed both cross‐sectional and longitudinal analyses to investigate the risk factors for IR. Results We found that nearly one‐third of young adult 21OHD patients had IR. Current GC use remained independently associated with IR (OR 13.30, 95% CI 2.54–69.55; p = 0.002), whereas neither genotype nor androgen levels showed an association. We followed 52 patients without IR at baseline; incident IR occurred in 57.1% (4/7) of GC‐naive patients and 68.9% (31/45) of previously GC‐exposed patients, with median times to IR onset of 14.7 and 13.1 months, respectively. Importantly, dexamethasone use was independently associated with incident IR (HR 7.04, 95% CI 1.81–27.34; p = 0.005). Daily 1000 mg metformin therapy for 6 months did not significantly improve IR (median HOMA‐IR, 2.50–2.82; p = 0.460) and only provided a modest benefit in body weight (median BMI, 23.6–22.5 kg/m2; p = 0.046). Conclusion These findings suggest that ongoing GC therapy, particularly dexamethasone, is a risk factor for IR in adults with 21OHD, and new onset IR generally emerged within approximately 1 year after regular treatment.

Waardenburg syndrome (WS) is a complex genetic disorder primarily characterized by auditory and pigmentary abnormalities, resulting from neural crest cell migration disorders. We reported 2 genetically confirmed SOX10-mutant WS cases illustrating critical management principles. Both patients underwent early auditory intervention (case 1: cochlear implantation at age 3; case 2: hearing aids from age 2), resulting in preserved age-appropriate language acquisition. Each case manifested delayed puberty with biochemical evidence of hypogonadotropic hypogonadism, necessitating gonadotropin therapy to potentiate virilization and preserve fertility. Multidisciplinary care and emerging therapeutic approaches offer hope for better management. Further studies are warranted to improve the diagnosis, treatment, and quality of life of patients with WS.

Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and infertility. Early hormonal intervention is preventive, but excessive glucocorticoid poses risks. Developing reliable methods for early TART diagnosis and monitoring is crucial. The present study aims to formulate a scoring system to identify high-risk infertility through analysis of TART ultrasound features. Grayscale and power Doppler ultrasound were employed in this retrospective study to evaluate testicular lesions in male CAH patients. Lesion assessment encompassed parameters such as range, echogenicity, and blood flow, and these were subsequently correlated with semen parameters. Results of 49 semen analyzes from 35 patients demonstrated a notable inverse correlation between lesion scores and both sperm concentration (rs = − 0.83, P < 0.001) and progressive motility (rs = − 0.56, P < 0.001). The ROC curve areas for evaluating oligospermia and asthenozoospermia were calculated as 0.94 and 0.72, respectively. Establishing a lesion score threshold of 6 revealed a sensitivity of 75.00% and specificity of 93.94% for oligospermia and a sensitivity of 53.85% and specificity of 100.00% for asthenozoospermia. These findings underscore the potential utility of incorporating ultrasound into routine CAH patient management, facilitating timely interventions to preserve male fertility.

Background The clinical manifestations of nonclassical 11beta-hydroxylase deficiency are very similar to those of non-classical 21-hydroxylase deficiency. For this study, we investigated the relationship between the clinical and molecular features of congenital adrenal hyperplasia caused by 11beta-hydroxylase deficiency and reviewed the related literature, which are expected to provide assistance for the clinical diagnosis and analysis of congenital adrenal hyperplasia. Methods Clinical data for 10 Chinese patients diagnosed with congenital adrenal hyperplasia in our hospital from 2018 to 2022 were retrospectively analyzed. We examined the effects of gene mutations on protease activity and constructed three-dimensional structure prediction models of proteins. Results We describe 10 patients with 11beta-hydroxylase gene mutations ( n = 5, 46,XY; n = 5, 46,XX), with 10 novel mutations were reported. Female patients received treatment at an early stage, with an average age of 2.08 ± 1.66 years, whereas male patients received treatment significantly later, at an average age of 9.77 ± 3.62 years. The most common CYP11B1 pathogenic variant in the Chinese population was found to be c.1360C > T. All mutations lead to spatial conformational changes that affect protein stability. Conclusions Our study found that there was no significant correlation between each specific mutation and the severity of clinical manifestations. Different patients with the same gene pathogenic variant may have mild or severe clinical manifestations. The correlation between genotype and phenotype needs further study. Three-dimensional protein simulations may provide additional support for the physiopathological mechanism of genetic mutations.

Importance:With the widespread use of anti-SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment. Objective:To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir. Design, Setting, and Participants:This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir. Interventions:Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60. Main Outcomes and Measures:The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set. Results:The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group (P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group (P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case. Conclusions and Relevance:In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound. Trial Registration:Chinese Clinical Trial Registry Identifier: ChiCTR2200066811.

Elevated concentrations of amino acids (AAs) are commonly observed in patients with nonalcoholic fatty liver disease (NAFLD). Individuals with hypopituitarism (HP) are at a heightened risk of developing NAFLD due to factors such as visceral obesity, increased insulin resistance (IR), and disturbances in lipid metabolism. However, the changes in AAs concentrations associated with HP remain poorly understood. Therefore, our study aimed to investigate whether individuals with HP, who were not receiving growth hormone replacement therapy (GHRT), exhibited altered AAs compared to controls (CTs), and whether these AAs were associated with IR, the presence of NAFLD, and the Metabolic Syndrome (MetS) score. The AAs profiles of 133 young males with HP (age: 24.5 ± 5.9; 57 with NAFLD and 76 without NAFLD) and 90 age and BMI-matched CTs were analyzed using untargeted metabolomics. The results revealed that most AAs were found to be elevated in subjects with HPs compared to CTs. Glutamate, glutamine, norleucine, and branched-chain amino acids (BCAAs) (leucine and valine) were correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), with glutamate and norleucine showing independent linkage. Glutamate and proline levels were specifically associated with MetS score, while alanine and proline linked to NAFLD. Given that elevated glutamate and BCAAs levels have higher prevalence of NAFLD, we hypothesized that the changes in AAs observed in HPs may be attributed to the impact of NAFLD and IR.

Abstract Context Measurement of plasma steroids is necessary for diagnosis of congenital adrenal hyperplasia (CAH). We sought to establish an efficient strategy for detection and subtyping of CAH with a machine-learning algorithm. Methods Clinical phenotype and genetic testing were used to provide CAH diagnosis and subtype. We profiled 13 major steroid hormones by liquid chromatography-tandem mass spectrometry. A multiclassifier system was established to distinguish 11β-hydroxylase deficiency (11βOHD), 17α-hydroxylase/17,20-lyase deficiency (17OHD), and 21α-hydroxylase deficiency (21OHD) in a discovery cohort (n = 226). It was then validated in an independent cohort (n = 111) and finally applied in a perspective cohort of 256 patients. The diagnostic performance on the basis of area under receiver operating characteristic curves (AUCs) was evaluated. Results A cascade logistic regression model, we named the “Steroidogenesis Score”, was able to discriminate the 3 most common CAH subtypes: 11βOHD, 17OHD, and 21OHD. In the perspective application cohort, the steroidogenesis score had a high diagnostic accuracy for all 3 subtypes, 11βOHD (AUC, 0.994; 95% CI, 0.983-1.000), 17OHD (AUC, 0.993; 95% CI, 0.985-1.000), and 21OHD (AUC, 0.979; 95% CI, 0.964-0.994). For nonclassic 21OHD patients, the tool presented with significantly higher sensitivity compared with measurement of basal 17α-hydroxyprogesterone (17OHP) (0.973 vs 0.840, P = 0.005) and was not inferior to measurement of basal vs stimulated 17OHP (0.973 vs 0.947, P = 0.681). Conclusions The steroidogenesis score was biochemically interpretable and showed high accuracy in identifying CAH patients, especially for nonclassic 21OHD patients, thus offering a standardized approach to diagnose and subtype CAH.

Objective:To investigate the effect of growth hormone replacement therapy(GHRT) on glucose and lipid metabolism in patients with hypopituitarism.Methods:Clinical data of patients with hypopituitarism who received GHRT in Department of Endocrine and Metabolic Diseases, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from December 2016 to February 2020 were retrospectively analyzed. The patients were divided into normal glucose regulation(NGR) group and impaired glucose regulation(IGR) group according to their glucose metabolism status before GHRT. The changes of the characteristics of glucose metabolism before and after GHRT were analyzed.Results:A total of 30 patients aged(23.0±5.2) years were included, 23 patients in NGR group and 7 patients in IGR group. After 12 months of GHRT, there were no significant changes in fasting plasma glucose(FPG), 2-hour postprandial plasma glucose(2hPG), and insulin sensitivity index(ISI) in both groups(all P>0.05), while homeostasis model assessment insulin resistance(HOMA-IR) in IGR group was significantly decreased compared with that before GHRT( P<0.05). None of the patients in NGR group progressed to IGR or diabetes mellitus, and none of the 7 patients in the IGR group progressed to diabetes mellitus, while 4 of them recovered from impaired glucose tolerance(IGT) to NGR. Triglyceride, total cholesterol, and low density lipoprotein-cholesterol levels were all significantly decreased in two groups(all P<0.05). Multivariate linear regression analysis showed that the increase of body mass index was an independent risk factor for the increase of FPG and 2hPG( P<0.05). Conclusion:12-month GHRT significantly improved their blood lipid profiles in patients with hypopituitarism without adversely affecting glucose homeostasis.

Diagnosis of nonclassic adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency (21-OHD) may be challenging due to its occult manifestations. To characterize clinical and molecular features of NCAH patients due to 21-hydroxylase deficiency, we retrospectively included 78 NCAH patients. Their phenotype and genotype were presented and compared. The transcription activities of novel CYP21A2 promoter variants were investigated using a dual-reporter luciferase assay system. This cohort included 53 females (68 %) and 25 males (32 %). The median of onset age was 13 years old (female: 13 range from 7 to 38; male: 11 range from 6 to 71). Menstrual cycle disorder was the most common complaint in females (62 %, n = 33) and for males, it was adrenal incidentalomas (52 %, n = 13). A total of 17 (22 %) patients complained of infertility. The most frequently variant was p.Ile173Asn (20 %, n = 31). Importantly, five variants in the promoter region including - 103/- 126 and - 196/- 296 were found in 21 (27 %) patients. Patients with promoter variants showed older onset age and less impaired hormone levels of 17-hydroxyprogesterone, ACTH, progesterone, and androstenedione. Compared with the wild-type promoter, the basic transcription activity of - 103/- 126 and - 196/- 296 promoter variants were reduced by 57% and 25%, respectively. Therefore, females with menstrual cycle disorders or infertility and males with adrenal incidentaloma should be considered of NCAH due to 21-OHD. When genotyping patients with NCAH, the promoter region of the CYP21A2 gene should be also investigated.

Background : Androgen insensitivity syndrome (AIS) is a rare X-linked recessive inherited disorder caused by mutations in AR , a gene encoding androgen receptor. The aim of this study was to expand genetic spectrum of AIS. Methods: We performed a retrospective study on consecutive patients diagnosed as AIS from 2010 to 2020 in a single tertiary center. Variant analysis of AR gene was performed by PCR-Sanger sequencing. The pathogenicity of novel variants was evaluated by dual-luciferase reporter assay and immunofluorescence of AR protein in vitro. Results: A total of 19 unrelated 46,XY patients were enrolled, 14 with complete insensitivity syndrome (CAIS) and 5 with partial insensitivity syndrome (PAIS). We identified 19 AR variants: 12 (63.2%) were missense variants and 7 variants (36.8%) resulted in premature stop codon. Eight AR variants were novel, including P15Afs*69, S258Efs*47, W435Gfs*44, C560F, C577W, C580Afs*46, K718X and V819G. Dual-luciferase reporter assay found residual transcription activity of approximately 1% in six novel variants, which may explain the CAIS phenotype. The AR mutant protein (V819G) showed transcription activity of 59%, consistent with mild clinical features in one PAIS patient. Interestingly, another AR mutant protein (K718X) related to CAIS showed increased transcription activity but impaired nuclear localization. Conclusions: We identified eight novel AR variants related to AIS. Both residual transcription activity of AR and nuclear localization of AR protein were associated with the severity of AIS.

Objective: Hypopituitarism (Hypo-Pit) is partial or complete insufficiency of anterior pituitary hormones. Besides hormone metabolism, the global metabolomics in Hypo-Pit are largely unknown. We aimed to explore potential biomarkers to aid in diagnosis and personalized treatment. Methods: Using both univariate and multivariate statistical methods, we identified 72 differentially abundant features through liquid chromatography coupled to high-resolution mass spectrometry, obtained in 134 males with Hypo-Pit and 90 age matched healthy controls. Results: Hypopituitarism exhibits an increased abundance of metabolites involved in amino acid degradation and glycerophospholipid synthesis, but decreased content of metabolites in steroid hormone synthesis and fatty acid beta-oxidation. Significantly changed metabolites included creatine, creatinine, L-alanine, phosphocholines, androstenedione, hydroprenenolone, and acylcarnitines. In Hypo-Pit patients, the increased ratio of creatine/creatinine suggested reduced creatine uptake and impaired creatine utilization, whereas the decreased level of beta-hydroxybutyrate, acetylcarnitine (C2) and a significantly decreased ratio of decanoylcarnitine (C10) to free carnitine suggested an impaired beta-oxidation. Furthermore, the creatine/creatinine and decanoylcarnitine/carnitine ratio were identified as diagnostic biomarkers for Hypo-Pit with AUCs of 0.976 and 0.988, respectively. Finally, we found that the creatinine and decanoylcarnitine/carnitine ratio could distinguish cases that were sensitive vs. resistant to human chorionic gonadotropin therapy. Conclusion: We provided a global picture of altered metabolic pathways in Hypo-Pit, and the identified biomarkers in creatine metabolism and beta-oxidation might be useful for the preliminary screening and diagnosis of Hypo-Pit.

Context: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic diseases caused by genetic deficiency in nine genes encoding steroidogenesis enzymes and cofactors. Objective: To establish a targeted next-generation sequencing (NGS) assay for all nine CAH candidate genes. Methods: We developed a customized targeted NGS assay of CAH candidate genes (CYP21A2, CYP17A1, CYP11B1, StAR, CYP11A1, POR, HSD3B2, H6PD, CYP11B2) and apply this assay plus MLPA of CYP21A2 in a total of 469 patients with CAH like signs and symptoms. Results: We totally identified 125 variants with seven variant types in eight genes. Variant types included missense variant (46.8 %), splicing variant (21.5 %), small indel (12.5 %), large structure variation (11.8 %), nonsense variant (4.1 %), UTR variant (2.9 %), synonymous variant (0.3 %). Successful genotyping, defined as biallelic pathogenic or likely pathogenic variants, was achieved in 98.5 % (336/341) of cases, including biallelic variants in CYP21A2 (n = 254), CYP17A1 (n = 45), CYP11B1 (n = 23), StAR (n = 7), HSD3B2 (n = 4), POR (n = 1), CYP11A1 (n = 1) and CYP11B2 (n = 1) gene. Importantly, the assay found one patient with CYP11B1 deficiency, one patient with non-classic POR deficiency and two patients with non-classic CYP17A1 deficiency while clinically diagnosed differently. Conclusions: Our NGS-based assay plus MLPA of CYP21A2 is a useful tool to genotype all subtypes of CAH. The test successfully achieved genotype in 98.5 % of patients with clinically determined CAH. It also efficiently facilitated the diagnosis of CAH in patients with rare subtypes as well as non-classic phenotypes.

The main functions of glucagon-like peptide-1(GLP-1) includes diminishing food intake and enhancing glucose-stimulated insulin secretion. Evidence from basic research suggests that reproduction system is also a target of GLP-1. GLP-1 receptor agonists are now widely used in managing patients with obesity and type 2 diabetes, thus, there is a need to explore the effects of GLP-1 on the human reproductive system. This paper is a Chinese translation of "Effects of Glucagon-like Peptide-1 on the Reproductive Axis in Healthy Men" , published on J Clin Endocrinol Metab[Izzi-Engbeaya C, Jones S, Crustna Y, et al. J Clin Endocrinol Metab, 2020, 105(4). DOI: 10.1210/clinem/dgaa072], with the permission from the original journal. This research studied the effects of acute GLP-1 infusion on sex hormones in healthy men through a randomized, single-blind, placebo-controlled study. The results showed that during GLP-1 infusion, the mean levels of serum luteinizing hormone(LH), follicle stimulating hormone(FSH), and testosterone, as well as the pulsatility of LH and testosterone were similar with vehicle infusion. The data from this study indicates that acute GLP-1 administration has no impact on reproductive hormone secretion in healthy men.

Objective: To explore the most suitable calculation method for insulin dosage in an insulin tolerance test (ITT) and to evaluate the clinical application value of the optimization coefficient (γ). Methods: In this study, 140 adult patients with congenital growth hormone deficiency (GHD) or acquired hypopituitarism were randomized into the following two groups: the conventional group (n = 70) and the optimized group (n = 70). Oral glucose tolerance tests (OGTTs), insulin release tests (IRTs), and ITTs were conducted. For ITTs, insulin doses were the product of body weight (kg) and related coefficient (0.15 IU/kg for the control group and γ IU/kg for the optimized group, respectively). Notably, γ was defined as −0.034 + 0.000176 × AUCINS + 0.009846 × BMI, which was based on our previous study. Results: In the ITTs, the rate of achieving adequate hypoglycemia with a single insulin dose was significantly higher for the optimized group compared with the conventional group (92.9 vs. 60.0%, P < 0.001). The optimized group required higher initial doses of insulin (0.23 IU/kg). Meanwhile, the two groups did not differ significantly in their nadir blood glucose (1.9 vs. 1.9 mmol/L, P = 0.828). Conclusion: This study confirmed that the proposed optimized calculation method for insulin dosage in ITTs led to more efficient hypoglycemia achievement, without increasing the incidence of serious adverse events.

Congenital lipoid adrenal hyperplasia (LCAH), as the most severe form of congenital adrenal hyperplasia (CAH), is caused by mutations in the steroidogenic acute regulatory protein (STAR). Affected patients were typically characterized by adrenal insufficiency in the first year of life and present with female external genitalia regardless of karyotype. Non-classic LCAH patients usually present from 2 to 4 years old with glucocorticoid deficiency and mild mineralocorticoid deficiency, even develop naturally masculinized external genitalia at birth when they have 46,XY karyotype. We described thirty patients from unrelated Chinese families, including three non-classic LCAH ones. Four novel mutations were reported, including c.556A > G, c.179-15G > T, c.695delG and c.306 + 3_c.306 + 6delAAGT. The c.772C > T is the most common STAR mutation in Chinese population, suggesting a possibility of founder effect. Enzymatic activity assay combined with clinical characteristics showed a good genotype-phenotype correlation in this study. Residual STAR activity more than 20 % may be correlated with non-classic LCAH phenotype. We support the perspective that onset age may be affected by multiple factors and masculinization should be the main weighting factor for diagnosis of non-classic LCAH. Compared with 46,XX LCAH patients, less 46,XY ones were found in our report. A less comprehensive inspection and an easy diagnosis due to classical phenotype both would reduce the possibility of 46,XY LCAH patients to be referred to specialists or geneticists.

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.

Idiopathic hypogonadotropic hypogonadism (IHH) patients are characterized by the absence of puberty and varying degrees of deteriorated metabolic conditions. Osteocalcin (OC) could regulate testosterone secretion and energy metabolism, but it remains unknown whether such an effect exists in IHH patients. Our study is aimed to examine the relationship between serum OC levels with testosterone and its responsiveness to gonadotropin stimulation and metabolic profiles in male IHH patients. A total of 99 male patients aged 18-37 years and diagnosed with IHH were enrolled in the current study, and the relationships between OC and testicular volume, baseline total testosterone (TT), free testosterone (FT), and peak TT (Tmax) levels after human chorionic gonadotropin (hCG) stimulation, gonadotropin responsiveness index (GRI), which is calculated by dividing Tmax by testicular volume, as well as metabolic profiles, such as 2-h post-challenge glucose (2hPG) and fat percentage (fat%), were analyzed. The results showed that OC had an independent negative relationship with testicular volume (r = -0.253, P = 0.012) and a positive association with Tmax (r = 0.262, P = 0.014) after adjusting for confounders. In addition, OC was a major determinant of GRI (adjusted R 2 for the model = 0.164, P = 0.012), fat% (adjusted R 2 for the model = 0.100, P = 0.004), and 2hPG (adjusted R 2 for the model = 0.054, P = 0.013) in IHH patients. In conclusion, OC is associated with testosterone secretion upon gonadotropin stimulation, glucose metabolism, and fat mass variations in IHH. This study was registered at clinicaltrials.gov (NCT02310074).