Altered individual-level morphological similarity network in children with growth hormone deficiency.

BACKGROUND: Accumulating evidences indicate regional grey matter (GM) morphology alterations in pediatric growth hormone deficiency (GHD); however, large-scale morphological brain networks (MBNs) undergo these patients remains unclear. OBJECTIVE: To investigate the topological organization of individual-level MBNs in pediatric GHD. METHODS: Sixty-one GHD and 42 typically developing controls (TDs) were enrolled. Inter-regional morphological similarity of GM was taken to construct individual-level MBNs. Between-group differences of topological parameters and network-based statistics analysis were compared. Finally, association relationship between network properties and clinical variables was analyzed. RESULTS: Compared to TDs, GHD indicated a disturbance in the normal small-world organization, reflected by increased Lp, γ, λ, σ and decreased Cp, Eglob (all PFDR < 0.017). Regarding nodal properties, GHD exhibited increased nodal profiles at cerebellum 4-5, central executive network-related left inferior frontal gyrus, limbic regions-related right posterior cingulate gyrus, left hippocampus, and bilateral pallidum, thalamus (all PFDR < 0.05). Meanwhile, GHD exhibited decreased nodal profiles at sensorimotor network -related bilateral paracentral lobule, default-mode network-related left superior frontal gyrus, visual network -related right lingual gyrus, auditory network-related right superior temporal gyrus and bilateral amygdala, right cerebellum 3, bilateral cerebellum 10, vermis 1-2, 3, 4-5, 6 (all PFDR < 0.05). Furthermore, serum markers and behavior scores in GHD group were correlated with altered nodal profiles (P ≤ 0.046, uncorrected). CONCLUSION: GHD undergo an extensive reorganization in large-scale individual-level MBNs, probably due to abnormal cortico-striatal-thalamo-cerebellum loops, cortico-limbic-cerebellum, dorsal visual-sensorimotor-striatal, and auditory-cerebellum circuitry. This study highlights the crucial role of abnormal morphological connectivity underlying GHD, which might result in their relatively slower development in motor, cognitive, and linguistic functional within behavior problem performance.

Response to Recombinant Human Growth Hormone (rhGH) Therapy in Children with Growth Hormone Deficiency.

OBJECTIVE: To determine the auxological response to recombinant human growth hormone (rhGH) therapy in children with growth hormone deficiency (GHD) presenting at the National Institute of Child Health, Karachi, Pakistan. STUDY DESIGN:  Observational study. Place and Duration of the Study: Department of Paediatric Endocrinology, National Institute of Child Health, Karachi, Pakistan, from January 2022 to December 2023. METHODOLOGY:  All pre-pubertal children with short stature aged 3-12 years diagnosed with GHD and who were prescribed rhGH therapy were included in the study. Children with any other underlying reason for short stature or any other comorbidity were excluded. Patients' demographics and baseline growth parameters were recorded in a pre-designed proforma. Patients were then followed up every three months till one year. Response to rhGH therapy was evaluated through comparison of growth parameters before and after one year of therapy. RESULTS: A total of 90 children including 47 (52.2%) males and 43 (47.8%) females with GHD were enrolled. Mean age of these patients was 7.92 ± 2.647 years. A statistically significant change in height (SD), Weight (SD), and BMI (SD) was observed before and after one year of therapy (p <0.001). Response to therapy in terms of height did not differ significantly with respect to gender (p = 0.955) or stimulated growth hormone levels (p = 0.911). However, response to rhGH therapy was significantly better in terms of increase in height, weight, and BMI in patients presenting earlier i.e. at age ≤8 years. CONCLUSION: Recombinant human growth hormone therapy was effective in children with short stature to achieve desirable growth. Children diagnosed and treated at a younger age (≤8years) achieve better height outcomes as compared to those presenting late. KEY WORDS:  Short stature, Growth hormone deficiency, Recombinant human growth hormone.

L-DOPA Test in the Diagnosis of Childhood Short Stature: Evaluation of Growth Hormone Peaks Over Time.

INTRODUCTION: In childhood, growth hormone (GH) deficiency (GHD) diagnosis is based on auxological assessment and biochemical provocative tests, whose reliability remains disputed. Recently, several papers have been published on standardising the duration of some tests. The aim of our study was to analyse the possible length reduction of the L-DOPA provocative test. METHODS: We retrospectively investigated the response of GH to L-DOPA in 256 children, analysing 267 tests (some patients were retested over time for the persistence of severe auxopathy). We studied the same data considering GH peak threshold both at 8 ng/mL (Italian GHD cut-off) and at 10 ng/mL (international cut-off). Based on stimulation tests, patients were divided into two groups: GHD and no-GHD short children. We described the results in the whole population and then clustering for gender and pubertal stage. We termed as index the test stopped at 90 min. RESULTS: The GH peak after L-DOPA mostly occurred at 60 min. The sensitivity of the index test was the highest, while the specificity was slightly higher using the 8 ng/mL threshold (specificity = 0.68; 95% CI 0.60-0.76) then using the 10 ng/mL threshold (specificity = 0.56; 95% CI 0.47-0.65) at 90 min. The two ROC curves showed moderate performance of the test at 90 min. While the negative predictive value was 100% in both tests, the positive predictive value was slightly better with 10 ng/mL cut-off. Considering the two groups established by GHD definition and placing a GH threshold at 10 ng/mL, stopping L-DOPA test time at 90 min would have changed the test result and subsequentially patient's classification in 3/267 of the analysed tests (1.1%), while with the Italian GH threshold value at 8 ng/mL in 7/267 of the tests (2.6%). CONCLUSIONS: Our research shows that omitting 120-min time reduces L-DOPA test specificity, especially with GHD cut-off at 10 ng/mL.

Indications for genetic diagnosis in children with growth hormone deficiency and born small for gestational age.

INTRODUCTION: The aim of the study is to analyze patients who do not respond adequately to human recombinant growth hormone (rhGH) treatment. MATERIAL AND METHODS: Four boys were analyzed: three patients diagnosed with SNP at the ages of 1) 8 years and 2 months, 2) 13 years and 2 months, 3) 16 years and 6 months, and patient 4) at the age of 6 years and 11 months - born small for gestational age (SGA). They underwent rhGH treatment. RESULTS: The expected growth improvement was not observed in all boys. Patient 1 was diagnosed with aortic coarctation, and after each attempt to increase the rhGH dose, nocturnal vomiting occurred - epilepsy was diagnosed. Patient 2 had severe foot pain. Patient 3 had delayed puberty - hypogonadotropic hypogonadism was diagnosed. Patient 4 had dysmorphic features. Genetic tests revealed the following: 1) mixed gonadal dysgenesis - modifying treatment; 2) Fabry disease - enzyme treatment and rhGH improved growth; 3) Kallmann syndrome - discontinuing rhGH for testosterone supplementation; 4) KBG syndrome. CONCLUSIONS: 1. The presence of dysmorphic features and symptoms atypical for growth hormone deficiencies could warrant genetic diagnostics before initiating treatment. 2. Lack of significant improvement in growth is an indication for reevaluation of patients who have not completed growth. 3. Genetic studies in this patient group often elucidate the causes of slow growth rate. 4. The case authors have developed a proposal for a multicentre program aimed at establishing indications for genetic diagnosis in children diagnosed with SNP and SGA treated with rhGH.

Primary response in GHD children treatment as a predictor for long-term therapy effectiveness therapy effectiveness.

INTRODUCTION: Short stature in growth hormone deficiency (GHD) can be treated with recombinant human growth hormone (rhGH), which is proven to be both safe and effective. However, a considerable number of patients does not achieve satisfying therapy outcomes. AIM OF THE STUDY: To evaluate the predictive effect of height increase in the first year of rhGH treatment on long-term therapy outcomes. MATERIAL AND METHODS: 165 short-stature children (mean age 10.72 ±3.33 years; 63% males), diagnosed with GHD, treated with rhGH for at least one year (mean follow-up 4.32 ±1.80 years), divided into 2 groups according to the change in height standard deviation score (SDS) after the first year of rhGH treatment: good responders (GR) and poor responders (PR). Then, in one-year intervals, patient's chronological age, bone age, height, weight, insulin-like growth factor level, and rhGH dose were all assessed. RESULTS: In the GR group, mean height velocity SDS up to five years of observation was 1.19 ±0.41/year and in the PR group 0.59 ±0.38/year. The differences were statistically significant (p < 0.05). CONCLUSIONS: The primary response to the rhGH treatment in GHD children seems to be a good predictor for long-term therapy outcomes.

Transient Isolated, Idiopathic Growth Hormone Deficiency-A Self-Limiting Pediatric Disease with Male Predominance or a Diagnosis Based on Uncertain Criteria? Lesson from 20 Years' Real-World Experience with Retesting at One Center.

In the majority of children with growth hormone (GH) deficiency (GHD), normal GH secretion may occur before the attainment of final height. The aim of the study was to assess the incidence of persistent and transient GHD and the effectiveness of recombined human GH (rhGH) therapy in children with isolated, idiopathic GHD with respect to the moment of therapy withdrawal and according to different diagnostic criteria of GHD. The analysis included 260 patients (173 boys, 87 girls) with isolated, idiopathic GHD who had completed rhGH therapy and who had been reassessed for GH and IGF-1 secretion. The incidence of transient GHD with respect to different pre- and post-treatment criteria was compared together with the assessment of GH therapy effectiveness. The incidence of transient GHD, even with respect to pediatric criteria, was very high. Normal GH secretion occurred before the attainment of near-final height. Application of more restricted criteria decreased the number of children diagnosed with GHD but not the incidence of transient GHD among them. Poor response to GH therapy was observed mainly in the patients with normal IGF-1 before treatment, suggesting that their diagnosis of GHD may have been a false positive. Further efforts should be made to avoid the overdiagnosis GHD and the overtreatment of patients.

Changes in body composition, adipokines, ghrelin, and FGF23 in growth hormone-deficient children during rhGH therapy.

INTRODUCTION: Beyond growth acceleration, growth hormone (GH) therapy improves body composition of GH-deficient (GHD) children due to the interaction of GH with lipid and carbohydrate metabolism, possibly mediated by adipokines secreted by adipose tissue and ghrelin. To promote linear growth, it is essential to have normal phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is a known regulator of serum phosphorus and may be responsible for the increased renal phosphorus reabsorption observed during GH therapy. This study aimed to assess the impact of one-year GH therapy on body composition, adipokines, acylated/unacylated ghrelin (AG/UAG), and FGF23 in GHD children. MATERIAL AND METHODS: A prospective observational study of 42 prepubertal, non-obese GHD children followed up in the first year of GH replacement therapy, investigating changes in adipokine profiles, AG/UAG, FGF23, and body composition. Data before therapy onset were compared with measurements obtained after 6 and 12 months of GH therapy. RESULTS: All children with a mean age of 9.2 ± 2.6 years grew at an accelerated pace. Total body fat decreased significantly, while the lipid profile improved, and total bone mineral density (BMD) significantly increased over the 12 months of treatment. Leptin and UAG levels decreased significantly, whereas adiponectin and AG values increased. A significant increase in plasma FGF23 and insulin growth factor 1 (IGF1) was accompanied by increased serum phosphate. Changes in FGF23 concentration did not have an impact on BMD. The strong association of FGF23 with IGF1 and height standard deviation (SD) could reveal a role of FGF23 in linear growth. In regression analysis models, GH therapy influences the changes of leptin and adiponectin, but not ghrelin, independently of body composition - lean or fat mass. CONCLUSIONS: GH replacement therapy improves body composition and adipokine profile in GHD children and directly impacts leptin and adiponectin concentrations independently of body composition. Also, GHD children have increased serum phosphate, correlated with upregulation rather than with suppression of FGF23, an unexpected observation given the phosphaturic role of FGF23. Further research is needed to identify the molecular mechanisms by which the GH/IGF1 axis influences adipokines secretion and plasma changes of FGF23.

Proteomic and metabolomic analysis of GH deficiency-induced NAFLD in hypopituitarism: insights into oxidative stress.

Objective: Individuals with hypopituitarism (HPs) have an increased risk of developing non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) due to growth hormone deficiency (GHD). We aimed to investigate the possible mechanisms underlying the relationship between GHD and NAFLD using proteomic and metabolomic insights. Methods: Serum metabolic alternations were assessed in male HPs using untargeted metabolomics. A rat model of HP was established through hypophysectomy, followed by recombinant human growth hormone (rhGH) intervention. The mechanisms underlying GHD-mediated NAFLD were elucidated through the application of label-free proteomics and phosphorylation proteomics. Results: Metabolomic analysis revealed that biomarkers of mitochondrial dysfunction and oxidative stress, such as alanine, lactate, and creatine, were significantly elevated in HPs compared to age-matched controls. In rats, hypophysectomy led to marked hepatic steatosis, lipid peroxidation, and reduced glutathione (GSH), which were subsequently modulated by rhGH replacement. Proteomic analysis identified cytochrome P450s, mitochondrial translation elongation, and PPARA activating genes as the major distinguishing pathways in hypophysectomized rats. The processes of fatty acid transport, synthesis, oxidation, and NADP metabolism were tightly described. An enhanced regulation of peroxisome ß-oxidation and ω-oxidation, together with a decreased NADPH regeneration, may exacerbate oxidative stress. Phosphoproteome data showed downregulation of JAK2-STAT5B and upregulation of mTOR signaling pathway. Conclusions: This study identified proteo-metabolomic signatures associated with the development of NAFLD in pituitary GHD. Evidence was found of oxidative stress imbalance resulting from abnormal fatty acid oxidation and NADPH regeneration, highlighting the role of GH deficiency in the development of NAFLD.

Growth hormone therapy does not impact the development of intracranial hypertension in children with Chiari malformation.

OBJECTIVES: Patients with Chiari malformation (CM) are prone to a variety of neurological sequelae, including benign intracranial hypertension (BIH). In these patients, BIH is attributed to impaired cerebrospinal fluid (CSF) flow due to anatomical abnormalities of the posterior fossa. Occasionally, patients with CM may require growth hormone therapy (GHT), which can increase the production of CSF. It is thought that patients with CM who undergo GHT are at high risk of BIH-associated symptoms (BIHAS). We describe the incidence of neurological symptoms in 34 patients with CM before and during GHT. METHODS: The database of a pediatric endocrinology center was queried for patients with CM who received GHT from 2010-22. Records were reviewed for adverse events. Demographic and radiological data were collected and analyzed. Patients with neoplastic disease, active inflammation, or acute trauma were excluded. CM diagnoses were independently assigned by a neuroradiology department. Patients were grouped based on the presence and nature of symptoms before and during GHT. Relationships between starting dose/BMI and occurrence of BIHAS/all GHT-associated symptoms were evaluated. RESULTS: GHT was not associated with new-onset or worsening of preexisting BIHAS in 33 out of 34 patients with CM. Five complex patients continued to have preexisting BIHAS, which did not worsen. Of the four patients who developed new-onset BIHAS during GHT, three patients' symptoms were attributed to other medical conditions. No patient permanently discontinued GHT due to BIHAS. CONCLUSIONS: Growth hormone therapy is likely a safe treatment in patients with Chiari malformation and is unlikely to cause BIHAS.

Composition of the microbiota in patients with growth hormone deficiency before and after treatment with growth hormone.

INTRODUCTION: Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have modulatory effects on bowel function and its microbiota. Our aim was to investigate whether low levels of GH and IGF-1 in patients with GH deficiency are associated with changes in gut physiology/integrity as well as in the composition of the gut microbiota. MATERIALS AND METHODS: We conducted a case-control study in 21 patients with GH deficiency, at baseline and after 6 months of GH treatment, and in 20 healthy controls. We analysed changes in anthropometric and laboratory characteristics and bacterial translocation and studied the composition of the microbiome by means of massive 16S rRNA gene sequencing. RESULTS: Growth hormone deficiency was accompanied by a significant increase in serum levels of sCD14, a marker of bacterial translocation (P < .01). This increase was reversed by GH treatment. We did not find any differences in the composition or α- or ß-diversity of the gut microbiota after treatment or between cases and controls. CONCLUSIONS: Our work is the first to demonstrate that the presence of GH deficiency is not associated with differences in gut microbiota composition in comparison with healthy controls, and changes in microbiota composition are also not found after 6 months of treatment. However, GH deficiency and low IGF-1 levels were associated with an increase in bacterial translocation, which had reversed after treatment.

Evolving growth hormone deficiency: proof of concept.

Introduction: We present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST). Methods: We performed a retrospective chart review of children who presented for short stature (height less < 2SD for mean/mid-parental height) and/or growth failure (sustained growth velocity < 0 SD) to pediatric endocrinology at Mount Sinai Kravis Children's Hospital, New York and who had 2 GSTs. Data collected from electronic medical records were analyzed using SPSS v28.0. Results: Of 53 patients included, 42 were males. Average GH peak on initial GST was 15.48 ± 4.92 ng/ml, at 10.07 ± 2.65 years, mean height -1.68 ± 0.56SD(28% had <2SD), IGF-1 -1.00 ± 0.88SD. After 2.23 ± 1.22 years, at 12.04 ± 2.41years, height SDs decreased to -1.82 ± 0.63SD and IGF-1 was -1.08 ± 0.84SD. At repeat GST, average GH peak was 7.59 ± 2.12 ng/dL, with 36% ≤7 ng/dl and 32% in puberty. 12 males reached adult height of 0.08 ± 0.69 SD with a mean height gain of 1.83 ± 0.56SD(p<0.005), IGF-1 of -1.15 ± 0.81SD after 4.64 ± 1.4 years of GH. Conclusion: We offer evidence for Evolving Growth Hormone Deficiency (EGHD) through repeat GST in children with persistent growth slowdown, even with pubertal progression; emphasizing the need for careful longitudinal follow-up to make accurate diagnosis.

GH provocative tests stimulate the growth in children with idiopathic short stature.

CONTEXT: Growth hormone (GH) deficiency in a child with short stature is diagnosed by GH secretion provocative tests. When the test response is considered adequate, the short stature is considered idiopathic (ISS). OBJECTIVE: To determine the effect of GH provocative tests on the growth rate in children with idiopathic short stature. DESIGN: Children with short stature with a normal response to at least one GH provocative test were enrolled. Height and growth velocity were measured prior to and after stimulus tests during the follow-up. METHODS: Height, mid-parental height, body weight, and body mass index were measured. The height and growth rate were converted to percentiles and Standard Deviation Scores (SDS) using reference ranges standardized by age and sex. GH provocative tests employed arginine or clonidine as secretagogues. RESULTS: Fourty-six children of both genders were enrolled. In thirty-six children, height was measured at the time of testing and on an average time prior to and after the tests of 210 days and 180 days respectively. After testing the children displayed a 3.4-fold increase in their estimated 90-day growth rate. The median (inter-quartile range, IQR) 90 days growth of children pre-and post-tests were 0.7 (0.2-1.0) cm and 2.4 (1.7-3.1) cm respectively with a mean 3,4-fold increase (p < 0.0001). The median (IQR) 90 days growth of children pre- and post-tests calculated as standard deviation scores (SDS) were -4.0 (-5.4--2.1) SDS and 0.1 (-1.9-1.4) SDS respectively (p < 0.0001). Ten children with ISS were observed for about 5 months before the GH provocative tests. A small increase in the growth rate was seen only in 2 out of 10 children before testing while it increased in all of them after the tests. The difference in the median growth rate at the first and the second observation was not significant (p = 0.219). CONCLUSIONS: Two sequential somatotropic axis provocative tests increase the growth rate in children with idiopathic short stature. The duration of this effect is yet to be determined.

Exploring height outcomes with adjuvant aromatase inhibition in growth hormone-deficient male survivors of childhood cancer.

BACKGROUND: Aromatase inhibitors (AI) may improve height in short stature conditions; however, the effect in childhood cancer survivors (CCS) is unknown. We assessed final adult height (FAH) in CCS treated with AI and GH compared with those treated with GH alone. METHODS: Retrospective cohort study of GH-deficient male CCS treated between 2007 and 2023. FAH was noted as the height at the fusion of growth plates or 18 years of age. Multivariable linear regression was used to examine treatment association with FAH, adjusting for other risk factors. RESULTS: Ninety-two patients were included; 70 were treated with GH and 22 with combination AI/GH. The mean age at GH initiation did not differ between groups. The mean age at AI initiation was 13.7 ± 1.9 years. A greater proportion of patients in the AI/GH group were treated with stem cell transplantation, abdominal radiation, total body irradiation, and cis-retinoic acid (p < .01). Multivariable linear regression demonstrated no significant treatment association with FAH Z-score (ß = 0.04, 95% CI: -0.9 to 0.9). History of spinal radiation (ß = -0.93, 95% CI: -1.7 to -0.2), lower starting height Z-score (ß = -0.8, 95% CI: -1.2 to -0.4), and greater difference between bone age and chronological age (ß = -0.3, 95% CI: -0.5 to -0.07) were associated with lower FAH Z-score. CONCLUSIONS: Adjuvant AI was not associated with increased FAH in male CCS compared with GH monotherapy. Future work is needed to determine the optimal adjunctive treatment to maximize FAH for this population.

Impact of Daily Growth Hormone Adherence on Height Velocity Among Children With Growth Hormone Deficiency (GHD).

OBJECTIVE: To describe adherence to daily somatropin treatment and impact on height velocity within 1 year of treatment start among patients with pediatric growth hormone deficiency in a real-world US population. METHODS: This retrospective cohort study included pediatric patients aged ≥3 years to <16 years with pediatric growth hormone deficiency prescribed somatropin by a pediatric endocrinologist at a US-based center of excellence between January 1, 2015 and December 31, 2020. Patient data were collected using hospital electronic health records linked to a specialty pharmacy patient prescription records. Adherence, evaluated over 12 months, was measured using the proportion of days covered metric and patients were categorized as adherent if their proportion of days covered ≥80%. Height velocity was annualized to compare across adherent and nonadherent patients. RESULTS: One hundred eighty-one patients were identified and included in this study, of which 70.2% were male,73.5% were white, and mean age (standard deviation [SD]) at index was 12.1 (2.8). In the height velocity analysis, 174 patients were included and the mean (SD) annualized change in height was 10.2 (5.7) cm/y in the adherent group (n = 108) and 9.8 (7.6) in the nonadherent group (n = 66). The difference in height velocity between the groups was not statistically significant. CONCLUSIONS: Minor improvements in average height velocity were observed in the patient group who were adherent to somatropin therapy, although not statistically significant. Lack of observed significance may be due to small sample sizes, short observation period, a likely heterogenous population in terms of growth hormone prescribing, data bias due to single-center origin, or potential patient misclassification.

Skin assessment in congenital untreated isolated GH deficiency.

PURPOSE: The separation between the inside and outside through the skin was fundamental for the evolution of prevertebrates, which grow through extrapituitary circuits, to vertebrates, which grow through the somatotrophic axis, namely pituitary growth hormone (GH). and circulating IGF1.Individuals with untreated isolated growth hormone (GH) deficiency (IGHD) due to a mutation in the GH-releasing hormone receptor (GHRH) gene, residing in Itabaianinha, Brazil, are vulnerable to skin cancer and have reduced sweating. However other aspects of their skin physiology are still unknown. Our objectives were to evaluate the number of skin cancers, skin aging, and functional aspects of the skin in this IGHD cohort. METHODS: Twenty-six IGHD individuals and 26 controls matched by age, sex, ethnicity, and occupation were submitted to a biochemical, dermatological and a functional skin assessment by the Multi Probe Adapter Cutometer® MPA 580. RESULTS: There was no difference in the number of skin cancers and in the degrees of photodamage between the groups. The melanin content in the forearm was similar between the groups but was lower in the buttocks (p = 0.005), as well as skin resistance (p < 0.0001) and elasticity (p = 0.003), lower in the IGHD. There was no difference in hydration and sebum content between the two groups. CONCLUSION: IGHD is apparently associated with a neutral profile in terms of skin cancer and photodamage, with similar melanin on the forearm and lower buttocks, lower skin resistance and elasticity, with hydration and sebum similar to controls.

Exploring the sex difference in cardiovascular risk during growth hormone therapy in adults.

OBJECTIVE: Given the previously identified sex differences in cardiovascular (CV) morbidity and mortality in patients with growth hormone deficiency (GHD) receiving GH replacement therapy (GHRT), our aim is to investigate sex-specific differences in the efficacy of (long-term) GHRT on CV risk profile and disease in subjects with GHD. Our hypothesis is that women will experience less beneficial effects than men. DESIGN: Retrospective nationwide cohort study. METHODS: We compared all men (n = 1335) and women (n = 1251) with severe GHD registered in the Dutch National Registry of GH Treatment in Adults database with respect to CV risk profile and morbidity at baseline and during follow-up. RESULTS: Men had a more unfavourable CV risk profile at baseline. During the first years of GHRT, the reduction in waist circumference, waist-to-hip ratio, total cholesterol, and triglyceride levels was greater in men than in women (all P < .05). Between-sex differences in effects during later follow-up were less clear. No sex differences were found in the risk of developing non-fatal cardiovascular or cerebrovascular diseases during GHRT. CONCLUSIONS: Our results suggest that men with GHD did indeed experience more beneficial effects of GHRT on body composition and lipoprotein metabolism than women, at least in the early years of treatment. Also, the more unfavourable CV risk profile at baseline in men did not translate into a sex difference in the risk of developing CV and cerebrovascular morbidity during GHRT.

Post hoc subgroup analysis of Asian children with paediatric GHD from the global phase 3 efficacy and safety study of once-weekly somatrogon vs. once-daily somatropin.

OBJECTIVES: Somatrogon is a long-acting recombinant human growth hormone used to treat patients with paediatric growth hormone deficiency (pGHD). This global phase 3 study compared the efficacy and safety of once-weekly somatrogon with once-daily somatropin in children with GHD. METHODS: Prepubertal patients were randomized 1:1 to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. The primary endpoint was height velocity (HV) at month 12; secondary endpoints included HV at month 6 and change in height standard deviation score (SDS) at months 6 and 12 and insulin-like growth factor 1 (IGF-1) SDS. RESULTS: This post hoc subgroup analysis focused specifically on Asian children (somatrogon: n=24 and mean age=7.76 years; somatropin: n=21 and mean age=8.10 years) across eight countries. Mean HV at month 12 was 10.95 cm/year (somatrogon) and 9.58 cm/year (somatropin); the treatment difference of 1.38 cm/year favoured somatrogon. The lower bound of the two-sided 95 % CI of the treatment difference (somatrogon-somatropin) was -0.20, similar to the overall study population (-0.24). Compared with the somatropin group, the somatrogon group had numerically higher HV at month 6 (8.31 vs. 11.23 cm/year); a similar trend was observed for height SDS and IGF-1 SDS at months 6 and 12. Safety and tolerability were similar between treatment groups; adverse events occurred in 83 % of somatrogon-treated children and 76 % of somatropin-treated children. CONCLUSIONS: This subgroup analysis demonstrated that somatrogon efficacy and safety in Asian children were consistent with the overall study population, where once-weekly somatrogon was non-inferior to once-daily somatropin. Clinicaltrials.gov: NCT02968004.

Gut Microbiota Moderates Multimodal Brain Structure-Function Integration and Behavioral Cognition in Growth Hormone Deficient Children.

INTRODUCTION: Previous brain studies of growth hormone deficiency (GHD) often used single-modal neuroimaging, missing the complexity captured by multimodal data. Growth hormone affects gut microbiota and metabolism in GHD. However, from a gut-brain axis (GBA) perspective, the relationship between abnormal GHD brain development and microbiota alterations remains unclear. The ultimate goal is to uncover the manifestations underlying GBA abnormalities in GHD and idiopathic short stature (ISS). METHODS: Participants included 23 GHD and 25 ISS children. The fusion independent component analysis was applied to integrate multimodal brain data (high-resolution structural, diffusion tensor, and resting-state functional MRI) covering regional homogeneity (ReHo), amplitude of low frequency fluctuations (ALFF), and white matter fractional anisotropy (FA). Gut microbiome diversity and metabolites were analyzed using 16S sequencing and proton nuclear magnetic resonance (1H-NMR). Associations between multimodal neuroimaging and cognition were assessed using moderation analysis. RESULTS: Six independent components (IC) of ReHo, ALFF, and FA differed significantly between GHD and ISS patients, with three functional components linked to the processing speed index. GHD individuals showed higher levels of acetate, nicotinate, and lysine in microbiota metabolism. Higher alpha diversity in GHD strengthened connections between ReHo-IC1, ReHo-IC5, ALFF-IC1, and the processing speed index, while increasing agathobacter levels in ISS weakened the link between ALFF-IC1 and the speech comprehension index. CONCLUSIONS: Our findings uncover differing brain structure and functional fusion in GHD, alongside microbiota metabolism of short-chain fatty acids. Additionally, microbiome influences connections between neuroimaging and cognition, offering insight into diverse GBA patterns in GHD and ISS, enhancing our understanding of the disease's pathophysiology and interventions.