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Background: Isolated growth hormone deficiency type II (IGHD II) is an autosomal dominant disorder characterized by a GH1 gene variant resulting in a significant reduction in growth hormone (GH) secretion and a subsequent decrease of plasma insulin-like growth factor 1 (IGF-1) levels and eventual growth impairment. Objective: This study aimed to identify causative variants in six Chinese families with IGHD II, exploring both clinical and genetic characteristics. Methods: Detailed clinical data, including clinical presentations, physical charateristics, medical and family histories, as well as genetic test results, were systematically examined. Results: Six children, comprising four males and two females, with a mean age of 4.64 ± 1.15 years, exhibited short stature with a mean height of -3.95 ± 1.41 SDS. Four of them had a family history of short stature, while one patient presented with pulmonary hypertension. All children demonstrated GH deficiency in growth hormone stimulation tests (mean peak GH value: 2.83 ± 2.46 ng/mL). Exome sequencing for the six patients and targeted gene sequencing for their family members revealed heterozygous variants in the GH1 gene, including Exon2-5del, c.334T>C, c.291 + 1G>A, c.291 + 2T>A, 1.5 kb deletion, and 1.7 kb deletion, with four variants being novel. Four patients underwent human recombinant growth hormone (rhGH) replacement therapy, initiating treatment at a mean age of 4.6 ± 0.7 years. The mean height increase in patients was 1.21 ± 0.3 SDS in the first six months of treatment and 1.79 ± 0.15 SDS in the first year. Conclusion: Our findings contribute to expanding the genotypic and phenotypic spectra of individuals with IGHD II. [ABSTRACT FROM AUTHOR]

Introduction: Human growth hormone (hGH) therapy in children can be administered by subcutaneous injection using either a manual non-connected device, which is a portable injection pen loaded with a pre-filled cartridge, or an electronic connected device. The electronic device is connected to a platform where adherence data is recorded and available for health care professionals (HCPs) and patient support programs. Real-world data used in the clinic, includes regular monitoring of adherence data which are shared with families during patients' visits and aim to determine the root causes of poor adherence. This study aimed to identify whether there are differences in growth during the first four years of treatment depending on the device, i.e. non-connected versus connected devices. Methods: This retrospective study reports treatment of either GH deficiency or short stature secondary to birth size small for gestational age (SGA) in 174 pediatric patients attending Miguel Servet Hospital, Zaragoza, Spain. hGH treatment was administered with manual non-connected devices in 87 patients and 87 patients used connected devices. Height was followed for 4 years after start of hGH therapy. Results: In total, 57% of subjects had GHD and 43% were SGA. Height standard deviation score (HSDS) at treatment start was higher (p<0.001) in the non-connected device group compared to the connected device group. Change of HSDS in the connected device group was significantly higher in the second (+0.13), third (+0.20) and fourth (+0.23) year of treatment compared to the non-connected group after adjustment for age and HSDS at treatment start, sex, indication, dose and Tanner stages during treatment, and timing of measurements. Discussion: These results support the use of the connected device for hGH treatment of pediatric growth disorders. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) deficiency (GHD) in children and adolescents can vary in severity and origin, with GH replacement therapy proving effective in achieving genetic target height. Optimal outcomes are seen in those treated early and with higher doses. As patients approach adult height, priorities shift towards optimizing metabolic effects, maintaining body composition, and enhancing bone mass and muscle strength. Transitioning from pediatric to adult care presents challenges, including accurately identifying candidates for continued GH therapy, reevaluating persistent GHD, and preventing treatment discontinuation. Assessing readiness for transition and self-management skills is crucial. This Policy and Practice Review provides a comprehensive overview of current policies, regulations, and guidelines pertinent to managing GHD transition in Belgium. We integrate perspectives from national academic and nonacademic clinical stakeholders in pediatric and adult endocrine care to provide an updated policy framework. This framework underscores the importance of sustained GH therapy during transition, particularly for individuals with persistent GHD, with the goal of optimizing practices and improving outcomes during this critical period. [ABSTRACT FROM AUTHOR]

The aim of this review article is to highlight the consequences of COGHD after the end of linear growth on bone mass and body composition and the opposing beneficial effects of continuing GH replacement in the transition period and young adults. The role of growth hormone in the period of late adolescence and young adulthood is well established, mainly in achieving peak bone mass and a favorable body composition, characterized by muscle mass increase and fat mass reduction. Patients with childhood onset growth hormone deficiency (COGHD), after reaching the adult height, have a reduced bone mineral density and muscle mass with increased fat mass compared to healthy controls. Inadequate body composition is a predictor for cardiovascular risk, while low bone mass in early youth hallmarks the risk of osteoporosis and bone fractures in later life. Cessation of growth hormone replacement (GHr) after completion of growth will lead to delayed peak bone mass and unbalanced body composition with increased abdominal fat deposits. According to numerous clinical studies monitoring the effects of GH treatment on the physical and psychological status of patients with persistent GHD after completion of growth, we suggest continuing this treatment between 16 and 25 years of age. It is advised that GHr in the transition period be administered in intermediate doses between those for the pediatric population and those for the adult population. Usual daily GHr doses are between 0.3 and 0.5 mg but need to be individually optimized, with the aim of maintaining IGF-I in the age-specific normal range. [ABSTRACT FROM AUTHOR]

Somatrogon‐ghla is a long‐acting, recombinant human growth hormone approved for the treatment of pediatric patients with growth hormone deficiency. Forty‐nine healthy, adult males were enrolled in a randomized, crossover study to compare somatrogon exposure after subcutaneous doses administered using a frozen vial presentation or a prefilled, multiple dose pen. Somatrogon, insulin‐like growth factor‐I, and IGF‐1 binding protein‐3 concentrations were collected for up to 240 hours post dose to assess pharmacokinetic and pharmacodynamic responses. There was a 2‐week washout between administration of the doses. Seven participants did not complete the study due to withdrawal of consent (n = 2) or loss to follow‐up. Two treatment‐emergent adverse events, headaches, were judged by the investigator as possibly related to study drug administration. Both were mild. Injection site reactions were observed in 6/48 participants after administration with the pen and 12/46 after administration using the vial. Drug and biomarker concentrations were assessed using validated assays and noncompartmental methods were used to determine pharmacokinetic and pharmacodynamic parameters. Bioequivalence was demonstrated for somatrogon area under the concentration‐time curve, but not for the peak somatrogon concentration, where the lower limit of the 90% confidence interval for the ratio of pen/vial was 74.2%, which is less than the lower limit, 80.0%, dictated by bioequivalence criteria. The IGF‐1 responses were largely within bioequivalence limits. It was concluded that the 2 formulations are comparable. [ABSTRACT FROM AUTHOR]

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Mutations in the pituitary-specific transcription factor Prophet of Pit-1 (PROP1) are the most common genetic etiology of combined pituitary hormone deficiency (CPHD). CPHD is associated with short stature, attributable to growth hormone deficiency and/or thyroid-stimulating hormone deficiency, as well as hypothyroidism and infertility. Pathogenic lesions impair pituitary development and differentiation of endocrine cells. We performed single-cell RNA sequencing of pituitary cells from a wild-type and a Prop1 -mutant P4 female mouse to elucidate population-specific differential gene expression. We observed a Smoc2 +ve population that expressed low Sox2 , which trajectory analyses suggest are a transitional cell state as stem cells differentiate into endocrine cells. We also detected ectopic expression of Sox21 in these cells in the Prop1df/df mutant. Prop1 -mutant mice are known to overexpress Pou3f4 , which we now show to be also enriched in this Smoc2 +ve population. We sought to elucidate the role of Pou3f4 during pituitary development and to determine the contributions of Pou3f4 upregulation to pituitary disease by utilizing double-mutant mice lacking both Prop1 and Pou3f4. However, our data showed that Pou3f4 is not required for normal pituitary development and function. Double mutants further demonstrated that the upregulation of Pou3f4 was not causative for the overexpression of Sox21. These data indicate loss of Pou3f4 is not a potential cause of CPHD, and further studies may investigate the functional consequence of upregulation of Pou3f4 and Sox21 , if any, in the novel Smoc2 +ve cell population. [ABSTRACT FROM AUTHOR]

Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report five patients from three families who present with short stature, immune dysfunction, atopic eczema and gastrointestinal pathology associated with recessive variants in QSOX2. QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts Growth hormone-mediated STAT5B nuclear translocation despite enhanced Growth hormone-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate Growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisation and import of phosphorylated-STAT5B. Altogether, QSOX2 deficiency modulates human growth by impairing Growth hormone-STAT5B downstream activities and mitochondrial dynamics, which contribute to multi-system dysfunction. Furthermore, our work suggests that therapeutic recombinant insulin-like growth factor-1 may circumvent the Growth hormone-STAT5B dysregulation induced by pathological QSOX2 variants and potentially alleviate organ specific disease. Defects in growth hormone (GH) action account for a substantial percentage of endocrine causes of growth failure. Here, the authors report that QSOX2 deficiency modulates human growth by impairing GH-STAT5B downstream activities and mitochondrial dynamics, contributing to multi-system dysfunction. [ABSTRACT FROM AUTHOR]

Background: Brain magnetic resonance imaging (MRI) is mandatory or highly recommended in many pediatric endocrinological conditions to detect causative anatomic anomalies and rule out neoplastic lesions. However, MRI can also show findings associated with the underlying clinical condition, as well as unrelated "incidentalomas". These latter findings are often abnormalities with a high incidence in the general population for which there is no clear literature regarding their management, especially in pediatric patients. The present study aimed to evaluate the number of unnecessary performed MRIs in pediatric endocrinology. Methods: Retrospective analysis on 584 MRI scans performed in 414 patients (254 growth hormone deficiency, 41 other causes of short stature, 116 central precocious puberty). Results: The MRI scans were completely normal in 67% of the individuals, and the prevalence of individuals who underwent more than one MRI was 18%, with no significant differences among the groups. The overall prevalence of incidentalomas was 17%. Among 170 repeated MRI scans, 147 (86%) were not required according to a dedicated protocol. Only five patients (four GHD, one Noonan) correctly repeated the MRI. All the repeated MRI scans did not reveal any progression in the findings. If we include the MRIs performed in cases of OCSS other than Noonan syndrome (n=32) and girls with CPP older than 6 years (n=89), an additional 121 MRIs could have been avoided, leading to a total number of unnecessary MRIs to 268 (46%). Conclusions: Only a few specific neuroimaging findings in endocrinologic pediatric patients warrant further investigation, while too often repeated imaging is carried out unnecessarily. We advocate the importance of guidelines to reduce costs for both the healthcare system and patients' families, as well as to alleviate physical and psychological distress for patients and caregivers. [ABSTRACT FROM AUTHOR]

Introduction: The glucagon stimulation test (GST) is widely used to assess growth hormone (GH) and cortisol secretion, nevertheless the precise mechanisms underpinning these hormonal responses remain unclear. We have endeavoured to explore the relationship between glucose and insulin fluctuations during GST and their impact on GH and cortisol secretion. Subjects and methods: We retrospectively studied 139 subjects (mean age 35.5 ± 15.1 years, BMI 26.6 ± 6.61 kg/m²), including 62 individuals with a history of pituitary disease (27 with an intact adrenal axis) and 77 healthy controls. Standard dose intramuscular GST was performed in all subjects. Results: Once BMI and age were excluded from multivariate model, the nadir of glucose concentration during GST was the sole variable associated with maximal GH secretion (DGH, p<0.0003), while neither glucose/insulin peak, nor Dglucose/Dinsulin concentrations contributed to DGH. 100% pass rate for GH secretion above 3 ng/ml or 1.07 ng/ml cut-offs was observed for glucose concentrations at, or below 60 mg/dl (3.33 mmol/l) (for Controls), or 62 mg/dl (3.44 mmol/l) (for Controls and patients with an intact adrenocortical axis). Such low glucose concentrations were obtained, however, only in about 30% of studied individuals. Conversely, cortisol secretion did not correlate with glucose or insulin fluctuations, suggesting alternative regulatory mechanisms. Conclusions: This study reveals that glucose nadir below 3.33 mmol/l is the only biochemical biovariable linked with optimal GH secretion during GST, whereas mechanisms responsible for cortisol secretion remain unclear. We emphasize the importance of glucose monitoring during GST to validate GH stimulation and support clinical decisions in GH deficiency management. [ABSTRACT FROM AUTHOR]

Various factors may affect cognition in patients with pituitary adenoma, including size and extension of the tumor, degree of pituitary hormone deficiencies, and treatment of the tumor, most often being transsphenoidal surgery (TSS). The aim of this cross-sectional study was to evaluate cognitive function in patients with clinically significant pituitary adenoma and to identify factors influencing cognition. Sixty-eight patients with pituitary adenoma were included. Of these, 31 patients were evaluated before TSS and 37 patients 12 months following TSS. Cognitive function was evaluated by using the Repeatable Battery for the Assessment of Neuropsychological Status. Patients had lower mean scores on cognitive assessment compared to age-adjusted normative data. Variability in cognition, analyzed by linear regression analysis, was explained by sex, educational level, and self-perceived fatigue, but not by pituitary hormone deficiencies, diabetes insipidus, or surgical treatment. Our results are in line with previous findings, namely that pituitary adenoma affects cognition. To better evaluate the factors affecting cognition, longitudinal studies are recommended. Such studies would allow for within-individual comparisons, effectively controlling for the considerable influence of sex and education on test results. [ABSTRACT FROM AUTHOR]

Growth hormone‐releasing hormone‐deficient (GHRH‐KO) mice have previously been characterized by lower body weight, disproportionately high body fat accumulation, preferential metabolism of lipids compared to carbohydrates, improved insulin sensitivity, and an extended lifespan. That these mice are long‐lived and insulin‐sensitive conflicts with the notion that adipose tissue accumulation drives the health detriments associated with obesity (i.e., diabetes), and indicates that GH signaling may be necessary for the development of adverse effects linked to obesity. This prompts investigation into the ultimate effect of diet‐induced obesity on the lifespan of these long‐lived mice. To this end, we initiated high‐fat feeding in mid and late‐life in GHRH‐KO and wild‐type (WT) mice. We carried out extensive lifespan analysis coupled with glucose/insulin tolerance testing and indirect calorimetry to gauge the metabolic effect of high‐fat dietary stress through adulthood on these mice. We show that under high‐fat diet (HFD) conditions, GHRH‐KO mice display extended lifespans relative to WT controls. We also show that GHRH‐KO mice are more insulin‐sensitive and display less dramatic changes in their metabolism relative to WT mice, with GHRH‐KO mice fed HFD displaying respiratory exchange ratios and glucose oxidation rates comparable to control‐diet fed GHRH‐KO mice, while WT mice fed HFD showed significant reductions in these parameters. Our results indicate that GH deficiency protects against the adverse effects of diet‐induced obesity in later life. [ABSTRACT FROM AUTHOR]

The study examines the complex relationship between growth hormone (GH) and thyroid hormones in hypo and hyperthyroid conditions in premature male rats, concentrating on the physiological impacts of hormonal alterations and genetic effects. It was done in an animal housing facility at the University of Mosul Faculty of Veterinary Medicine. A study of 50 male rats, 30 days old and weighing 160 ± 5g, was conducted over 21 days. The first control group (G1) received normal saline subcutaneously. The second group (G2) induced by growth hormone deficiency via sodium diethyldithiocarbamate (SDDT) subcutaneously, the third group (G3) were given a growth hormone drug (Norditropin) subcutaneously, while fourth group (G4) induced hypothyroidism by Propylthiouracil (PTU) orally, and the fifth group (G5) induced hyperthyroidism by (Levothyroxine) orally. This experiment showed that thyroid stimulating hormone (TSH) has a high significance value at p>0.05 in G4 and G2 compared to G1. However, Triiodothyronine (T3) and Thyroxin (T4) are significant in G3 and G5. Regarding Reverse Triiodothyronine (rT3) in G3 and G4 display highest level in contrast to the other groups. Thyroid- binding globulin (TBG) and Thyroid peroxidase antibodies (TPO) were greatest in G4, whereas growth hormone (GH) and IGF-1 were highest in G2 and G5. The gene expression results showed that GH and IGF-1are up-regulated in comparison to the rest of the groups by using a modified conventional PCR with the formula. In conclusion, one hormonal agent system may significantly affect other hormonal activities, stressing the need for a complete endocrine approach. [ABSTRACT FROM AUTHOR]

Introduction: Heterozygous variants in the ACAN gene may underlie disproportionate short stature with characteristically accelerated bone age (BA) maturation and/or early-onset osteoarthritis (OA). Methods: The objective of this study was to describe phenotype, analyze genotype-phenotype correlations, and assess the response of growth hormone (GH) treatment in children with a heterozygous ACAN variant. Thirty-six subjects (23 boys, 13 girls) with ACAN deficiency and treated for ≥1 year with GH were identified in the Dutch National Registry of GH treatment in children. Results: We identified 25 different heterozygous ACAN variants in 36 subjects. Median (interquartile range) height SDS at start of GH was −2.6 SDS (−3.2 to −2.2). Characteristic features such as disproportion, advanced BA, early-onset OA, and dysmorphic features like midface hypoplasia and brachydactyly were present in the majority of children, but in ∼20%, no specific features were reported. Subjects with a truncating ACAN variant had a shorter height SDS compared to subjects with a non-truncating variant (−2.8 SDS and −2.1 SDS, respectively, p = 0.002). After 3 years of GH, height gain SDS in prepubertal children was 1.0 SDS (0.9–1.4). In pubertal children, height SDS remained relatively stable. Conclusion: The phenotype of subjects with pathogenic heterozygous ACAN variants is highly variable, and genetic testing for ACAN deficiency should be considered in any child with significant short stature, even in the absence of disproportion, specific dysmorphic features, or BA advancement. Furthermore, children with ACAN deficiency may benefit from GH with a modest but significant response, which is sustained during 3 years of treatment. [ABSTRACT FROM AUTHOR]

We report growth hormone (GH) deficiency due to presumed GH releasing hormone (GHRH) resistance in an adolescent with pseudohypoparathyroidism type 1B (PHP1B) due to paternal uniparental disomy of chromosome 20 (patUPD20). A male patient aged 11 years 10 months with obesity and mild developmental delay was found to have hypocalcemia, hyperphosphatemia, and an elevated parathyroid hormone level. History included muscle cramps and leg pain with activity. Examination showed round facies, short stature, and obesity. He was in puberty and bone age was advanced by > 2 years. Detailed genetic workup, including nucleotide sequence analysis of GNAS exons 1-13 and STX16 , methylation-sensitive multiplex ligation-dependent probe amplification and analysis of several microsatellite markers for chromosome 20, established the diagnosis of PHP1B due to patUPD20. Muscle cramps and hypocalcemia resolved with calcium carbonate, ergocalciferol, and calcitriol treatment. He was short with linear growth deceleration at around age 13 years. Peak GH concentration was insufficient following stimulation testing. Growth velocity improved with human GH treatment. Although rare, resistance to GHRH can occur in PHP1B and patients with this disorder should be evaluated for GH insufficiency if they present with short stature and reduced growth velocity. Treatment with recombinant human GH may improve growth velocity in such patients. [ABSTRACT FROM AUTHOR]

Background/Objectives: Obesity can be associated with impaired growth hormone (GH) secretion, with possible negative repercussions on bone health. We aimed to investigate the relationships between GH secretory capacity, evaluated with GHRH + arginine stimulation test, and bone parameters, assessed with a dual-energy X-ray absorptiometer, in a population of adult female patients affected by overweight and obesity. Methods: We assessed 276 women affected by overweight or obesity referred to the High-Specialization Center for the Care of Obesity, Umberto I Polyclinic, between 2014 and 2019 with signs or symptoms of growth hormone deficiency (GHD). Results: A total of 97 patients were diagnosed with GHD, and 179 patients with normal GH secretion were considered our control group. GHD patients showed a significantly reduced trabecular bone score (TBS) (p = 0.01). Bone quality parameters corrected for body mass index (BMI) had a positive and significant linear correlation with stimulated GH secretory capacity. Conclusions: In conclusion, bone quality, evaluated by TBS and hip structural analysis, correlates with GH-stimulated secretory capacity. GHD may act as an additive factor in the alteration of bone microarchitecture in patients affected by obesity, who are already at a higher risk of fractures. [ABSTRACT FROM AUTHOR]

Context Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. Objective We determined serum levels of PAPP-As and STCs in association with IGF axis components in prepubertal and pubertal patients with PWS, also analyzing the effect of GH treatment. Methods Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at 6 months of treatment in 11 children. Results Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and they had higher concentrations of free IGF-I, IGFBP-5, and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and had increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs, and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. Conclusion The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Key points: 1. GHD children undergo an extensive and significant reorganization in large-scale individual-level MBNs. 2. Abnormal morphological connectivity was found in cortico-striatal-thalamo-cerebellum loops, cortico-limbic-cerebellum, dorsal visual-sensorimotor-striatal, and auditory-cerebellum circuitry underlying pediatric GHD. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the incidence and risk factors of new-onset hypopituitarism after gamma knife radiosurgery (GKRS) for pituitary adenomas in a single center. Methods: In this retrospective study, 241 pituitary adenoma patients who underwent GKRS from 1993 to 2016 were enrolled. These patients had complete endocrine, imaging, and clinical data before and after GKRS. The median follow-up time was 56.0 (range, 12.7–297.6) months. Results: Fifty patients (20.7%) developed new-onset hypopituitarism after GKRS, including hypogonadism (n = 22), hypothyroidism (n = 29), hypocortisolism (n = 20), and growth hormone deficiency (n = 4). The median time to new-onset hypopituitarism was 44.1 (range, 13.5–141.4) months. The rates of new-onset hypopituitarism were 7%, 16%, 20%, 39%, and 45% at 1, 3, 5, 10, and 15 years, respectively. For those patients treated with a single GKRS, sex (p = 0.012), suprasellar extension (p = 0.048), tumor volume (≥ 5 cm3) (p < 0.001), tumor progression (p = 0.001), pre-existing hypopituitarism (p = 0.011), and previous surgery (p = 0.009) were significantly associated with new-onset hypopituitarism in univariate analysis. In the multivariate analysis, tumor volume (≥ 5 cm3) and tumor progression were associated with new-onset hypopituitarism (hazard ratio [HR] = 3.401, 95% confidence interval [CI] = 1.708–6.773, p < 0.001 and HR = 3.594, 95% CI = 1.032–12.516, p = 0.045, respectively). For patients who received 2 or more times GKRS, no risk factors associated with new-onset hypopituitarism were found. Conclusion: New-onset hypopituitarism was not uncommon after GKRS for pituitary adenomas. In this study, large tumor volume (≥ 5 cm3) and tumor progression were associated with new-onset hypopituitarism after a single GKRS. [ABSTRACT FROM AUTHOR]

This article presents a case study of a Colombian family with a rare variant of Multiple Endocrine Neoplasia type 1 (MEN1). The study follows the medical history and diagnoses of the affected family members and emphasizes the importance of genetic screening and surveillance in early detection and personalized treatment of MEN1. The study also identifies a frameshift variant in the MEN1 gene that may contribute to the variability in clinical manifestations observed in the family. While the findings provide valuable insights, further research is needed to confirm their significance due to the limited sample size of the study. [Extracted from the article]

The present review focuses on growth hormone (GH) deficiency in pediatric and adult patients following surgery for hypothalamic-pituitary tumors, with a special emphasis on hormone replacement therapy with recombinant human growth hormone (rhGH). The symptoms and metabolic changes associated with GH deficiency are reviewed, and the potential risks and therapeutic outcomes of rhGH treatment in these patients are discussed. This review emphasizes the importance of rhGH in the normalization of growth in children and the improvement of quality of life (QoL) and metabolic health in adults. Aspects related to efficacy, safety, dosage, duration of treatment, and QoL in this population are analyzed. The need for regular follow-up and dose adjustment to maintain the optimal IGF-I levels in these patients is emphasized, as is the importance of individualized assessment and collaboration with a specialized multidisciplinary medical team to make the appropriate therapeutic decisions. Furthermore, continuous follow-up are necessary to optimize the clinical outcomes in this patient population. [ABSTRACT FROM AUTHOR]

Background: Growth retardation and short final height is a common complication of chronic kidney disease (CKD) beginning in childhood, with profound deleterious effects on quality of life, mental health, and social achievement. Despite optimal treatments of causative factors for growth retardation in children with CKD, more than 50% of patients reach end‐stage renal failure with a height >2 SD below the mean, and most do not demonstrate "catch‐up" growth after receiving a kidney transplant. Four decades ago, recombinant human growth hormone (rhGH) treatment was introduced after studies showed increased growth velocity and improved height SDS in uremic subjects. Since then, an abundance of published data showed significant improvements in health‐related quality of life, and most studies revealed no significant adverse effects. Clinical practice guidelines recommended rhGH treatment in CKD Stages 3–5D and after transplantation. Despite these guidelines, this therapy remained underutilized. Most commonly cited barriers to the implementation of rhGH treatment were the need for daily injections, financial challenges, physicians' unfamiliarity with guidelines, and fear of adverse events. Conclusions: rhGH has been shown to improve growth and final height in short children with CKD, with minimal adverse effects. Despite data of its successful use generated over 3 decades, this treatment is underutilized. More judicious utilization of the treatment should emphasize educating patients, their care givers, and members of the multidisciplinary treating team. Additional studies are needed to assess the longer‐term rhGH treatment in larger cohorts of patients, leading to additional supportive data and clearer recommendations. [ABSTRACT FROM AUTHOR]

Short stature affects approximately 2.5% of children. Some of them, when diagnosed with growth hormone deficiency (GHD), benefit from recombinant human growth hormone (rhGH) therapy; in others, this treatment is controversial. We aimed to present the clinical characteristics of Polish short stature children in the context of current GHD diagnostic standards, as obtaining more data gives a broader foundation for the potential modifications of diagnostic and therapeutic recommendations. This retrospective analysis was based on a cohort of 277 short stature children divided into two subgroups depending on their peak growth hormone (GH) cutoff level, set at 10 ng/mL: 138 had growth hormone deficiency (GHD) and 137 had normal growth hormone secretion (GHN). These subgroups were then compared based on the extracted clinical data. In the obtained result, no significant differences between the GHD and GHN subgroups were found in any of the variables, including the following: gender distribution, birth weight, bone age delay, height SDS, IGF-1 SDS, vitamin D levels, celiac disease indices, prevalence of hypothyroidism or anemia. As our results point to major clinical similarities between the GHD and GHN children, it seems that distinguishing patients with normal GH secretion from those with deficient GH secretion based on a 10 ng/mL cutoff value might not be clinically relevant. [ABSTRACT FROM AUTHOR]

Objective: Optic nerve hypoplasia (ONH), the congenital underdevelopment of the optic nerve, is an increasing cause of visual impairment and is associated with pituitary dysfunction. Past studies have focused on the relationship between ONH, pituitary deficiencies, and brain imaging. However, recent studies have demonstrated the true risk for hypopituitarism lies with the presence or absence of ONH, irrespective of midline brain findings. This study reviewed the relationship between the health of the optic nerve (visual acuity) and pituitary gland (number and age of development of pituitary deficiencies) as a way to stratify risk, regardless of imaging findings. Design, Patients and Measurements: Retrospective chart review of 197 patients seen at a single center from 2013 to 2022. Visual assessment was defined by distance acuity, and the presence of nystagmus or afferent pupillary defect. Pituitary deficiencies were diagnosed per Endocrine Society guidelines. Results: In children with bilateral ONH (bONH), profound visual impairment was associated with more pituitary deficiencies between 0 and 15 years of age. The odds of having any pituitary deficiency were 4.9 times higher (95% confidence interval [95% CI]: 2.4–10.1) for patients with bONH versus unilateral ONH (uONH). Central hypothyroidism was the most common first presenting pituitary deficiency followed by growth hormone across all patients. Conclusion: This study shows a significant association between severity of visual impairment and increased probability of pituitary deficiencies in children with bONH versus uONH. Children with ONH require urgent endocrine evaluation due to risk of pituitary deficiencies, but risk stratification may also be based on severity of visual impairment. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study is to interpret plasma renin concentrations (PRCs) correctly in a clinical setting, it is essential to understand to what extent physical activity influences the concentration. Reference values for different postural positions exist for adults, but data for children are sparse. In this study, the effect of 30 min of rest on plasma renin concentrations in paediatric patients was examined. Methods: In total, 41 paediatric patients, undergoing either arginine or clonidine provocation tests for growth hormone deficiency, were included. For each stimulation test, two blood samples were drawn. One at time 0 min and one after 30 min of rest. In total, renin concentrations were determined in 86 serum samples. Results: Renin concentrations decreased from 0 to 30 min with a median value of −20.5% (inter‐quartile range: −33.0% to −12.8%). This decrease was not dependent on sex, age, medication or comorbidity, and the variance of renin did not differ between 0 and 30 min. Conclusion: Renin concentrations in children differ according to postural position, which is comparable to adults. Thus, the clinical interpretation of renin results needs to consider the preanalytical conditions applied in the local reference population. [ABSTRACT FROM AUTHOR]

Context Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention. Objective To determine whether high-dose GH can overcome GH resistance in this specific patient resulting in normal insulin-like growth factor (IGF)-1 levels and improved growth rates. Methods Single patient trial of ascending doses of GH followed by a dose stable phase: total 12 months of treatment. The patient has a heterozygous variant in the GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature. Daily subcutaneous GH was administered, starting at 50 µg/kg/day and escalating to 250 µg/kg/day until goal IGF-1 achieved. The subject continued on 250 µg/kg/day for a total treatment duration of 12 months. The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the midpoint of the normal range. Secondary endpoints included height velocity and the change in height SDS during the first year of treatment. Results A dose of GH of 250 µg/kg/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height. Conclusion A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels. [ABSTRACT FROM AUTHOR]

Introduction: To analyse the perspectives of healthcare professionals (HCPs) regarding the acceptance of digital health solutions for growth hormone (GH) deficiency care. This study identified factors impacting HCPs' intent to use and recommend digital solutions supporting recombinant-human growth hormone (r-hGH) therapy in Italy and Korea with a use case of connected drug delivery system (Aluetta® with Smartdot™) integrated in a platform for GH treatment support (the Growzen™ digital health ecosystem). Methods: Participatory workshops were conducted in Rome, Italy, and Seoul, Korea, to collect the perspectives of 22 HCPs on various predefined topics. HCPs were divided into two teams, each moderated by a facilitator. The workshops progressed in five phases: introduction of the project and experts, capturing views on the current context of digitalisation, perceived usefulness and ease of use of Aluetta® with Smartdot™, exploration of the perception of health technology evolution, and combined team recommendations. Data shared by HCPs on technology acceptance were independently analysed using thematic analysis, and relevant findings were shared and validated with experts. Results: HCPs from both Italy and Korea perceived Aluetta® with Smartdot™ and the Growzen™ based digital health ecosystem as user-friendly, intuitive, and easy-to-use solutions. These solutions can result in increased adherence, a costeffective healthcare system, and medication self-management. Although technology adoption and readiness may vary across countries, it was agreed that using digital solutions tailored to the needs of users may help in data-driven clinical decisions and strengthen HCP--patient relationships. Conclusion: HCPs' perspectives on the digitalisation in paediatric GH therapies suggested that digital solutions enable automatic, real-time injection data transmission to support adherence monitoring and evidence-based therapy, strengthen HCP--patient relationships, and empower patients throughout the GH treatment process. [ABSTRACT FROM AUTHOR]

Introduction: Normosmic isolated hypogonadotropic hypogonadism (nIHH) is a clinically and genetically heterogeneous disorder. Deleterious variants in over 50 genes have been implicated in the etiology of IHH, which also indicates a possible role of digenicity and oligogenicity. Both classes of genes controlling GnRH neuron migration/development and hypothalamic/pituitary signaling and development are strongly implicated in nIHH pathogenesis. The study aimed to investigate the genetic background of nIHH and further expand the genotype-phenotype correlation. Methods: A total of 67 patients with nIHH were enrolled in the study. NGS technology and a 38-gene panel were applied. Results: Causative defects regarded as at least one pathogenic/likely pathogenic (P/LP) variant were found in 23 patients (34%). For another 30 individuals, variants of unknown significance (VUS) or benign (B) were evidenced (45%). The most frequently mutated genes presenting P/LP alterations were GNRHR (n = 5), TACR3 (n = 3), and CHD7, FGFR1, NSMF, BMP4, and NROB1 (n = 2 each). Monogenic variants with solid clinical significance (P/LP) were observed in 15% of subjects, whereas oligogenic defects were detected in 19% of patients. Regarding recurrence, 17 novel pathogenic variants affecting 10 genes were identified for 17 patients. The most recurrent pathogenic change was GNRHR: p.Arg139His, detected in four unrelated subjects. Another interesting observation is that P/LP defects were found more often in genes related to hypothalamic-pituitary pathways than those related to GnRH. Conclusions: The growing importance of the neuroendocrine pathway and related genes is drawing increasing attention to nIHH. However, the underestimated potential of VUS variants in IHH etiology, particularly those presenting recurrence, should be further elucidated. [ABSTRACT FROM AUTHOR]

Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) lasts for 5–7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24–48-h periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center. Hibernating ground squirrels have negligible hunger despite a months-long period of food deprivation and cold exposure. Here, authors show that prolonged anorexia is enabled by inhibition of the hypothalamic feeding center due to central hypothyroidism. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is associated with several endocrine disorders, including diabetes, obesity, and primary hypogonadism. Here, we present a man with DS who manifested with atypical hypogonadotropic hypogonadism and in whom weight loss resulted in the improvement of hypothalamic GH deficiency. A 27-year-old man with DS and severe obesity was admitted for hypoxia resulting from obesity hypoventilation syndrome. Laboratory tests showed normal levels of LH and FSH despite low testosterone and free testosterone levels. Moreover, thyroid stimulating hormone and prolactin levels were slightly elevated, although a euthyroid function was observed, and GH and IGF-1 levels were low. Endocrinological stimulation tests revealed hypogonadotropic hypogonadism and hypothalamic GH deficiency. Reduction in body weight by 35.3% resulted in the improvement of the IGF-1, thyroid stimulating hormone, and prolactin levels to the reference range, whereas the LH and FSH levels remained low, despite slight elevation. Levels of leptin, which suppresses the hypothalamus-gonadotroph-gonadal axis and upregulates thyrotropin-releasing hormone expression, decreased with weight loss. Furthermore, ghrelin, whose levels increase with weight loss, stimulates GH secretion. Thus, leptin and ghrelin could have contributed to the observed changes in the pituitary hormone profile after weight loss. [ABSTRACT FROM AUTHOR]

Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)–GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC. [ABSTRACT FROM AUTHOR]

LIM homeobox 4 (LHX4) is a transcription factor crucial for anterior pituitary (AP) development. Patients with LHX4 mutation suffer from combined pituitary hormone deficiency (CPHD), short statures, reproductive and metabolic disorders and lethality in some cases. Lhx4-knockout (KO) mice fail to develop a normal AP and die shortly after birth. Here, we characterize a zebrafish lhx4-KO model to further investigate the importance of LHX4 in pituitary gland development and regulation. At the embryonic and larval stages, these fish express lower levels of tshb mRNA compared with their wildtype siblings. In adult lhx4-KO fish, the expressions of pituitary hormone-encoding transcripts, including growth hormone (gh), thyroid stimulating hormone (tshb), proopiomelanocortin (pomca) and follicle stimulating hormone (fshb), are reduced, the pomca promoter-driven expression in corticotrophs is dampened and luteinizing hormone (lhb)-producing gonadotrophs are severely depleted. In contrast to Lhx4-KO mice, Lhx4-deficient fish survive to adulthood, but with a reduced body size. Importantly, lhx4-KO males reach sexual maturity and are reproductively competent, whereas the females remain infertile with undeveloped ovaries. These phenotypes, which are reminiscent of those observed in CPHD patients, along with the advantages of the zebrafish for developmental genetics research, make this lhx4-KO fish an ideal vertebrate model to study the outcomes of LHX4 mutation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Growth hormone receptor deficiency (GHRD) results in low serum insulin‐like growth factor 1 (IGF1) and high, but non‐functional serum growth hormone (GH) levels in human Laron syndrome (LS) patients and animal models. This study investigated the quantitative histomorphological and molecular alterations associated with GHRD. Pituitary glands from 6 months old growth hormone receptor deficient (GHR‐KO) and control pigs were analyzed using a quantitative histomorphological approach in paraffin (9 GHR‐KO [5 males, 4 females] vs. 11 controls [5 males, 6 females]), ultrathin sections tissue sections (3 male GHR‐KO vs. 3 male controls) and label‐free proteomics (4 GHR‐KO vs. 4 control pigs [2 per sex]). GHR‐KO pigs displayed reduced body weights (60% reduction in comparison to controls; p <.0001) and decreased pituitary volumes (54% reduction in comparison to controls; p <.0001). The volume proportion of the adenohypophysis did not differ in GHR‐KO and control pituitaries (65% vs. 71%; p =.0506) and GHR‐KO adenohypophyses displayed a reduced absolute volume but an unaltered volume density of somatotrophs in comparison to controls (21% vs. 18%; p =.3164). In GHR‐KO pigs, somatotroph cells displayed a significantly reduced volume density of granules (23.5%) as compared to controls (67.7%; p <.0001). Holistic proteome analysis of adenohypophysis samples identified 4660 proteins, of which 592 were differentially abundant between the GHR‐KO and control groups. In GHR‐KO samples, the abundance of somatotropin precursor was decreased, whereas increased abundances of proteins involved in protein production, transport and endoplasmic reticulum (ER) stress were revealed. Increased protein production and secretion as well as significantly reduced proportion of GH‐storing granules in somatotroph cells of the adenohypophysis without an increase in volume density of somatotroph cells in the adenohypophysis could explain elevated serum GH levels in GHR‐KO pigs. [ABSTRACT FROM AUTHOR]

Study Design and Objective: Randomised, double-blind, crossover trial to confirm bioequivalence of somapacitan, a long-acting growth hormone (GH), in 5 mg/1.5 mL and 10 mg/1.5 mL strengths in equimolar doses. Methods: Healthy participants were randomised (1:1:1) to subcutaneous somapacitan treatment in one dosing period with 5 mg/1.5 mL and two periods with 10 mg/1.5 mL. Eligibility criteria included age 18–45 years and body mass index 18.5–24.9 kg/m2. Exclusion criteria included history of GH deficiency, previous GH treatment, weight > 100.0 kg and participation in any clinical trial of an investigational medicinal product within 45 days or five times the half-life of the previous investigational product before screening. Area under the curve from time 0 until last quantifiable observation (AUC0–t), maximum serum concentration (Cmax), time to Cmax and terminal half-life of somapacitan and safety were assessed. Results: In total, 33 participants were randomised. For AUC0–t, estimated treatment ratio (ETR) (5 mg/1.5 mL versus 10 mg/1.5 mL) was 0.95 (90% confidence interval [CI] 0.89–1.01). Point estimate and 90% CIs were within the acceptance range (0.80–1.25). For Cmax, ETR was 0.77 (90% CI 0.68–0.89). Point estimate and 90% CIs were outside the acceptance range (0.80–1.25). Mean insulin-like growth factor-I (IGF-I) and IGF-I standard deviation score concentration–time curves for each strength were almost identical. No new safety issues were identified. Conclusions: Bioequivalence criterion for somapacitan 5 mg/1.5 mL and 10 mg/1.5 mL was met for AUC0–t but not for Cmax. The two strengths had equivalent IGF-I responses. Trial Registration: ClinicalTrials.gov, NCT03905850 (3 April 2019). Plain Language Summary: Somapacitan is a long-acting growth hormone used to treat people with growth hormone deficiency. Somapacitan is injected under the skin with an injection pen. The dose is based on a person's body weight and how they respond to treatment. We compared two strengths of injection pen, containing either 5 or 10 mg of somapacitan per 1.5 mL. For both strengths, participants were given the same dose. We wanted to understand whether the body absorbs these different strengths into the bloodstream in the same way. We also measured levels of insulin-like growth factor-I (IGF-I), a hormone formed when growth hormone is present in the blood, to see the effect of different strengths of somapacitan on the body. In our study, 33 healthy adults received one round of injection using the somapacitan 5 mg pen and two rounds using the somapacitan 10 mg pen, all at least 3 weeks apart. We found no differences in the amount of somapacitan being absorbed into the bloodstream, nor how fast it was absorbed. The peak amount of somapacitan in the bloodstream was higher in people using the 10 mg pen. There were no differences in IGF-I levels following use of either injection pen. Overall, our results show both strengths of somapacitan lead to similar responses in the body. Having different strength options could allow doctors to adjust the dose of somapacitan more easily, depending on a patient's response to treatment. [ABSTRACT FROM AUTHOR]

This article provides a list of scientific articles that examine the role of growth hormone-releasing hormone (GHRH) in inflammation and redox biology. Chronic inflammation and oxidative stress are linked to cancer development and severity. GHRH and its receptors are found in various cancers and may act as growth factors. GHRH antagonists have shown promise in inhibiting tumor growth and exerting anti-inflammatory and antioxidative effects. The articles also discuss the potential therapeutic applications of GHRH antagonists in cancer treatment and the involvement of other factors such as P53 and transcription factor 6. [Extracted from the article]

Introduction: Craniopharyngiomas (CPs) are benign brain tumors accounting for 5 - 11% of intracranial tumors in children. These tumors often recur and can cause severe morbidity. Postoperative radiotherapy efficiently controls and prevents progression and recurrence. Despite advancements in neurosurgery, endocrinological, visual, and neuropsychological complications are common and significantly lower the quality of life of patients. Methods: We performed a retrospective study, including all patients younger than sixteen diagnosed with CP between July 1989 and August 2022 and followed up in Hôpital Universitaire de Bruxelles. Results: Nineteen children with CP were included, with median age of 7 years at first symptoms and 7.5 at diagnosis. Common symptoms at diagnosis were increased intracranial pressure (63%), visual impairment (47%), growth failure (26%), polyuria/polydipsia (16%), and weight gain (10.5%). As clinical signs at diagnosis, growth failure was observed in 11/18 patients, starting with a median lag of 1 year and 4 months before diagnosis. On ophthalmological examination, 27% of patients had papillary edema and 79% had visual impairment. When visual disturbances were found, the average preoperative volume was higher (p=0.039). Only 6/19 patients had gross total surgical resection. After the first neurosurgery, 83% experienced tumor recurrence or progression at a median time of 22 months. Eleven patients (73%) underwent postsurgical radiotherapy. At diagnosis, growth hormone deficiency (GHD) was the most frequent endocrine deficit (8/17) and one year post surgery, AVP deficiency was the most frequent deficit (14/17). Obesity was present in 13% of patients at diagnosis, and in 40% six months after surgery. There was no significant change in body mass index over time (p=0.273) after the first six months post-surgery. Conclusion: CP is a challenging brain tumor that requires multimodal therapy and lifelong multidisciplinary follow-up including hormonal substitution therapy. Early recognition of symptoms is crucial for prompt surgical management. The management of long-term sequelae and morbidity are crucial parts of the clinical path of the patients. The results of this study highlight the fundamental importance of carrying out a complete assessment (ophthalmological, endocrinological, neurocognitive) at the time of diagnosis and during follow-up so that patients can benefit from the best possible care. [ABSTRACT FROM AUTHOR]

Purpose: The impact of delayed diagnosis on tumor-related prognosis appears to be minimal in individuals with intracranial germ cell tumors (iGCTs). However, its effect on neuroendocrine functions remains unclear. We aimed to assess the effects of delayed diagnosis on neuroendocrine function in individuals with suprasellar GCTs. Methods: We conducted a retrospective cohort study of 459 individuals with suprasellar GCTs and categorized them into two groups based on disease duration: delayed diagnosis (> 6 months) and non-delayed diagnosis (= 6 months). We compared endocrinological symptoms, neuroendocrine dysfunction and its grading (categorized into 0-3 grades based on severity), and recovery from neuroendocrine dysfunction in both groups. Results: Patients with delayed diagnosis exhibited higher incidences of amenorrhea, slow growth, fatigue, and polyuria/polydipsia. Neuroendocrine dysfunction, including central adrenal insufficiency (CAI), central hypothyroidism (CHT), arginine vasopressin deficiency (AVP-D), growth hormone deficiency, hypogonadism, and hyperprolactinemia, was more pronounced in the delayed diagnosis group at diagnosis, the end of treatment, and the last follow-up. Furthermore, individuals with delayed diagnosis showed higher grades of neuroendocrine dysfunction at diagnosis (OR=3.005, 95% CI 1.929-4.845, p<0.001), end of oncologic treatment (OR=4.802, 95% CI 2.878-8.004, p<0.001), and last follow-up(OR=2.335, 95% CI 1.307-4.170, p=0.005) after adjusting for confounders. Finally, less recovery, particularly in CAI, CHT, and AVP-D, was seen among the group with delayed diagnosis after treatment. Conclusion: Among individuals with suprasellar GCTs, delayed diagnosis is associated with increased, more severe, and less recovered neuroendocrine dysfunction, emphasizing the importance of early diagnosis and treatment to reduce neuroendocrine dysfunction. [ABSTRACT FROM AUTHOR]

Sirtuin 1 (SIRT1) inhibits growth hormone (GH) intracellular signaling for the insulin-like growth factor 1 (IGF-1) synthesis via the janus kinase (JAK)/signal transducer and activator of transcription proteins (STATs) pathway. The aim of this study was to compare SIRT1 concentrations in children with GH deficiency (GHD) and so-called idiopathic short stature (ISS, non-GH deficient), in order to determine the possible impact of changes in serum SIRT1 concentrations on the GH-IGF-1 axis. The study group included 100 short-stature children: 38 with GHD and 62 with ISS (maxGH in two stimulation tests <10 and ≥10 ng/mL, respectively). The control group consisted of 47 healthy, normal-height children. For each child, the concentrations of SIRT1, IGF-1 and insulin-like growth factor-binding protein 3 (IGFBP-3) were determined and the IGF-1/IGFBP-3 molar ratio was calculated. The level of SIRT1 was significantly higher in both groups of short children than in the controls (p < 0.0001), but there were no differences between GHD and ISS (mean ± SD: 0.89 ± 0.45 for ISS; 1.24 ± 0, 86 for GHD; and 0.29 ± 0.21 for controls). A significant negative correlation was found between SIRT1 and height standard deviation score (SDS), IGF-1 and IGF-1/IGFBP-3, but not between SIRT1 and maxGH. Elevated SIRT1 levels may serve as one of the mechanisms through which the secretion of IGF-1 is reduced in children with short stature; however, further research is required to confirm this issue. [ABSTRACT FROM AUTHOR]

Objective: During the process of transition from paediatric to adult health care, counselling concerning fertility is an important issue and is based mainly on serum markers of gonadal function. Here, we analysed these markers in adolescents with various underlying endocrine diseases at the time of transition. Methods: After reaching near adult height and late puberty (girls: bone age [BA] ≥14 years, and boys: BA ≥16 years), we assessed stages of puberty according to Tanner and measured testes or ovarian volumes and serum markers of gonadal function (anti‐Mullerian hormone [AMH], inhibin B, 17β‐estradiol, testosterone). Results: One hundred and ten patients (56 females and 54 males) were included from May 2010 to March 2016 with multiple pituitary hormone deficiency (MPHD; n = 17), growth hormone deficiency (GHD; n = 35), Turner syndrome (TS; n = 27), short stature after being born small for gestational age (SGA; n = 20) and Klinefelter syndrome (KS; n = 11). Female and male adolescents exhibited mature secondary sexual characteristics. The levels of serum inhibin B and AMH were lower in TS and female MPHD than in GHD and SGA, each independently (p < 0.05). The levels of serum AMH were higher whereas serum inhibin B were lower in male MPHD and KS (p < 0.05). Ovary volumes were significantly smaller in patients with TS, and testicular volumes were smaller in patients with KS. Conclusions: After current established treatments with sex steroids, the development of secondary sexual characteristics was mature. However, impaired markers of fertility have been identified in patients with TS, KS and MPHD, reflecting gonadal dysgenesis in TS and KS, but gonadal immaturity in MPHD as gonadal gonadotropin stimulation is lacking throughout development. Consequently, in patients with MPHD, these markers cannot reliably predict individual fertility, which warrants consideration and incorporation in future treatment concepts. [ABSTRACT FROM AUTHOR]

Acromegaly is a rare endocrine disorder caused by hypersecretion of growth hormone (GH) from a pituitary adenoma. Elevated GH levels stimulate excess production of insulin-like growth factor 1 (IGF-1) which leads to the insidious onset of clinical manifestations. The most common primary central nervous system (CNS) tumors, meningiomas originate from the arachnoid layer of the meninges and are typically benign and slow-growing. Meningiomas are over twice as common in womenas inmen, withage-adjusted incidence(per 100,000individuals)of 10.66and 4.75, respectively. Several reports describe co-occurrence of meningiomas and acromegaly. We aimed to determine whether patients with acromegaly are at elevated risk for meningioma. Investigation of the literature showed that cooccurrence of a pituitary adenoma and a meningioma is a rare phenomenon, and themajority of cases involve GH-secreting adenomas. To the best of our knowledge, a systematic review examining the association between meningiomas and elevated GH levels (due to GH-secreting adenomas in acromegaly or exposure to exogenous GH) has never been conducted. The nature of the observed coexistence between acromegaly and meningioma -whether it reflects causation or mere co-association -is unclear, as is the pathophysiologic etiology. [ABSTRACT FROM AUTHOR]

Partial or complete deficiency of anterior or posterior pituitary hormone production leads to central hypoadrenalism, central hypothyroidism, hypogonadotropic hypogonadism, growth hormone deficiency, or arginine vasopressin deficiency depending on the hormones affected. Hypopituitarism is rare and likely to be underdiagnosed, with an unknown but rising incidence and prevalence. The most common cause is compressive growth or ablation of a pituitary or hypothalamic mass. Less common causes include genetic mutations, hypophysitis (especially in the context of cancer immunotherapy), infiltrative and infectious disease, and traumatic brain injury. Clinical features vary with timing of onset, cause, and number of pituitary axes disrupted. Diagnosis requires measurement of basal circulating hormone concentrations and confirmatory hormone stimulation testing as needed. Treatment is aimed at replacement of deficient hormones. Increased mortality might persist despite treatment, particularly in younger patients, females, and those with arginine vasopressin deficiency. Patients with complex diagnoses, pregnant patients, and adolescent pituitary-deficient patients transitioning to adulthood should ideally be managed at a pituitary tumour centre of excellence. [ABSTRACT FROM AUTHOR]

Objective: Postoperative nonfunctioning pituitary tumor (NFPT) regrowth is a significant concern, but its predictive factors are not well established. This study aimed to elucidate the pathological characteristics of NFPTs indicated for reoperation for tumor regrowth. Methods: Pathological, radiological, and clinical data were collected from patients who underwent repeat operation for NFPT at Moriyama Memorial Hospital (MMH) between April 2018 and September 2023. For comparison, we also gathered data from patients who underwent initial surgery for NFPT during the same period at MMH. Results: Overall, 61 and 244 NFPT patients who respectively underwent reoperation and initial operation were evaluated. The mean period between the previous operation and reoperation was 113 months. Immunonegativity for any adenohypophyseal hormone was significantly more frequent in the reoperation group than in the initial operation group. In addition, the rate of hormone-negative but transcription factor-positive (H-/TF+) tumors among silent gonadotroph tumors was significantly higher in the reoperation group than in the initial operation group. Furthermore, seven silent corticotroph tumors (SCTs) in the reoperation group were ACTH-negative but TPIT-positive. Because most of the previous surgeries were performed in other hospitals a long time ago, we could procure the previous pathological results with immunohistochemistry (IHC) only from 21 patients. IHC for TF had not been performed in all the previous specimens. IHC for adenohypophyseal hormone was almost the same as the current results, and many H-/TF+ tumors were previously diagnosed as NCT. In addition, the reoperated patients were classified into 3 groups on the basis of the condition of the previous operation: gross total resection (GTR), 12 patients; subtotal resection (STR), 17 patients; and partial resection (PR), 32 patients. The mean Ki-67 LI in the GTR, STR, and PR subgroups were 1.82, 1.37, and 0.84, respectively, with the value being significantly higher in the GTR subgroup than in the PR subgroup (P < 0.05). Conclusions: The ratio of H-/TF+ tumors is significantly higher in symptomatically regrown tumors than in the initial cases, which used to be diagnosed as NCT. PR cases tend to grow symptomatically in a shorter period, even with lower Ki-67 LI than GTR cases. [ABSTRACT FROM AUTHOR]

Background: Pituitary adenomas comprise clinical and pathological characteristics of functional and non-functional subtypes. To enhance our understanding of diagnostic presentations, our study aimed to know the clinicopathological characteristics of pituitary adenomas of both functional and non-functional subtypes. The purpose of our study was to investigate the clinicopathological characteristics of pituitary adenomas, including demographic characteristics, clinical presentations, hormone secretion patterns, invasiveness, and cellular characteristics. Methods: A total of 41 cases of pituitary adenomas were analyzed, with 63.4% classified as non-functional adenomas (NFPA) and 36.6% as functional adenomas (FPA). Clinical presentations vary, with vision loss and headaches commonly occurring in both NFPA and FPA. In FPAs, serum hormone levels varied and were categorized into growth hormone-secreting (53.3%), ACTH-secreting (26.7%), PRL-secreting (13.3%), and FSH-secreting (6.7%) subtypes. Moreover, clinical presentations in FPA included diplopia, giddiness, vomiting, ptosis, and limb weakness. Clinical features varied across subtypes, with acromegaly in growth hormone-secreting adenomas, moon facies and weight gain in ACTH-secreting adenomas, poor facial growth in PRL-secreting adenomas, and vision loss in FSH-secreting adenomas. Meanwhile, NFPA were predominantly macroadenomas (88.5%) and exhibited various morphological patterns. Results: The proliferation index is higher in functional adenomas (mean 1.32) as compared to non-functional (mean 0.91). Clinical presentations varied across functional and non-functional adenomas. Growth hormone-secreting adenomas were the most common functional subtype, while LH and null cell adenomas were common non-functional subtypes. Two cases were invasive adenomas with a low Ki67 index. Sheets were the most common morphological pattern. PCA analysis revealed significant differences between the two groups, with PC 1 explaining 92.111% of the variance. Conclusions: Our study elucidates the clinicopathological characteristics of pituitary adenomas, highlighting significant differences between functional and non-functional subtypes. These findings underscore the importance of tailored diagnostic and management strategies to optimize outcomes for patients with pituitary adenomas. [ABSTRACT FROM AUTHOR]

Children who receive cranial radiation therapy (RT) as a component of treatment for malignancy are often at risk of long-term central endocrine toxicity secondary to radiation to the hypothalamic-pituitary axis (HPA). A comprehensive analysis was performed of central endocrine late effects in survivors of childhood cancer treated with RT as part of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium. A systematic review of the risk of RT-related central endocrine effects was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of 4629 publications were identified, of which 16 met criteria for inclusion in dose modeling analysis, with a total of 570 patients in 19 cohorts. Eighteen cohorts reported outcomes for growth hormone deficiency (GHD), 7 reported outcomes for central hypothyroidism (HT), and 6 reported outcomes for adrenocorticotropic hormone (ACTH) deficiency. Normal tissue complication probability modeling for GHD (18 cohorts, 545 patients) yielded D 50 = 24.9 Gy (95% CI, 20.9-28.0) and γ 50 = 0.5 (95% CI, 0.27-0.78). The normal tissue complication probability model fit for whole brain irradiation in children with a median age of >5 years indicated a 20% risk of GHD for patients who receive a mean dose of 21 Gy in 2-Gy fractions to the HPA. For HT, among 7 cohorts (250 patients), D 50 = 39 Gy (95% CI, 34.1-53.2) and γ 50 = 0.81 (95% CI, 0.46-1.35), with a 20% risk of HT in children who receive a mean dose of 22 Gy in 2-Gy fractions to the HPA. For ACTH deficiency (6 cohorts, 230 patients), D 50 = 61 Gy (95% CI, 44.7-119.4) and γ 50 = 0.76 (95% CI, 0.5-1.19); there is a 20% risk of ACTH deficiency in children who receive a mean dose of 34 Gy in 2-Gy fractions to the HPA. RT dose to the HPA increases the risk of central endocrine toxicity, including GHD, HT, and ACTH deficiency. In some clinical situations, these toxicities may be difficult to avoid, and counseling of patients and families with respect to anticipated outcomes is important. [ABSTRACT FROM AUTHOR]

Background and Objective Surgery is the treatment of choice for growth hormone (GH)-secreting pituitary adenoma. The remission of random GH depends on various factors. We aimed to evaluate the predictors related to remission of random GH following surgical treatment. Methods We collected the data retrospectively from the chart review from a single unit of neurosurgery. The diagnostic criteria for remission were a random GH < 1 ng/mL or nadir GH < 0.4 ng/mL after an oral glucose tolerance test. Results Data from a total of 110 (females 62 [56.4%]) patients were available for follow-up and were analyzed. The mean age was 36.5 years (14–69 years). Vision impairments were seen in 39 (35.5%) patients. The mean duration of symptoms before surgery was 34 months. The mean volume of the tumor was 7.2 mL (0.44–109.8 mL). Knosp grade 3 and 4 tumors were seen in 41.5% of cases. The mean preoperative random GH level was 68.9 ng/mL. Transsphenoidal surgery was done in 107 (97.3%) cases. The gross total resection could be done in 36 (32.7%) cases. At 3 months, 25 (26%) patients had a biochemical remission. In univariable analysis, lower Knosp grade, preoperative GH level < 40 ng/mL, gross total resection, and male gender were associated with remission at 3 months. In regression analysis, preoperative GH and male gender were related to remission at 3 months. Conclusion The preoperative GH level < 40 ng/mL is associated with higher chances of remission after surgery for GH-secreting pituitary adenoma. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]