Growth Hormone Deficiency Research Articles

Efficacy and Safety of Somapacitan Relative to Somatrogon and Lonapegsomatropin in Pediatric Growth Hormone Deficiency: Systematic Literature Review and Network Meta-analysis.

Since direct comparisons of long-acting growth hormones (LAGHs) are lacking, analyses were performed to indirectly compare the efficacy and safety of somapacitan versus somatrogon and lonapegsomatropin in children with growth hormone deficiency (GHD). A systematic literature review (SLR) identified studies of once-weekly LAGHs for the treatment of pediatric GHD. Indirect comparisons (ICs) using a Bayesian hierarchical network meta-analysis and a random effects model were performed using daily growth hormone (GH) 0.034mg/kg/day (base case) or 0.024-0.034mg/kg/day (alternative analyses) as the common comparator to compare height outcomes to 52weeks [annualized height velocity, height velocity standard deviation score (SDS), and height SDS]. Identified evidence did not allow IC of safety or longer-term efficacy outcomes so these were qualitatively described. The SLR identified two somapacitan trials, three somatrogon trials (one included in alternative analyses only), and one lonapegsomatropin trial comparing the LAGH with daily GH in treatment-naïve pre-pubertal children for IC. ICs revealed no differences at 52weeks between somapacitan versus somatrogon and lonapegsomatropin, as well as daily GH, with respect to all growth outcomes considered in children with GHD. All three LAGHs had sustained efficacy and were generally well tolerated, with comparable efficacy and safety to daily GH, with the exception of observed injection site pain for somatrogon. No efficacy and safety differences were identified in comparisons of once weekly somapacitan versus somatrogon and lonapegsomatropin, as well as daily GH. All treatments were generally well tolerated, with the exception of observed injection site pain for somatrogon.

The effect of 30 min of supine rest on plasma renin concentrations in paediatric patients.

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. 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. 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. 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.

Elucidating the relationship between blood glucose dynamics and growth hormone responses in glucagon stimulation tests among children with short stature

Introduction: The use of glucagon as a provocative agent for growth hormone (GH) assessment is a cornerstone in pediatric endocrinology. Glucagon's role as a GH secretagogue is integral to growth hormone stimulation tests (GHSTs), which diagnose suspected GH deficiency (GHD) in children. These tests are crucial for assessing the hypothalamic-pituitary-adrenal (HPA) axis's integrity. Despite its prevalent use, the exact mechanisms by which glucagon prompts GH release and the impact of ensuing blood glucose (BG) fluctuations are not fully understood. Objectives: This study aims to explore the relationship between GH and BG levels in children with short stature following glucagon administration. Patients and Methods: A retrospective cohort study involved 42 pediatric patients, aged 6 to 11, with short stature. We analyzed GH and BG levels before and after intramuscular glucagon Simulation test (GST). Blood samples were taken at baseline and multiple intervals post-injection. Results: The results revealed that the mean glucose peaked at 60 minutes and declined to a nadir at 120 minutes, which corresponded with a significant rise in GH levels. GH concentrations peaked at 120 minutes post-injection, with 31% of children showing peak GH levels of less than 7 μg/L. Notably, the study found an inverse correlation between BG and GH at peak glucose times, suggesting a complex interplay between glucose dynamics and GH response. Discussion: Our findings indicate a dynamic interrelation between BG and GH post-glucagon injection, challenging traditional interpretations of GST results. The study reinforces the notion that GHST results should be interpreted with consideration of patient-specific factors such as BMI to ensure accurate evaluation of GH reserve and subsequent clinical decision-making. Conclusion: The study corroborates the dynamic nature of GH and glucose responses following glucagon administration and highlights the need for personalized approaches in interpreting GHSTs. Further investigation is warranted to elucidate the mechanisms influencing this complex relationship, which is crucial for accurate diagnosis and management of GHD in children.

Baseline Clinical Factors Associated with Cessation of Growth Hormone Therapy in Patients with Severe Growth Hormone Deficiency - Real World Evidence

Background: Growth hormone replacement is indicated in adults with severe growth hormone (GH) deficiency, adult growth hormone deficiency assessment (AGHDA) score of at least 11 and are receiving treatment for other pituitary hormone deficiencies. There are no data looking at the cessation of GH replacement in adult patients with severe GH deficiency and the factors that predict the likelihood of patients continuing or stopping growth hormone replacement. Methods: We audited patients on the GH register between January 2006 and January 2023 in Hull University Teaching Hospitals NHS foundation Trust, a UK tertiary hospital. Baseline characteristics, the cause of GH deficiency, AGHDA score at diagnosis and the reason for stopping GH were collected. Proportions were compared between patients adhering to GH replacement and those who had ceased it. Logistic regression analysis was used to identify factors independently associated with cessation of GH. Results: The study comprised 141 adult patients with a mean age of 52 years, of which 75 (53%) were female. 54 (38%) individuals had discontinued GH replacement therapy. Predominant reasons for discontinuation were lack of therapeutic benefit (46%) and a change in clinical indication (26%). Among patients who discontinued GH therapy, the most frequent cause of GH deficiency was idiopathic (57%), while for those on GH replacement, pituitary surgery was the leading cause of GH deficiency (53%). Logistic regression analysis showed no baseline factor was statistically significantly associated with GH cessation, except female gender which had a borderline significance (P = 0.05). Conclusions: In this real-world investigation of patients with severe GH deficiency, over two in five individuals who discontinued GH therapy cited the absence of perceived benefits. We show a borderline association of female gender with GH cessation and large population-based studies will be needed to investigate this and other causes of GH cessation.

The Enigma That Is ROHHAD Syndrome: Challenges and Future Strategies

Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is a rare syndrome presenting in early childhood associated with a high risk of mortality between 50 and 60%. It is characterised by rapid, early onset of obesity between 1.5–7 years, along with central hypoventilation and hypothalamic dysfunction, such as central hypothyroidism, hyperprolactinemia, disorders of sodium and water balance, growth hormone deficiency, adrenocortical insufficiency, or disorders of puberty and features of autonomic dysregulation. Up to half of cases have neural crest tumours, most commonly ganglioneuromas or ganglioneuroblastomas. The incidence of ROHHAD syndrome in any population is unknown. Currently, there is no specific diagnostic or genetic biomarker for ROHHAD, and diagnosis is based on clinical signs and symptoms, which is often challenging, and consequently may be delayed or unrecognised. Early diagnosis is important, as without intervention, ROHHAD is associated with high morbidity and mortality. Aetiology remains unclear; an autoimmune origin has been postulated, with immunosuppressive agents being used with variable benefit. With no cure, multidisciplinary management is largely supportive. Therefore, there are many unanswered questions in ROHHAD syndrome. In this review article, we outline the challenges posed by ROHHAD syndrome, including aetiology, genetics, diagnosis, screening, management, and prognosis. We present research priorities to tackle these issues to improve outcomes.

Long-term effectiveness and safety of long-acting growth hormone preparation in children with growth hormone deficiency.

To evaluate the long-term effectiveness of weekly vs. daily growth hormone (GH) administration in children with GH deficiency. This study, part of the "LG Growth Study", included a total of 996 children with GH deficiency (773 receiving daily GH and 193 receiving weekly GH). Anthropometric data were collected at baseline and every 12months; clinical and laboratory data were collected at baseline and throughout the study. At baseline, the weekly GH group was older, shorter in mid-parental height (MPH), and had more pubertal boys compared to the daily GH group (age: 8.46±3.44 vs. 7.46±2.89 years, p<0.001; MPH:-0.88±0.73 SD vs.-1.02±0.84 SD, p=0.044; pubertal boys: 34.0 vs. 16.9 %, p=0.006). Height velocity and change in height SDS during the first 12months were higher in the daily GH group (height velocity: 9.06±1.72 vs. 8.67±1.98 cm/year, p=0.028; height SDS change: 0.78±0.39 vs. 0.61±0.41, p<0.001). However, height SDS at 24 and 48months were similar between groups. No significant differences in overall height velocity, annualized treatment continuation rate, and safety profile were observed over 48months. Weekly GH therapy appears to be an effective and safe alternative to daily GH treatment in children with GH deficiency over a 4-year period. Further research with larger sample sizes and longer follow-up is needed to confirm these findings and assess the extended safety and effectiveness of LAGH.

Hsa_circ_0002473 inhibits GH3 cell proliferation and GH secretion as a competitive endogenous RNA for has-miR-4645-3p.

Growth hormone deficiency (GHD) diagnosis still lacks a gold standard or ideal diagnostic marker. Unlike other epigenetic mechanisms, non-coding RNAs regulate post-transcriptional levels. The information on non-coding RNAs in the field of GHD is limited. Therefore, this study aimed to explore the role of hsa_circ_0002473 as a competitive endogenous RNA for has-miR-4645-3p in attenuating the inhibitory effect of has-miR-4645-3p on SSTR2. In this study, we screened three significantly expressed circular RNAs (circRNAs) in five children with GHD, and selected the highest expressed hsa_circ_0002473 as the study object, and screened has-miR-4645-3p, which is the most likely to bind to hsa_circ_0002473, according to the microRNA (miRNA)-circRNA regulatory network, to study the role and mechanism of has-miR-4645-3p as a competitive endogenous RNA of has-miR-4645-3p on GH3 cells. Somatostatin receptor 2 (SSTR2) inhibits GH3 cell proliferation, and miRNA binding to SSTR2 inhibits the latter expression. Both bioinformatics and dual-luciferase reporter analyses showed targeting relationships between hsa_circ_0002473 and has-miR-4645-3p and between has-miR-4645-3p and SSTR2. We constructed the hsa_circ_0002473/has-miR-4645-3p axis and transfected it into GH3 cells and found that overexpression of hsa_circ_0002473 inhibited the proliferation and growth hormone (GH) secretion of GH3 cells, and that hsa-miR-4645-3p promoted the proliferation and GH secretion of GH3 cells by targeting SSTR2. Co-culture revealed that the inhibitory effect of hsa_circ_0002473 was reversed by has-miR-4645-3p. In conclusion, our findings suggest that hsa_circ_0002473 can act as a competitive endogenous RNA for has-miR-4645-3p to regulate GH3 cell proliferation and secretion by targeting SSTR2.

Gene and transcript expression patterns, coupled with isoform switching and long non-coding RNA dynamics in adipose tissue, underlie the longevity of Ames dwarf mice.

Our study investigates gene expression in adipose tissue of Ames dwarf (df/df) mice, whose deficiency in growth hormone is linked to health and extended lifespan. Recognizing adipose tissue influence on metabolism, aging, and related diseases, we aim to understand its contribution to the health and longevity of df/df mice. We have identified gene and transcript expression patterns associated with critical biological functions, including metabolism, stress response, and resistance to cancer. Intriguingly, we identified genes that,despite maintaining unchanged expression levels, switch between different isoforms, impacting essential cellular functions such as tumor suppression, oncogenic activity, ATP transport, and lipid biosynthesis and storage. The isoform switching is associated with changes in protein domains, retention of introns, initiation of nonsense-mediated decay, and emergence of intrinsically disordered regions. Moreover, we detected various alternative splicing events that may drive these structural alterations. We also found changes in the expression of long non-coding RNAs (lncRNAs) that may be involved in the aging process and disease resistance by regulating crucial genes in survival and metabolism. Through weighted gene co-expression network analysis, we have linked four lncRNAs with 29 genes, which contribute to protein complexes such as the Mili-Tdrd1-Tdrd12 complex. Beyond safeguarding DNA integrity, this complex also has a wider impact on gene regulation, chromatin structure, and metabolic control. Our detailed investigation provides insight into the molecular foundations of the remarkable health and longevity of df/df mice, emphasizing the significance of adipose tissue in aging and identifying new avenues for health-promoting therapeutic strategies.

A 2024 Update on Growth Hormone Deficiency Syndrome in Adults: From Guidelines to Real Life.

Background: Adult growth hormone deficiency (GHD) has been recognized since the late 1980s. The clinical manifestations of adult GHD are often nonspecific, and diagnosis relies on GH stimulation tests, which are intricate, costly, time-consuming, and may carry the risk of adverse effects. Diagnosis is further complicated by factors like age, sex, and BMI, which affect GH response during testing. Therefore, GH replacement therapy remains challenging, requiring careful individualized evaluation of risks and benefits. The aim of this review is to provide an update on diagnosing and treating adult GHD, addressing current limitations and challenges based on recent studies. Methods: We conducted a comprehensive review of the literature regarding the diagnosis and management of adult GHD by searching PubMed and EMBASE. Only articles in English were included, and searches were conducted up to August 2024. Results: A review of guidelines and literature up to 2024 highlights the significant heterogeneity in the data and reveals various protocols for managing GHD, covering both diagnostic and therapeutic approaches. Conclusions: Despite diagnostic and treatment advances, managing adult GHD remains challenging due to variable presentation and the need for personalized GH therapy. Future efforts should aim to improve and standardize diagnostic and treatment protocols.

Sex Difference in Paediatric Growth Hormone Deficiency: Fact or Fiction?

Sex Difference in Paediatric Growth Hormone Deficiency: Fact or Fiction?

The clinical and genetic aspects of six individuals with GH1 variants and isolated growth hormone deficiency type II.

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. This study aimed to identify causative variants in six Chinese families with IGHD II, exploring both clinical and genetic characteristics. Detailed clinical data, including clinical presentations, physical charateristics, medical and family histories, as well as genetic test results, were systematically examined. 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. Our findings contribute to expanding the genotypic and phenotypic spectra of individuals with IGHD II.

7394 Testicular Function in Young Adults with Growth Hormone (GH) Deficiency Previously Treated with GH: Comparison with Normal Controls

Abstract Disclosure: R. Cannarella: None. A. Crafa: None. S. Sapienza: None. M.M. Caruso: None. A.E. Calogero: None. Background: We have previously reported that treatment with recombinant human growth hormone (rhGH) can influence testicular growth and puberty onset in children with GH deficiency (GHD), and suggested GH as a determinant of testicular growth in childhood (doi: 10.3389/fendo.2021.619895). Limited evidence is available on testicular function in post-pubertal GHD patients. Objective: This prospective controlled study was undertaken to evaluate testicular function in young GHD adults previously undergone to GH treatment. Patients and Methods: Post-pubertal patients with non-syndromic GHD (&amp;gt;18 years), in whom GH therapy was discontinued after reaching the therapeutic goal, were required to have a complete evaluation of testicular function. Those who agreed were enrolled in our study. Age-matched healthy men older than 18 years served as controls. Exclusion criteria were: the presence of varicocele, urogenital infections, cryptorchidism, hypospadias, hypogonadism, testicular trauma or torsion, and other congenital or acquired disorders capable of interfering with testicular function. The study outcomes were: serum gonadotropins and total testosterone (TT), conventional sperm parameters, and testicular volume (TV) measured by ultrasound examination. Between-group analysis was performed using the Student’s t-test for independent samples or the Mann-Whitney test, for normally or non-normally distributed variables, respectively. Data were reported as mean±standard deviation for non-skewed data and median (interquartile range) for skewed data. Results: 26 patients with GHD and 25 age-matched controls (18.8±3.3 years vs. 20.1±3.6 years; p=0.18) were enrolled. Patients and controls did not differ for serum luteinizing hormone [2.6 (1.5-4.9) IU/L vs. 3.5 (2.8-4.8) IU/L); p=0.2], follicle-stimulating hormone [3.4 (2.2-4.3) IU/L vs. 3.1 (2.3-4.3) IU/L); p=1.0], and TT [5.7 (4.7-6.8) ng/dL vs. 6.0 (5.1-7.4) ng/dL); p=0.4] levels. At semen analysis, GHD patients had lower semen volume (2.1±1.4 mL vs. 3.5±1.5 mL; p=0.002), total sperm count [135.0 miL/ejaculate (54.3-229.0) vs. 231.3 miL/ejaculate (124.8-285.0); p=0.03], progressive motility [25.5% (15.0-34.0%) vs. 32.0% (30.0-36.5); p=0.02], and total motility [56.0% (49.0-62.0) vs. 66.5% (62.5-70.0); p=0.0001] compared to controls. No difference was found in sperm concentration [73.0 miL/mL (45.0-92.0) vs. 68.0 miL/mL (39.0-90.0); p=1.0] and normal morphology [8.5% (7.0-12.0) % vs. 10.0% (7.5-14.0); p=0.3]. Importantly, GHD patients had lower right (13.3±3.4 mL vs. 16.9±4.1 mL; p=0.001) and left (12.5±3.4 mL vs. 16.3±3.8 mL; p=0.0005) TV. Conclusion: This study provides the first evidence of lower TV and slightly worse semen parameters in patients with GHD compared to healthy controls. Serum GH levels during growth may be important for achieving normal testicular volume and spermatogenesis in adulthood. Presentation: 6/2/2024

9277 Testicular Function in Young Adults with Growth Hormone (GH) Deficiency Previously Treated with GH: Comparison with Normal Controls

Abstract Disclosure: R. Cannarella: None. A. Crafa: None. S. Sapienza: None. M.M. Caruso: None. A.E. Calogero: None. Background: We have previously reported that treatment with recombinant human growth hormone (rhGH) can influence testicular growth and puberty onset in children with GH deficiency (GHD), and suggested GH as a determinant of testicular growth in childhood (doi: 10.3389/fendo.2021.619895). Limited evidence is available on testicular function in post-pubertal GHD patients. Objective: This prospective controlled study was undertaken to evaluate testicular function in young GHD adults previously undergone to GH treatment. Patients and Methods: Post-pubertal patients with non-syndromic GHD (&amp;gt;18 years), in whom GH therapy was discontinued after reaching the therapeutic goal, were required to have a complete evaluation of testicular function. Those who agreed were enrolled in our study. Age-matched healthy men older than 18 years served as controls. Exclusion criteria were: the presence of varicocele, urogenital infections, cryptorchidism, hypospadias, hypogonadism, testicular trauma or torsion, and other congenital or acquired disorders capable of interfering with testicular function. The study outcomes were: serum gonadotropins and total testosterone (TT), conventional sperm parameters, and testicular volume (TV) measured by ultrasound examination. Between-group analysis was performed using the Student’s t-test for independent samples or the Mann-Whitney test, for normally or non-normally distributed variables, respectively. Data were reported as mean±standard deviation for non-skewed data and median (interquartile range) for skewed data. Results: 26 patients with GHD and 25 age-matched controls (18.8±3.3 years vs. 20.1±3.6 years; p=0.18) were enrolled. Patients and controls did not differ for serum luteinizing hormone [2.6 (1.5-4.9) IU/L vs. 3.5 (2.8-4.8) IU/L); p=0.2], follicle-stimulating hormone [3.4 (2.2-4.3) IU/L vs. 3.1 (2.3-4.3) IU/L); p=1.0], and TT [5.7 (4.7-6.8) ng/dL vs. 6.0 (5.1-7.4) ng/dL); p=0.4] levels. At semen analysis, GHD patients had lower semen volume (2.1±1.4 mL vs. 3.5±1.5 mL; p=0.002), total sperm count [135.0 miL/ejaculate (54.3-229.0) vs. 231.3 miL/ejaculate (124.8-285.0); p=0.03], progressive motility [25.5% (15.0-34.0%) vs. 32.0% (30.0-36.5); p=0.02], and total motility [56.0% (49.0-62.0) vs. 66.5% (62.5-70.0); p=0.0001] compared to controls. No difference was found in sperm concentration [73.0 miL/mL (45.0-92.0) vs. 68.0 miL/mL (39.0-90.0); p=1.0] and normal morphology [8.5% (7.0-12.0) % vs. 10.0% (7.5-14.0); p=0.3]. Importantly, GHD patients had lower right (13.3±3.4 mL vs. 16.9±4.1 mL; p=0.001) and left (12.5±3.4 mL vs. 16.3±3.8 mL; p=0.0005) TV. Conclusion: This study provides the first evidence of lower TV and slightly worse semen parameters in patients with GHD compared to healthy controls. Serum GH levels during growth may be important for achieving normal testicular volume and spermatogenesis in adulthood. Presentation: 6/2/2024

6369 Weiss-Kruszka Syndrome and Growth Hormone Deficiency, Adrenal Insufficiency, and Morbid Obesity

Abstract Disclosure: T. Falcon-Rodriguez: None. N. Solano: None. A. Diaz: None. Background: Weiss-Kruszka syndrome (WKSA) is a rare autosomal dominant genetic disorder caused by heterozygous loss-of-function variants in the ZNF462 gene. Individuals affected by this condition exhibit distinctive craniofacial features, ptosis, dysgenesis of the corpus callosum, hearing loss, intellectual disability, and hypotonia. There is one other case report that described a boy with empty sella syndrome with growth hormone deficiency and delayed puberty. Case Presentation: We present the case of a 15-year-old boy who initially came under the care of endocrinology at age 9 due to severe obesity and short stature. Past medical history included ADHD (for which he was on stimulants since age 5), microcephaly, VUR, asthma, and developmental delay. He grew along the 2nd percentile for height from the ages of 6 and 13, after which his growth velocity notably decelerated. His initial bone age at 9 years old was advanced by 3 years. His BMI had exceeded the 99th percentile since age 3. His family history was relevant for maternal type 1 diabetes mellitus, paternal height of 165 cm, and maternal height of 160 cm. Upon physical examination, notable findings included short stature, severe obesity, a low anterior hairline, arched eyebrows, upslanted palpebral fissures, low-set ears, a tubular and short nasal bridge, and an exaggerated cupid's bow. At age 9, the patient was diagnosed with growth hormone (GH) deficiency following a clonidine and glucagon stimulation test, with a GH peak of 1.9 ng/mL (normal &amp;gt;7 ng/mL). Additionally, he was diagnosed with adrenal insufficiency (cortisol peak of 5 ug/dL, after 250 mcg of cosyntropin). A brain/sella MRI revealed a hypoplastic pituitary gland. Subsequently, hydrocortisone replacement was initiated at a dose of 6 mg/m2/day, and GH treatment at a weekly dose of 0.3 mg/kg. Despite treatment with growth hormone and IGF-1 levels on the upper side of the normal range, his growth velocity did not improve significantly. He reached his peak adult height of 150 cm at age 15. His BMI had consistently been at the 99th percentile. According to his mother, he did not have issues with satiety, and his portion sizes were considered normal. He did not consume fast foods or sugary drinks, and his level of physical activity was suboptimal. Whole Exome Sequencing identified a heterozygous de novo pathogenic variant in the ZNF462 gene, specificallyc.2664 C&amp;gt;A, p.(C888*) (NM_021224.4), consistent with the diagnosis of Weiss-Kruszka syndrome (OMIM # 618619). Conclusion: We present, to our knowledge, the first report of morbid obesity and central adrenal insufficiency in a child with WSKA. GH deficiency had been previously reported in 1 patient with WSKA. The finding of a hypoplastic pituitary gland supports the diagnosis of GH deficiency and central adrenal insufficiency. Presentation: 6/3/2024

7858 Increasing Severity of Growth Hormone Deficiency is Associated with Lower Vertebral Strength

Abstract Disclosure: R. Boutin: None. M. Haines: None. R. Shahid: None. C. Mark: None. C. Gill: None. M. Bredella: None. K.K. Miller: Other; Self; Pfizer, Inc. L.E. Dichtel: Consulting Fee; Self; Lumos Pharma. Grant Recipient; Self; Lumos Pharma, Perspectum Ltd. Research Investigator; Self; Recordati, Novo Nordisk. Stock Owner; Self; Marea Therapeutics. Other; Self; Third Rock Ventures. Objective: Growth hormone (GH) stimulates osteoblast differentiation, while insulin-like growth factor-1 (IGF-1) stimulates osteoblast proliferation and bone formation. Retrospective studies have demonstrated a 2-to-3-fold increased fracture risk in adults with GH deficiency (GHD) due to organic hypothalamic or pituitary disease, particularly at vertebral sites. Adults with overweight/obesity produce relatively less GH than lean individuals, and serum IGF-1 levels are associated positively with BMD in adults with obesity. Yet, no published studies have examined the relationship between degree of GHD across these groups and vertebral strength, an understudied measure of bone quality in part because HR-pQCT cannot image this skeletal site. We hypothesized that there would be an inverse association between degree of GHD and vertebral strength, independent of age and BMI. Methods: Cross-sectional study of 134 estrogen-replete (with regular menses or taking estrogen) women: 16 with GHD secondary to hypopituitarism (HP, severe GHD), 91 with obesity (OB) without a hypothalamic/pituitary disorder (relative GHD), and 37 lean controls (LC) without a hypothalamic/pituitary disorder (normal GH production). Peak-stimulated GH was assessed by GHRH-arginine testing. CT imaging at the L4 vertebra was performed to determine vertebral cross-sectional area and total integrated volumetric bone mineral density (Int.vBMD), from which estimates of vertebral strength were calculated. Results: Mean age [44±9 (mean±SD) (HP) vs. 35±7 (OB) vs. 30±7 (LC) y, p&amp;lt;0.005] and BMI [30±6 (HP) vs. 34±6 (OB) vs. 22±2 (LC) kg/m2, p&amp;lt;0.004] differed between all groups. As expected, peak-stimulated GH was highest in LC (28.3 ± 9.5 ng/mL) followed by OB (12.4 ± 8.9 ng/mL) and HP (2.4 ± 1.7 ng/mL), p&amp;lt;0.0001. IGF-1 Z-scores were higher in LC (0.0 ± 0.6) and OB (0.0 ± 0.7) vs. HP (-1.4 ± 0.7), p&amp;lt;0.0001. Int.vBMD and vertebral strength were higher in LC and OB vs. HP [Int.vBMD (g/cm3) LC 0.21±0.04 and OB 0.21±0.04 vs. HP 0.16±0.03, and vertebral strength (N) LC 4540±850 and 4743±91 vs. HP 3542±651, both p&amp;lt;0.0001], which remained significant when adjusted for age and BMI (p≤0.01). Peak-stimulated GH and IGF-1 Z-scores were positively associated with vertebral strength (GH R=0.33, p=0.003 and IGF-1 Z-score R=0.41, p&amp;lt;0.0001) and Int.vBMD (GH R=0.46, p&amp;lt;0.0001 and IGF-1 Z-score R=0.40, p&amp;lt;0.0001), which remained significant when adjusted for age and BMI. Among the subset of patients without organic pituitary disease (LC and OB only), IGF-1 Z-scores remained positively associated with vertebral strength (R=0.24, p&amp;lt;0.03) and Int.vBMD (R=0.22, p&amp;lt;0.05). Conclusions: These findings suggest that severe GHD is associated with impaired vertebral volumetric bone density and strength. Moreover, the relative GHD of obesity may contribute to lower vertebral bone density and strength in otherwise healthy adults with overweight/obesity. Presentation: 6/3/2024

6545 Weekly Somapacitan Reduces Serum C-reactive Protein Levels in Adult Patients with Growth Hormone Deficiency

Abstract Disclosure: Y. Seki: None. S. Morimoto: None. M. Ikemoto: None. N. Takano: None. K. Yamashita: None. K. Bokuda: None. D. Watanabe: None. A. Ichihara: None. Background: Adult growth hormone deficiency (GHD) is known to be associated with increased inflammation. Our previous research revealed a significant association between GHD and elevated serum C-reactive protein (CRP) levels. Limited studies have demonstrated a significant association between GH replacement therapies and CRP levels; only two reports showed a significant reduction in serum CRP levels with daily somatropin. This study aimed to investigate the effects of weekly somapacitan on serum CRP levels in adult patients with GHD. Methods: We prospectively observed serum CRP levels as the primary outcome before and 6 months after somapacitan treatment in adult patients with GHD with no history of GH supplementation therapy within the past 6 months. Secondary outcomes included anthropometric data, IGF-1 levels, and kidney and liver functions. The somapacitan dose was titrated based on IGF-1 levels during the 6-month treatment period. Results: Eight adult patients (mean age 50±17, male 4 [50%]) with GHD received weekly somapacitan treatment. Of the patients, 2 (25%) had ACTH deficiency, 2 (25%) had TSH deficiency, and 2 (25%) had gonadotropin deficiency. Two patients (25%) were on glucocorticoid replacement. The somapacitan dose at 6 months was 1.9 (1.5-2.6) mg/week. Weekly somapacitan significantly increased serum IGF-1 level (48 [29-122] to 125 [63-205] ng/mL, P = 0.001) and IGF-1 SD score (-3.3 [-5.3-0.9] to -0.7 [-3.0-0.8], P = 0.008) and significantly decreased serum CRP level (0.243 [0.056-0.464] to 0.093 [0.036-0.290] ng/mL, P = 0.008). However, it did not affect body weight (80.6±11.6 to 79.8±10.5 kg, P = 0.67) or serum creatinine (0.74±0.13 to 0.68±0.21 mg/dL, P = 0.35) and alanine aminotransferase (60 [20-99] to 48 [21-85] U/L, P = 0.23) levels. Changes in CRP levels were significantly correlated with changes in IGF-1 levels (rs = -0.83, P = 0.010) and IGF-1 SD scores (rs = -0.79, P = 0.021). Conclusion: GH supplementation therapy with weekly somapacitan reduced serum CRP levels in adult patients with GHD without affecting body composition or kidney and liver functions. Presentation: 6/3/2024

7795 Gender based differences in peripubertal growth patterns may offer insight into the twofold representation of boys compared to girls among children referred for growth hormone stimulation tests

Abstract Disclosure: Y. Dekel: None. L. Horowitz : None. R. Gendelman: None. M. Cohen: None. Background: Growth hormone (GH) stimulation tests are essential in the diagnostic assessment of pediatric GH deficiency (GHD). However, the tests bare multiple limitations, resulting from both intrinsic and child-related factors. Thus, referral decisions are key in making a correct diagnosis. Several studies demonstrated a gender bias in referral for short stature evaluation with a higher proportion of boys referred and diagnosed with GHD. Moreover, the boys had higher height z-scores upon referral. About 100 GH stimulation-tests are conducted annually at our pediatric endocrinology unit. We aimed to characterize the children that underwent GH stimulation-testing between 2017-2021, specifically focusing on differences based on: 1) gender 2) GH secretion status (deficient vs. sufficient). Methods: A retrospective review of charts of children aged 0-18 years that performed GH stimulation-tests at the Rambam pediatric endocrinology unit between the years 2017-2021 was conducted. Children followed at an outside clinic that had a first GH stimulation-test elsewhere, were excluded. Data was collected through the electronic database and by manually screening medical charts. The IBM SPSS statistics package 21 version was used for analysis. Results: Four-hundred children were included in the study, 266 boys (66.5%) and 134 girls (33.5%). Mean age 8.8±4.2 years, mean height z-score -2.3±0.7 and mean mid-parental height standard-deviation-scores (MPH-SDS) -0.6±0.7. The mean difference between MPH-SDS and child height-z-score was 1.7±0.8 SDS. Mean age was younger in girls compared with boys, 7.3±3.3 and 9.6±4.4 years respectively (p&amp;lt;0.001). Age distribution differed between genders, while refferals peaked between 3-4 years of age in both girls and boys, a second peak at 13-14 years of age was evident only in boys. Interestingly, there was no significant difference between boys and girls in height z-score, difference from MPH-SDS or rates of GHD. Overall, 93 (23.3%) children were diagnosed with GHD, 32 girls (24%) and 61 boys (23%). Children with GHD were younger and had higher BMI-SDSs compared to GH sufficient children, age 7.8±3.8, 9.2±4.3 years respectively (p=0.003), BMI z-score 0.17±1.38, -0.47±1.15 respectively (p&amp;lt;0.001). Conclusion: Twice as many boys than girls were referred for GH stimulation tests in our cohort. Based on differences in age distribution, the peripubertal physiologic growth deceleration that occurs later in boys, likely contributes to this finding. This male-to-female ratio is similar to ratios reported in the literature regarding short stature referrals; however, in contrast to the literature, in our cohort it could not be explained by an anthropometric bias in referral criteria. Presentation: 6/3/2024

12256 Sustained Efficacy Of Weekly Somapacitan In Children With GHD: 3-year Results From Phase 3 REAL4 Study

Abstract Disclosure: B.S. Miller: Consulting Fee; Self; Abbvie, Ascendis Pharma, BioMarin, Bristol-Myers Squibb, EMD Serono, Endo Pharmaceuticals, Novo Nordisk, Orchard Therapeutics, Pfizer, Provention Bio, Tolmar. Grant Recipient; Self; Alexion, Abbvie, Aeterna Zentaris, Amgen, Amicus, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health Pfizer, Prevail Therapeutics, Sangamo Therapeutics. J.C. Blair: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Ipsen. Other; Self; Novo Nordisk. M. Højby Rasmussen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. A. Maniatis: Research Investigator; Self; Novo Nordisk, Ascendis, OPKO, Pfizer. J. Mori: Advisory Board Member; Self; Novo Nordisk. Consulting Fee; Self; JCR. Speaker; Self; Novo Nordisk, Pfizer, JCR. V. Böttcher: Advisory Board Member; Self; Merck. Speaker; Self; Novo Nordisk, Merck. Other; Self; Ferring, Lilly, Merck, Novo Nordisk. H. Kim: None. M. Polak: Advisory Board Member; Self; Ipsen, Novo Nordisk, Pfizer. Grant Recipient; Self; Ipsen, Novo Nordisk, Pfizer, Sandoz, Merck, Sanofi. Speaker; Self; Novo Nordisk, Pfizer, Ipsen. R. Horikawa: Advisory Board Member; Self; Novo Nordisk, Pfizer, Ascendis, Lumos Pharma. Grant Recipient; Self; Sandoz. Speaker; Self; Novo Nordisk, Pfizer, JCR. Growth hormone (GH) replacement therapy for children with GH deficiency (GHD) traditionally required daily subcutaneous injections. Somapacitan (Novo Nordisk A/S) is a reversible albumin-binding GH derivative administered once-weekly and the only long-acting GH (LAGH) approved for the treatment of both adults and children with GHD. REAL4 is a randomized, open-label, multi-national, phase 3 trial, consisting of a 52-week main phase and a three-year (week 52 to 208) extension period (NCT03811535). The trial included 200 GH-treatment-naïve, prepubertal children with GHD. Participants received either once-weekly somapacitan (0.16 mg/kg; n=132) or once-daily GH (Norditropin® 0.034 mg/kg; n=68) for 52 weeks. Afterwards, participants receiving daily GH switched to 0.16 mg/kg/week somapacitan (switch group), while those receiving somapacitan continued treatment (soma/soma group). Growth-related endpoints included height velocity (HV), HV standard deviation score (SDS), height SDS, and bone age. The 3-year (156-week) results are presented here. A total of 188 participants (125 in the soma/soma group and 63 in the switch group) completed 3 years of treatment. Improvements in HV, HV SDS, height SDS, and bone age were similar between the groups. In year 3 (week 104 to 156), mean (SD) HV was 7.4 (1.5) cm/year in the soma/soma group and 7.8 (1.4) cm/year in the switch group. The mean (SD) change in height SDS from baseline to week 156 was 2.04 (0.85) in the soma/soma group and 2.38 (1.14) in the switch group, with mean (SD) height SDS at week 156 of -0.95 (0.98) and -1.08 (0.93) in the soma/soma and switch groups, respectively. Mean BMI SDS remained within normal range in both groups at week 156. No safety or tolerability issues were identified. During the extension period (week 52 to 156), a low proportion of the participants reported injection site reactions. No neutralizing antibodies were detected at any of the visits. In conclusion, once-weekly somapacitan showed sustained efficacy and tolerability for three years, as well as for two years following the switching from daily GH treatment in this pivotal phase 3 REAL4 trial. The safety profile of somapacitan was similar to the well-known safety profile of daily GH. Presentation: 6/3/2024

9242 SOX11 mutations cause hypogonadotropic hypogonadism through both hypothalamic and pituitary level deficits

Abstract Disclosure: B. Sun: None. S. Stockman: None. M. Stamou: None. L. Plummer: None. K. Salnikov: None. D. Kotan: None. K. Topaloglu: None. S.B. Seminara: None. R. Balasubramanian: None. AbstractPurpose: Human SOX11 mutations cause Coffin-Siris Syndrome (CSS) which is clinically characterized by aplasia or hypoplasia of the distal phalanx/nail of the fifth digit, developmental delay, cognitive impairment, and distinctive facial features. Recent studies show hypogonadotropic hypogonadism (HH) occurs in ∼20% of patients with SOX11 mutations. The genotypic-phenotypic spectrum of SOX11 mutations in patients presenting with Idiopathic Hypogonadotropic Hypogonadism (IHH) is unknown. Methods: Exome sequencing data from 1810 unrelated IHH probands (anosmic and normosmic forms) were reviewed for SOX11 rare sequence variants (RSVs) [minor allele frequency &amp;lt;0.1%]. Rare variant association analysis (RVAS) and domain-based enrichment for SOX11 RSVs was performed between the IHH and gnomAD population cohort. RSVs predicted as pathogenic/likely pathogenic by ACMG criteria were deemed as pathogenic RSVs and detailed phenotypic analysis was undertaken for these variants. Results: A total of 4 pathogenic SOX11 RSVs were identified in 5 IHH cases. RVAS analysis showed that SOX11 inactivating RSVs (frameshift/non-sense) across the entire protein was enriched in the IHH cohort (2 RSVs in 3 IHH cases (p.S303X [de-novo]; p p.S345Afs*13); p&amp;lt;0.0001) while SOX11 missense RSVs was enriched only within the SOX11-HMG domain (2 RSVs in 2 IHH cases (p.G84D [de-novo]; p.P114S; p=0.003). Phenotypic review of individuals with pathogenic SOX11-RSVs revealed a spectrum of endocrine defects including: anosmic and normosmic forms of IHH, growth-hormone (GH) deficiency, neuroimaging defects (pituitary microadenoma and hypothalamic mass), and hypothyroidism. Additionally, we also identified a pathogenic SOX11 HMG domain RSV in a patient with functional HH (p.R100Q). CSS-associated features were present in almost all individuals with pathogenic SOX11 RSVs. Conclusions: This study validates SOX11 mutations as causal for IHH and reiterates the critical importance of the SOX11-HMG domain in disease pathogenesis. The spectrum of endocrine abnormalities in SOX11-related human disorders includes IHH, functional HH, GH deficiency, pituitary lesions, and hypothyroidism. The association of congenital anosmic and normosmic forms of IHH, functional HH, and anatomic abnormalities of the pituitary gland suggest that the pathogenesis of HH in SOX11-disorder may stem from both hypothalamic and pituitary level deficits. Presentation: 6/1/2024

8474 SOX11 mutations cause hypogonadotropic hypogonadism through both hypothalamic and pituitary level deficits

Abstract Disclosure: B. Sun: None. S. Stockman: None. M. Stamou: None. L. Plummer: None. K. Salnikov: None. D. Kotan: None. K. Topaloglu: None. S.B. Seminara: None. R. Balasubramanian: None. AbstractPurpose: Human SOX11 mutations cause Coffin-Siris Syndrome (CSS) which is clinically characterized by aplasia or hypoplasia of the distal phalanx/nail of the fifth digit, developmental delay, cognitive impairment, and distinctive facial features. Recent studies show hypogonadotropic hypogonadism (HH) occurs in ∼20% of patients with SOX11 mutations. The genotypic-phenotypic spectrum of SOX11 mutations in patients presenting with Idiopathic Hypogonadotropic Hypogonadism (IHH) is unknown. Methods: Exome sequencing data from 1810 unrelated IHH probands (anosmic and normosmic forms) were reviewed for SOX11 rare sequence variants (RSVs) [minor allele frequency &amp;lt;0.1%]. Rare variant association analysis (RVAS) and domain-based enrichment for SOX11 RSVs was performed between the IHH and gnomAD population cohort. RSVs predicted as pathogenic/likely pathogenic by ACMG criteria were deemed as pathogenic RSVs and detailed phenotypic analysis was undertaken for these variants. Results: A total of 4 pathogenic SOX11 RSVs were identified in 5 IHH cases. RVAS analysis showed that SOX11 inactivating RSVs (frameshift/non-sense) across the entire protein was enriched in the IHH cohort (2 RSVs in 3 IHH cases (p.S303X [de-novo]; p p.S345Afs*13); p&amp;lt;0.0001) while SOX11 missense RSVs was enriched only within the SOX11-HMG domain (2 RSVs in 2 IHH cases (p.G84D [de-novo]; p.P114S; p=0.003). Phenotypic review of individuals with pathogenic SOX11-RSVs revealed a spectrum of endocrine defects including: anosmic and normosmic forms of IHH, growth-hormone (GH) deficiency, neuroimaging defects (pituitary microadenoma and hypothalamic mass), and hypothyroidism. Additionally, we also identified a pathogenic SOX11 HMG domain RSV in a patient with functional HH (p.R100Q). CSS-associated features were present in almost all individuals with pathogenic SOX11 RSVs. Conclusions: This study validates SOX11 mutations as causal for IHH and reiterates the critical importance of the SOX11-HMG domain in disease pathogenesis. The spectrum of endocrine abnormalities in SOX11-related human disorders includes IHH, functional HH, GH deficiency, pituitary lesions, and hypothyroidism. The association of congenital anosmic and normosmic forms of IHH, functional HH, and anatomic abnormalities of the pituitary gland suggest that the pathogenesis of HH in SOX11-disorder may stem from both hypothalamic and pituitary level deficits. Presentation: 6/1/2024