Growth Hormone Replacement Therapy Research Articles

Motor proficiency in young children with Prader-Willi syndrome: a preliminary report

BACKGROUND: Systematic documentation of motor characteristics in young children with Prader-Willi syndrome (PWS) is vital as access to treatments improves. AIM: To characterize motor proficiency (MP) in young children with PWS. METHOD: Participants included 6 children (3 male and 3 female) with PWS and 13 children with neurotypical development (NT), (9 male and 4 female) ages 4-6 years. Five out of six children with PWS had been on growth hormone replacement therapy (GHRT) for >3 years. Some children with PWS exhibited cognitive delays and others performed within the average range (Intellectual quotient mean± standard deviation = 65.3 ± 7.62, range = 47 – 94). MP was measured using the Short Form of the Bruininks-Oseretsky Test of Motor Proficiency-Second Edition (BOT-2-SF). RESULTS: Children with PWS scored lower than children with NT in all areas of MP except for fine motor integration. All children with PWS scored well-below average for total MP; children with NT scored average (n=10) or above-average (n=3) for total MP, respectively. CONCLUSION: At this young age children with PWS universally exhibited poor MP despite most of them being on GHRT and some exhibited intellectual functioning in the average range. Evidence of BOT-2-SF floor effects underscores the need to refine assessment procedures and enhance measurement precision for this population.

Long-acting growth hormone in the treatment of growth hormone deficiency in children: a systematic literature review and network meta-analysis

The purpose of this study is to compare the relative efficacy and safety of long-acting growth hormone (LAGH) as a growth hormone replacement therapy in prepubertal children with growth hormone deficiency (GHD). We searched the PubMed, Embase, CNKI, and Wanfang databases from inception to July 2023 and identified eleven relevant studies. PEG-LAGH showed better effect on height velocity (mean difference [MD]: − 0.031, 95% credibility interval [CrI]: − 0.278, 0.215) than somatrogon (MD: 0.105, 95% CrI: − 0.419, 0.636), somapacitan (MD: 0.802, 95% CrI: − 0.451, 2.068) and lonapegsomatropin (MD: 1.335, 95% CrI: − 0.3, 2.989) when compared with daily growth hormone (DGH). Furthermore, in terms of height standard deviation score, PEG-LAGH demonstrated better improvement (MD: − 0.15, 95% CrI: − 1.1, 0.66) than somatrogon (MD: − 0.055, 95% CrI: − 1.3, 0.51) and somapacitan (MD: 0.22, 95% CrI: − 0.91, 1.3). PEG-LAGH (risk ratio [RR]: 1.00, 95% CrI: 0.82, 1.2) reduced the risk of adverse events compared with other LAGH (somatrogon, RR: 1.1, 95% CrI: 0.98, 1.2; somapacitan, RR: 1.1, 95% CrI: 0.96, 1.4; lonapegsomatropin, RR, 1.1, 95% CrI: 0.91, 1.3) and was comparable with DGH. This is the first study to indirectly compare the LAGH thorough a network meta-analysis and provide evidence of the optimal efficacy of various LAGH specifically PEG-LAGH and acceptable safety profile in prepubertal children with GHD.

Empty sella in somatotropic pituitary adenomas; a series of 23 cases.

We aimed to investigate empty sella syndrome in somatotrophic pituitary adenoma for possible etiology, complications, and treatment options. Among over 2,000 skull base masses that have been managed in our center since 2013, we searched for growth hormone-producing adenomas. Clinical, surgical, and imaging data were retrospectively collected from hospital records to check for sella that lacked pituitary tissue on routine imaging. In 220 somatotrophic adenomas, 23 patients had an empty sella with surgical and follow-up data. The mean age of the sample was 46 years with the same male-to-female ratio. Five cases had partial empty sella and the rest were complete empty sellas. The most common simultaneous hormonal disturbance was high prolactin levels. Six had adenoma invasion into the clivus or sphenoid sinus and 10 had cavernous sinus intrusion. Peri-operative low-flow and high-flow cerebrospinal fluid (CSF) leaks were encountered in one and two patients, respectively, which were successfully sealed by abdominal fat. The majority of cases required growth hormone replacement therapy while it was controlled without any replacement therapy in nine patients. No pituitary hormonal disturbance occurred after transsphenoidal surgery except for hypothyroidism in one patient. An empty sella filled with fluid can be detected frequently in pituitary adenomas, especially in the setting of acromegaly. The pituitary gland may be pushed to the roof of the sella and might be visible as a narrow rim on imaging or may be detected in unusual places out of the sella. The pathophysiology behind such finding originates from soft and hard tissue changes and CSF pressure alternations during abundant growth hormone production.

Serum afamin and its implications in adult growth hormone deficiency: a prospective GH-withdrawal study.

Adult growth hormone deficiency (AGHD) is associated with a high prevalence of metabolic syndrome (MS), which contributes to the unfavorable cardiovascular risk profile in these patients. Insulin like growth factor-1 (IGF-1) is a widely used biomarker, however it does not always reflect the cardiometabolic risk and has a poor relationship with clinical efficacy endpoints. Consequently, there is an unmet need for biomarkers to monitor responses to GH-replacement. Afamin is a hormone-like glycoprotein, expressed in the liver. Higher afamin levels are strongly associated with MS and insulin resistance (IR). Although both MS and IR are very common in AGHD, afamin has not been investigated in these patients. To investigate afamin as a potential biomarker in patients with AGHD. Participants included 20 AGHD patients (11 GH-substituted and 9 GH-unsubstituted) and 37 healthy controls. Subjects underwent routine laboratory examinations, anthropometric measurements, body composition analysis using multi-frequency bioelectrical impedance analysis (InBody720) and measurement of serum afamin concentrations. In GH-substituted subjects, GH-substitution was withdrawn for 2 months. Measurements were carried out right before GH-withdrawal, at the end of the 2-month withdrawal period, and 1 month after reinstituting GH-replacement therapy (GHRT). GH-unsubstituted patients demonstrated higher afamin levels compared to controls (p=0.03). Afamin positively correlated with skeletal muscle mass, bone mineral content, total body water, extracellular- and intracellular water content, insulin (all, p<0.01), HOMA-IR (p=0.01) and C-peptide (p=0.03) levels in AGHD but not in healthy controls. In GH-substituted patients 2-month of GH-withdrawal caused significant changes in body composition, including decreased fat-free mass, skeletal muscle mass, total body water, and intracellular water content (all, p<0.01); but these changes almost fully recovered 1 month after reinstituting GHRT. Unexpectedly, afamin levels decreased after GH-withdrawal (p=0.03) and increased with reinstitution (p<0.01). Changes of afamin levels during GH-withdrawal positively correlated with changes of HOMA-IR (r=0.80; p<0.01) and changes of insulin (r=0.71; p=0.02). Higher afamin levels in unsubstituted AGHD patients might indicate severe metabolic dysregulation. Significant changes accompanying GH-withdrawal and reinstitution, along with strong correlations with measures of IR, suggest that afamin could be a promising biomarker to monitor GHRT-associated changes of insulin sensitivity.

Multidisciplinary efforts to improve the diagnosis and treatment of cirrhosis due to anterior pituitary hypopituitarism

More and more clinical evidence confirms that hypopituitary dysfunction can lead to liver cirrhosis. The causes of hypopituitary dysfunction include sellarneoplastic diseases, hereditary diseases, perinatal adverse events, etc. Clinically, growth hormone deficiency (GHD) often the first cause in hypopituitary dysfunction.Hypopituitary dysfunction, especially GHD, can lead to liver cirrhosis, which in turn can result in damage to multiple organs such as the secondary lungs, spleen, and heart.Therefore, its clinical manifestations are complex, and the patients are first diagnosed in various departments.Reliable clinical observations have shown that GH replacement therapy at the early stage of the disease can effectively prevent and reverse the progression of cirrhosis, or even avoid inappropriate or unnecessary combined transplantation of liver or liver-related organs.Multidisciplinary collaboration and attention to the new findings that hypopituitary dysfunction can lead to liver cirrhosis will help to improve the accurate diagnosis and treatment of liver cirrhosis.

Postoperative hypothalamic-pituitary dysfunction and long-term hormone replacement in patients with childhood-onset craniopharyngioma.

Hypothalamic-pituitary axis dysfunction is a common complication in post-operative craniopharyngioma(CP) patients, and it greatly impacts the long-term quality of life of such patients. To better understand the effects of postoperative hypothalamic-pituitary dysfunction and long-term hormone replacement therapy in patients with childhood CP, we assessed approximately 200 patients with childhood-onset CP postoperatively. Clinical details of patients with childhood-onset CP who underwent sellar tumor resection in Beijing Children's Hospital and Beijing Tiantan Hospital from 2018 to 2019 were retrieved retrospectively. The participants were followed up to assess the effects of post-operative long-term hormone replacement therapy and assess the tumor recurrence rate. The median age of admission was 8.1 (1.8, 14.3) years. Headache (45.5%), visual impairment (39.5%), and nausea (33.0%) were the most common clinical manifestations. ACP accounted for 95% of all CP cases. The incidence of central adrenal insufficiency and central hypothyroidism within the first week after surgery was 56.2% and 70.3%, respectively. At the same time 85.5% of the patients required at least one dose of desmopressin to control urine output. Total survival and tumor recurrence rates were 98.6% and 26.1%, respectively, with a median follow-up time of 29.7 (19.0, 40.3) months. During the follow-up period, 28.1% patients met the diagnostic criteria for short stature, while 54.4% fit the criteria for obesity. In addition, 94.4% of the patients were taking at least one kind of hormone substitution, and 74.7% were taking three or more. The prevalence of levothyroxine, glucocorticoid, desmopressin, and growth hormone replacement therapy was 87.3%, 77.5%, 78.9% and 31.0%, respectively. The proportion of patients treated with the substitutive combination of levothyroxine, hydrocortisone, and desmopressin was 54.9%. This study is a large-sample systematic postoperative endocrine function evaluation of patients with childhood-onset CP. Due to the high prevalence of post-operative hypothalamic-pituitary dysfunction, patients with CP usually require long-term multiple hormone substitution therapy. Individualized management and accurate hormone replacement dosage for postoperative childhood-onset CP patients are of great importance.

SAT643 Patient Preference Questionnaire Response After Switching To Somapacitan After Taking Daily Gh: 2-year Results From REAL4

Abstract Disclosure: J. Blair: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Ipsen. Other; Self; Novo Nordisk. B.S. Miller: Consulting Fee; Self; Abbvie, Bristol-Myers Squibb, Novo Nordisk, Pfizer, Inc., EMD Serono, Endo Pharmaceuticals. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Abbvie, Amgen Inc, Novo Nordisk, Pfizer, Inc. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. A.K. Maniatis: Research Investigator; Self; Novo Nordisk, Pfizer, Inc. J. Mori: Advisory Board Member; Self; Novo Nordisk. Speaker; Self; Novo Nordisk, Pfizer, Inc. V. Boettcher: Advisory Board Member; Self; Merck. Speaker; Self; Novo Nordisk, Merck. Other; Self; Ferring Pharmaceuticals, Lilly USA, LLC, Merck, Novo Nordisk. H. Kim: None. R. Beck Bang: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. L. De Fries Jensen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. M. Polak: Advisory Board Member; Self; Ipsen, Novo Nordisk, Pfizer, Inc. Grant Recipient; Self; Ipsen, Novo Nordisk, Pfizer, Inc., Sandoz, Sanofi, Merck. Speaker; Self; Novo Nordisk, Ipsen. R. Horikawa: Advisory Board Member; Self; Novo Nordisk, Pfizer, Inc. Grant Recipient; Self; Sandoz. Speaker; Self; Novo Nordisk, Pfizer, Inc. Growth hormone (GH) replacement therapy in children requires daily subcutaneous (s.c.) injections. Although beneficial to growth and other health related outcomes, daily injections can be burdensome for patients and their caregivers. This is acutely apparent in pediatric patients, such as children with GH deficiency (GHD), where both the child and parent/caregiver’s lifestyle are affected. Indeed, concerns have been raised that this burden is linked to lower adherence rates for daily GH treatment and a subsequent reduction in the efficacy of treatment. Somapacitan is a long-acting reversible albumin-binding human GH derivative in development for once-weekly s.c. administration in children with GHD. REAL4 is an ongoing multi-national, randomized, open labelled phase 3 trial consisting of a 52-week main phase and three-year extension period (NCT03811535). During the main phase, results showed that once-weekly s.c. somapacitan (0.16 mg/kg/week) has a similar efficacy and safety profile compared to daily GH (0.034 mg/kg/day Norditropin®) treatment (non-inferiority confirmed). Following the main phase, patients who had been taking daily GH (n=68) switched to once-weekly s.c. somapacitan. After 4 weeks (week 56), the parents/caregivers of these patients were asked to complete a patient preference questionnaire. Results from this questionnaire are presented here. The first question asked was: Which treatment do you prefer? Responses showed 45/50 (90%) preferred once-weekly somapacitan, 5/50 (10%) had no preference, and no respondents preferred daily GH treatment. Of the 45 respondents who preferred the somapacitan treatment regime, 38 (84.4%) ‘very strongly’ or ‘strongly’ preferred it, while 7 (15.6%) had a not very strong preference. Among the reasons respondents preferred somapacitan were: number of times needing to do injections (27/45; 60%); less worried about remembering to do injections (21/45; 46.7%); and child less worried about getting injections and child less annoyed about getting injections (both 15/45; 33.3%), as well as others. Finally, when asked which treatment they would be most adherent to, most (35/45; 77.8%) answered that they would be more adherent to once-weekly somapacitan compared to the daily GH treatment regime. In conclusion, these results indicate that once-weekly somapacitan treatment is preferred by parents/caregivers with a child that has switched from daily GH. The main reason for this preference being a reduction in the number of injections needed. Notably, these respondents believe they will be more adherent to GH replacement therapy with once-weekly somapacitan. Presentation: Saturday, June 17, 2023

FRI340 Growth Hormone Deficiency Post Carbon Monoxide Poisoning

Abstract Disclosure: A.Y. Ghamlouche: None. O. Alzohaili: None. A.H. Elkadry: None. Carbon monoxide (CO) is the poisonous byproduct of combustion of fossil fuels, that is odorless and tasteless. In toxic levels CO leads to the impaired functioning of red blood cell’s ability to transport oxygen to tissues.1 Following CO toxicity, white matter demyelination and necrosis of the Globus pallidus that further results in other neurologic disorders, is common.2 A novel and underrecognized consequence of CO poisoning is growth hormone deficiency (GHD). GHD is the most common pituitary hormone deficiency following a traumatic brain injury.3 Four cases of GHD were described following an event of CO poisoning. Recommended GHD diagnosis criteria of less than 5.0 ng/mL was used with these patients. The Insulin Tolerance Test (ITT) and Glucagon stimulation test (GST) were administered. All patients had no causes of GHD in their medical history prior to their encounters with CO poisoning. A 44-year-old male with exposure in 2020, came for an evaluation in January of 2022 complaining of memory impairment, brain fog, mental fatigue, cognitive decline, anxiety, poor libido, and neuropathy. showed a GH peak of 1.1 ng/mL during the ITT a peak of 1.0 ng/mL during the GST. A 51-year-old male with exposure in 2016, came for an evaluation in December of 2020 complaining of memory impairment, blurry vision, fatigue, physical weakness, mood changes, and stuttered speech. Results showed a GH peak of 4.4 ng/mL during ITT and a GH peak of 0.157 ng/mL during the GST.A 43-year-old female with exposure in 2017, came for an evaluation in January of 2022 complaining of memory loss, attention issues, anxiety, depression, fatigue, weight gain and neuropathy. Results showed a GH peak of 1.7 ng/mL during ITT and a GH peak of 2.6 ng/mL during the GST. A 42-year-old male with exposure in 2018, came for an evaluation in November of 2019 complaining of memory impairment, headaches, tremors, fatigue, anxiety, depression, declining cognition, insomnia, poor libido, lack of concentration, and poor vision. Results showed a GH peak of 3.6 ng/mL during ITT and a GH peak of 0.109 ng/mL during the GST. All 4 patients were started on GH replacement therapy following their tests. All patients responded well, and showed significant improvements in quality of life. A possible connection can be drawn between pituitary gland damage and hypoxia from CO poisoning.

FRI348 Ectopic Posterior Pituitary As A Cause Of Panhypopituitarism Presenting With Hyponatremia

Abstract Disclosure: C. Choo: None. Background: Ectopic posterior pituitary gland (EPP) can occur from defective embryogenesis affecting neuronal migration, or from neurodegeneration of the hypothalamic nuclei. While isolated growth hormone deficiency is most common, it is also associated with pan-hypopituitarism. The posterior pituitary function is often preserved. Clinical Case: We report a case of pan-hypopituitarism from congenital EPP, presenting with hyponatremia. A 63-year-old male with hyperlipidemia was admitted for gastroenteritis. Serum sodium was 106mmol/L [reference range 136-146mmol/L] on admission but he was otherwise asymptomatic and haemodynamically stable. This initially improved with intravenous fluids, however subsequently stagnated at 121mmol/L despite achieving euvolemia. Thyroid and cortisol axes were evaluated in view of persistent hyponatraemia. 8am cortisol was low at 119nmol/L with inappropriately normal ACTH 13.9 pg/mL [reference range 7.2 – 62.3 pg/mL]. Thyroid function test showed central hypothyroidism consistently on repeat testing with a low fT4 of 6.1 pmol/L and 7.7 pmol/L [reference range 8.8-14.4pmol/L] and inappropriately normal TSH of 2.98MU/L and 2.41MU/L respectively [reference range 0.65-3.70MU/L]. 1mcg short synacthen test done following suspicion of hypocortisolism peaked at 468 nmol/L. He had no symptoms or signs of hypocortisolism or hypothyroidism. He was a bachelor and had clinical features of hypogonadism including short stature (142cm), high-pitched voice, scarce sexual hair and pubescent sized testes. His mid-parental height is unknown as his parents were deceased. FSH, LH, testosterone and IGF-1 were all undetectable. Prolactin was otherwise normal 9.4ug/L [reference range 4.2-16.4ug/L]. Radiographs of the forearm showed unfused epiphyseal plates at the distal radius and ulna. Thus, the diagnosis of pan-hypopituitarism was made. Magnetic resonance imaging of the pituitary revealed a T1 hyperintense nodule at the floor of the third ventricle, suggestive of ectopic posterior pituitary. There was otherwise minimal normally enhancing tissue in the pituitary fossa, and the posterior pituitary bright spot and infundibulum were absent. He was started on hydrocortisone and subsequently levothyroxine replacement, with resolution of hyponatraemia (serum sodium 139nmol/L). He did not develop polyuria or polydipsia to suggest diabetes insipidus. Due to financial concerns however, he declined growth hormone and testosterone replacement therapy. Conclusion: Most reports of EPP are in the pediatric population often presenting with short stature. This was a seemingly ordinary case of hyponatraemia initially deemed to be from hypovolaemia. His atypical clinical features led to the eventual diagnosis of EPP with panhypopituitarism at a rather late age, highlighting the importance of a thorough clinical examination necessitating further evaluation. Presentation: Friday, June 16, 2023

OR21-01 Pre-treatment Blood Transcriptome Predicts First-year Growth And IGF-I Response To Somapacitan Treatment In Children With GH Deficiency

Abstract Disclosure: T. Garner: Grant Recipient; Self; Novo Nordisk. P.E. Clayton: Grant Recipient; Self; Novo Nordisk. M. Hojby: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P. Murray: Grant Recipient; Self; Novo Nordisk. A. Stevens: Grant Recipient; Self; Novo Nordisk. Background: Growth hormone (GH) replacement therapy often requires daily subcutaneous injections that can be burdensome for patients and their caregivers. Somapacitan is a long-acting, once-weekly GH derivative in development for treating GH deficiency (GHD) in children. Somapacitan reduces treatment burden and shows a similar efficacy and safety profile as daily GH in children with GHD. Here, we investigate the prediction of first-year growth and insulin-like growth factor-I (IGF-I) response based on baseline blood transcriptome in children with GHD treated with somapacitan or daily GH. Methods: 200 treatment-naïve prepubertal children with GHD were enrolled into REAL4, a randomised, multinational, open-labelled, and active-controlled phase 3 trial. 128 consented to a baseline blood transcriptome profile. Children were treated with once-weekly somapacitan (n=81) or daily GH (n=47) for 52 weeks and categorised based on treatment response: the upper quartile of height velocity (HV; cm/year) was defined as good responders, and the lower quartile as poor responders. We split the somapacitan group into training (70%) and testing (30%) sets for prediction validation of HV and the GH response marker: ΔIGF-I standard deviation score (SDS). Gene expression was assessed between the target quartile and the remaining quartiles for both HV and ΔIGF-I SDS to identify the top 100 differentially expressed genes by adjusted p-value. Classes were balanced using a synthetic minority oversampling technique and Boruta, a feature selection algorithm, was used to refine gene lists. We performed random forest and calculated “out of box” (OOB) area under the curve (AUC) and OOB error rate (ER), measures of predictive accuracy and robustness, respectively. Results: HV prediction from the transcriptome was excellent for both treatments (AUC range: 0.95-0.99). It was more robust for identifying good responders (ER: 7.0-7.5%) than poor responders (ER: 13.2-17.5%). Genes previously identified as predictive of growth response for daily GH (Stevens et al., 2021. The Pharmacogenomics J., 21:594-607) were demonstrated to have high predictive value for once-weekly somapacitan and daily GH treatment in this study (AUC range: 0.84-0.97, ER &amp;lt;22%). Using the somapacitan group for validation, HV prediction (AUC range: 0.78-0.81) was stronger than ΔIGF-I SDS prediction (AUC range: 0.63-0.72). Conclusions: We demonstrate pre-treatment blood transcriptome predicts first-year growth response for somapacitan. This represents an independent validation of earlier observations and shows that genes predictive of growth response for daily GH treatment in children with GHD are also predictive for once-weekly somapacitan. Further, we demonstrate that the pre-treatment blood transcriptome predicts growth response better than it predicts IGF-I SDS response. Presentation: Saturday, June 17, 2023

THU174 Model-Based Analysis Of IGF-I Response, Dosing, And Monitoring For Once-Weekly Somapacitan In Children With GH Deficiency

Abstract Disclosure: R.J. Kildemoes: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. Y. Kamal Lyauk: Employee; Self; Novo Nordisk. J.C. Blair: Speaker; Self; Novo Nordisk, Pfizer, Inc., Ipsen. Other; Self; Novo Nordisk. B.S. Miller: Consulting Fee; Self; Novo Nordisk, Abbvie, Endo Pharmaceuticals, Ascendis Pharma, Bristol-Myers Squibb, Pfizer, Inc., EMD Serono, BioMarin Pharmaceutical, Tolmar. Research Investigator; Self; Alexion Pharmaceuticals, Inc., Abbvie, Aeterna Zentaris, Amicus, Lumos Pharma, Novo Nordisk, Lysogene, OPKO Health, Pfizer, Inc., Prevail Therapeutics, Sangamo Therapeutics. J. Mori: None. M. Højby Rasmussen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P.F. Backeljauw: Consulting Fee; Self; Novo Nordisk, Novartis Pharmaceuticals, Ascendis Pharma, BioMarin Pharmaceutical, Tolmar Pharmaceuticals, Cavalry Biosciences, Ipsen. Research Investigator; Self; Novo Nordisk, Novartis Pharmaceuticals, Ipsen. Growth hormone (GH) replacement therapy improves overall health and adult height in children with GH deficiency (GHD). GH stimulates insulin-like growth factor-I (IGF-I) release, the biomarker commonly used for guiding GH dose adjustments to ensure optimal long-term safety and efficacy. This study aims to provide model-based insights into the dose-IGF-I responses of once-weekly somapacitan, a novel long-acting GH, compared to daily GH in pediatric patients with GHD. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was used to characterize somapacitan dose-IGF-I response and to predict the response to change of dosing day and missed dosing of somapacitan. Analyses included dosing information and 1473 PK samples from 210 GHD patients treated with somapacitan across three trials: phase 1 (NCT01973244), phase 2 (NCT02616562; REAL3), and phase 3 (NCT03811535; REAL4), as well as 1381 IGF-I samples from 186 GHD patients treated with somapacitan from REAL3 and REAL4. A clear dose-response relationship was observed with increasing somapacitan exposure and increasing change from baseline IGF-I SDS. A linear model permitted the development of a tool to calculate the estimated average weekly IGF-I exposure from a single IGF-I sample obtained at any time within the somapacitan dosing interval at steady state. In practice, the use of this tool will require knowledge of the timing of the somapacitan injection relative to the timing of the IGF-I sample collection. IGF-I SDS simulations support flexible dosing day changes while maintaining a minimum of 4 days between doses. In this study, we present a practical guide that may inform clinicians about the expected weekly average IGF-I concentration in somapacitan-treated pediatric patients with GHD from a single sample taken on any chosen day during the weekly dosing interval. The ability to determine weekly average IGF-I enhances our understanding of somapacitan dosing and should support physicians in monitoring long-term safety and efficacy of this therapy. Furthermore, we provide insights on flexibility to change of dosing day and missed dosing of somapacitan. Presentation: Thursday, June 15, 2023

Multi-Institutional Phase I Feasibility Trial of Vertebral Body Sparing CSI for Pediatric Brain Tumors

Craniospinal irradiation (CSI) is an essential part of curative treatment for several pediatric brain tumors. Proton CSI allows for sparing of the organs anterior to the vertebral bodies (VBs), but this technique still includes the entire VB in the target for growing children. providing no advantage in marrow sparing or adverse effects on growth. Advances in proton therapy including Proton Beam Scanning (PBS) allow for delivery of proton CSI with substantial vertebral body sparing (VBS). We sought to determine the feasibility of VBS CSI using PBS based on the effects on tumor control and growth, and the occurrence of grade III/IV hematologic toxicity. Clinical and treatment characteristics were recorded for 20 pediatric patients with medulloblastoma (n = 14) or germ cell tumor (GCT) (n = 6) who received proton VBS CSI without concurrent chemotherapy or with concurrent single-agent vincristine in a multi-institutional clinical trial. The following standard variables were extracted for each patient: age, histology, radiation dose, chemotherapy regimen, and growth hormone replacement status. Complete blood counts (CBC) with differential and data on height/weight were recorded at baseline pre-RT, weekly during RT, and after completion of cancer treatment. Hematologic toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 (CTCAE v4). Median age of 13 male and 7 female patients receiving proton VBS CSI was 10 years (range: 5.1 - 15.1). All GCT patients (n = 6, 30%) received pre-RT chemo. Median CSI dose was 23.4 Gy (range: 21.0 - 37.8), and total dose to tumor bed was 54 Gy in 18 patients (90%) while 2 patients with pure germinoma received a total dose of 36 and 37.5 Gy, respectively. 11 patients (55%) did not receive concurrent vincristine. At a median follow up of 26.4 months (range: 12.5 - 56.3) from the start of RT, no patients relapsed. 17 patients (85%) developed grade ≥3 hematologic toxicity including grade 3 lymphopenia (n = 16), leukopenia (n = 9), neutropenia (n = 8), anemia (n = 1), and grade 4 neutropenia (n = 1). The patient who developed grade 4 neutropenia had low white blood counts prior to RT. 14 patients (70%) received post-RT chemo. No patients required platelet transfusion during RT. Those findings are similar to historical controls. 4 patients started growth hormone replacement therapy after RT. No patients developed spine deformities after the completion of treatment. Proton VBS CSI is a feasible and well tolerated treatment for children with brain tumors. Longer follow up is needed to assess for late effects on tumor control. It is too early to assess for height in this cohort but for the patients that had longer follow up, normal height was achieved.

Investigation of the metabolic and endocrinological differences between daily and weekly growth hormone replacement therapy, somapacitan, in patients with adult growth hormone deficiency: A real-world pilot study.

In this real-world pilot study, we evaluated the metabolic and endocrinological effects in patients with adult growth hormone deficiency (AGHD) who switched from daily growth hormone (GH) replacement therapy to weekly GH replacement therapy using somapacitan. Eleven patients with AGHD, whose medical treatment aside from GH replacement therapy did not change, were enrolled. We investigated the metabolic and endocrinological parameters between at switching and 6 months after switching from daily GH formulation to somapacitan. The results showed that body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (FPG), and liver functions were significantly improved 6 months after switching compared to those at switching (each P < .05). Besides, the improvement in HOMA-IR was significantly associated with the period of daily GH replacement therapy before switching (P = .048), while age, sex, improvement in BMI or liver functions, presence of any hormonal deficiency, and the existence of any hormonal replacement therapy significantly associated (P > .05). In addition, switching to GH replacement therapy did not affect endocrinological parameters. In conclusion, this study might indicate that weekly GH replacement therapy with somapacitan could have more beneficial points than daily GH replacement therapy. Considering the cohort of this study was small, future studies with larger cohorts should be necessary to confirm the results of this study.

The consequences of growth hormone deficiency in adults

Adult growth hormone deficiency (GHD) is a result of the decreased growth hormone (GH) production and secretion from the anterior pituitary gland in adulthood, that cannot be explained by the physiological ageing process. GHD is associated with numerous deleterious consequences such as adverse changes in body composition, carbohydrate and lipid metabolism, alterations in the cardiovascular system, and deterioration in the quality of life (QoL). Most of these complications are at least partially reversible during recombinant human growth hormone (rhGH) replacement therapy. Thus, physicians and particularly endocrinologists, should consider GHD diagnosis and select patients who could benefit from rhGH therapy.

Effect of Growth Hormone and Estrogen Replacement Therapy on Bone Mineral Density in Women with Turner Syndrome: A Meta-Analysis and Systematic Review.

Osteoporosis is a serious implication of Turner syndrome (TS). Common methods for the treatment of TS are growth hormone (GHT) and estrogen replacement therapy (ERT). We examined the relationship between the treatment of TS and bone mineral density (BMD) of the lumbar spine. The purpose of our study was to show the currency of BMD states among patients with TS for treatment with GHT and ERT. We searched databases for studies published from inception to April 2023. The articles were related to TS, osteoporosis, ERT, GHT, BMD and treatment patients with TS. We applied the selection criteria: lumbar spine values at L1-L4; dual-energy X-ray absorptiometry (DXA); treatment which was applied: one group of articles: ERT and two group of articles: GHT; results performed as means ± SD. In total, 79 articles were analyzed, of which 20 studies were included and 5 were considered for meta-analysis. The total number of women in the articles selected was 71. Based on the results of the meta-analysis, the effect of ERT on BMD demonstrated a significant increase in BMD (the standardized mean difference in the random model was 0.593 g/cm2, 95% CI: 0.0705 to 1.116; p = 0.026), which showed that treatment with estrogen particularly increases bone mass during treatment, which contributes to reducing the risk of fractures. The effect of GHT on BMD demonstrated a non-significant decrease in BMD in patients with TS. The results for growth hormone show that this therapy does not improve bone density. However, our review emphasizes the beneficial effect of supplementing growth hormone (GH) on the clinical presentation of TS.

Model-Based Analysis of IGF-I Response, Dosing, and Monitoring for Once-Weekly Somapacitan in Children With GH Deficiency.

Growth hormone (GH) replacement therapy improves longitudinal growth and adult height in children with GH deficiency (GHD). GH stimulates insulin-like growth factor (IGF)-I release, the biomarker used for monitoring GH activity during treatment. This study aims to provide model-based insights into the dose-IGF-I responses of once-weekly somapacitan, a novel long-acting GH, compared with daily GH in children with GHD. Analyses included dosing information and 1473 pharmacokinetic samples from 210 somapacitan-treated pediatric patients with GHD across 3 trials, including phase 1 (NCT01973244), phase 2 (NCT02616562; REAL 3), and phase 3 (NCT03811535; REAL 4), as well as 1381 IGF-I samples from 186 patients with GHD treated with somapacitan in REAL 3 and REAL 4. Pharmacokinetic/pharmacodynamic modeling to characterize somapacitan dose-IGF-I response and predict the response to dosing day changes. Relationships were established between somapacitan dose, exposure, change from baseline IGF-I SD score (SDS), and height velocity (HV). A linear model permitted the development of a tool to calculate estimated average weekly IGF-I exposure from a single IGF-I sample obtained at any time within the somapacitan dosing interval at steady state. In practice, the use of this tool requires knowledge of somapacitan injection timing relative to IGF-I sample collection timing. IGF-I SDS simulations support flexible dosing day changes while maintaining at least 4 days between doses. We characterized the dose-IGF-I response of somapacitan in children with GHD. To support physicians in IGF-I monitoring, we present a practical guide about expected weekly average IGF-I concentrations in these patients and provide insights on dosing day flexibility.

Hormonal changes in veterans with Gulf War Illness

AimsGulf War Illness (GWI) is a multi-system condition of complex etiology and pathophysiology without specific treatment. There is an overlap between the symptoms of GWI and endocrinopathies. This study aimed to identify hormonal alterations in 1990–91 Gulf War (GW) veterans and the relationship between GWI and hormonal dysregulation. Main methodsData from 81 GW veterans (54 with GWI and 27 controls without GWI) was analyzed in a cross-sectional, case-control observational study. Participants completed multiple questionnaires, neuropsychiatric assessments, and a comprehensive set of hormone assays including a glucagon stimulation test (GST) for adult growth hormone deficiency (AGHD) and a high-dose adrenocorticotropic hormone (ACTH) stimulation test for adrenal insufficiency. Key findingsThe GWI group had lower quality of life and greater severity of all symptoms compared to controls. Pain intensity and pain-related interference with general activity were also higher in the GWI group. AGHD was observed in 18 of 51 veterans with GWI (35.3 %) and 2 of 26 veterans without GWI (7.7 %) (p = 0.012 for interaction). Veterans with GWI also exhibited reduced insulin-like growth factor 1 (IGF-1) levels and IGF-1 Z-scores compared to controls. One participant with GWI met the criteria for adrenal insufficiency. No significant changes were observed in other hormonal axes. SignificanceThe frequency of AGHD was significantly higher in veterans with GWI compared to controls. Recombinant human growth hormone replacement therapy (GHRT) may become a breakthrough therapeutic option for this subgroup. A large clinical trial is needed to evaluate the efficacy of GHRT in patients with GWI and AGHD.

Management of Neonatal Isolated and Combined Growth Hormone Deficiency: Current Status.

Congenital growth hormone deficiency (GHD) is a rare disease caused by disorders affecting the morphogenesis and function of the pituitary gland. It is sometimes found in isolation but is more frequently associated with multiple pituitary hormone deficiency. In some cases, GHD may have a genetic basis. The many clinical signs and symptoms include hypoglycaemia, neonatal cholestasis and micropenis. Diagnosis should be made by laboratory analyses of the growth hormone and other pituitary hormones, rather than by cranial imaging with magnetic resonance imaging. When diagnosis is confirmed, hormone replacement should be initiated. Early GH replacement therapy leads to more positive outcomes, including reduced hypoglycaemia, growth recovery, metabolic asset, and neurodevelopmental improvements.

Retraction: Effect of weekly long-acting growth hormone replacement therapy compared to daily growth hormone on children with short stature: a meta-analysis.

[This retracts the article DOI: 10.3389/fendo.2021.726172.].

Role of Estrogen and Estrogen Receptor in GH-Secreting Adenomas.

Acromegaly is a rare disease with several systemic complications that may lead to increased overall morbidity and mortality. Despite several available treatments, ranging from transsphenoidal resection of GH-producing adenomas to different medical therapies, complete hormonal control is not achieved in some cases. Some decades ago, estrogens were first used to treat acromegaly, resulting in a significant decrease in IGF1 levels. However, due to the consequent side effects of the high dose utilized, this treatment was later abandoned. The evidence that estrogens are able to blunt GH activity also derives from the evidence that women with GH deficiency taking oral estro-progestins pills need higher doses of GH replacement therapy. In recent years, the role of estrogens and Selective Estrogens Receptor Modulators (SERMs) in acromegaly treatment has been re-evaluated, especially considering poor control of the disease under first- and second-line medical treatment. In this review, we analyze the state of the art concerning the impact of estrogen and SERMs on the GH/IGF1 axis, focusing on molecular pathways and the possible implications for acromegaly treatment.