Sleep matters: rethinking its role in growth hormone deficiency treatment.

The availability of recombinant human growth hormone (rhGH) in the mid1980s has fostered a renewed interest in potential clinical applications of growth hormone (GH). In addition to the treatment of GH-deficient children and adults, rhGH may have beneficial effects in the treatment of patients with burns, bone fractures, or Turner’s syndrome, in improving the exercise capacity of elderly individuals, and in reversing the catabolic effects of glucocorticoids, chemotherapy, and AIDS (1–5). While GH is synthesized and stored in the pituitary, its release is regulated by two hypo-thalamic peptides: growth hormone releasing hormone/factor (GHRH/ GHRF) and the inhibitory hormone somatostatin (Fig. 7.1). Most cases of idiopathic GH deficiency are due to a hypothalamic defect and not a pituitary deficiency in GH, and therefore an alternate approach to rhGH treatment of GH-deficient patients would be to administer a GH secretagogue to release endogenous GH (6). For this reason, GRF(l–44)-NH2 and its truncated analogues, e.g., GRF(l–29)-NH2, have been studied over the past decade as an alternate approach in the treatment of GH deficiency (7,8). Although rhGH and GHRF analogues are clinically effective, their high cost and lack of oral bioavailability have restricted their clinical applications.

Somatrogon (NGENLA®), a long-acting human growth hormone based on C-terminal peptide technology, is in development by Pfizer and OPKO Health for the treatment of growth hormone deficiency in pediatric and adult patients. Administered as a once-weekly subcutaneous injection, somatrogon reduces treatment burden relative to once-daily human growth hormone therapy while providing non-inferior efficacy. Somatrogon received its first approval in October 2021 in Canada for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone (growth hormone deficiency). This article summarizes the milestones in the development of somatrogon leading to this first approval for the treatment of growth hormone deficiency.

Growth hormone deficiency (GHD) is a relatively uncommon and heterogeneous endocrine disorder presenting in childhood with short stature. However, during the neonatal period, the metabolic effects of GHD may to require prompt replacement therapy to avoid possible life-threatening complications. An increasing amount of data suggests the importance of an early diagnosis and treatment of GHD because of its auxological, metabolic, and neurodevelopmental features with respect to the patients diagnosed and treated later in life.The available results show favourable auxological outcomes for patients with GHD diagnosed and treated with r-hGH early in life compared with those from patients with GHD who do not receive this early diagnosis and treatment. Because delayed referral for GHD diagnosis and treatment is still frequent, these results highlight the need for more attention in the diagnosis and treatment of GHD.Despite these very encouraging data regarding metabolic and neurodevelopmental features, further studies are needed to better characterize these findings. Overall, the importance of early diagnosis and treatment of GHD needs to be addressed.

Background Treatment for medulloblastoma can lead to significant long-term endocrine sequelae, including growth hormone (GH) deficiency. There has been some concern that GH replacement can increase the risk of tumor relapse. Our goal was to assess the risk of recurrence after GH therapy in medulloblastoma (MB) patients treated with ­modern, molecularly informed protocols. Methods We conducted a retrospective observational cohort study at a tertiary pediatric hospital from January 1999 to December 2022. Patients < 18 years old with MB who received craniospinal irradiation (CSI) were included, treated according to contemporary risk-adapted protocols. Epidemiological, molecular, and clinical data were collected. Results A total of 148 patients with MB were treated with CSI, with a median age of 8.3 years (IQR 5.9-10.8). The molecular subgroups included Group 4 (n = 69, 46.6%), Group 3 (n = 27, 18.2%), WNT (n = 21, 14.2%), and SHH (n = 20, 13.5%). During follow-up, 79 patients (53.4%) were diagnosed with GH deficiency, and 73 of them initiated GH therapy. We found no association between sex (P = 1), presence of metastases (P = .14), or molecular subgroup (P = .71) and the use of GH therapy. Thirty-four patients (22.9%) relapsed during follow-up, with 10 of them receiving GH therapy (13.7% of all patients on GH). Progression-free survival (PFS) was higher among those who received GH replacement therapy, even within each subgroup independently. In a multivariate analysis of patients who had not relapsed at least 2 years post-diagnosis, GH replacement was associated with significantly improved overall survival (OS) and a trend toward improved PFS (PFS: HR 0.35, 95% CI, 0.12-1.08, P = .068; OS: HR 0.34, 95% CI, 0.12-0.99, P = .049). Conclusions The use of GH is not associated with an increased risk of recurrence or death in children with medulloblastoma treated with CSI according to current protocols. Our results provide further reassurance that all children with requiring treatment for growth hormone deficiency after medulloblastoma therapy should be offered physiological growth hormone replacement.

Having noted symptomatic osteoporotic vertebral collapse in young adult survivors of childhood malignancy, bone mineral density (BMD) was examined at three sites by dual-energy X-ray absorptiometry in 64 patients treated in childhood for intracranial malignancy (group 1; n = 21) or acute leukaemia (group 2; n = 43). Patients in group 1 were selected for growth hormone deficiency (GHD) by auxological and biochemical criteria before the end of puberty (Tanner stage V). Seven patients (six men; mean (+/- SEM) age at study, 28.0 +/- 2.9 years; mean age at diagnosis, 8.7 +/- 1.5 years) in this group had been treated with human pituitary growth hormone (GH) for 1-12 years; and 14 patients (nine men; mean age at study, 26.8 +/- 1.0 years; mean age at diagnosis, 10.7 +/- 1.4 years) had not received GH. Bone densities in group 1 were normal in the GH-treated patients at the femoral neck (98.4 +/- 3.8% of control), lumbar spine (100.4 +/- 6.1% of control) and Ward's triangle (101.0 +/- 6.1% of control) but markedly reduced in the untreated group (femoral neck, 81.2 +/- 2.6% of control (p = 0.002); lumbar spine, 79.1 +/- 4.1% of control (p = 0.04); Ward's triangle, 80.1 +/- 3.6% of control (p = 0.01)). The majority of patients in group 2 had been treated for acute lymphoblastic leukaemia (ALL) and were in three subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant growth hormone (rhGH) is used for the treatment of growth hormone deficiency (GHD). Children with growth hormone deficiency characterized by short stature. The aim of this study was to assess the efficacy of rhGH as a therapeutic intervention for treatment of children with GHD in Misurata following a year of therapy. Medical records of 174 GHD children attended the department of pediatric endocrinology in the Misrata Specialized Center for Diabetes and Endocrine. From June 2012 to January 2022 were retrospectively evaluated. Among them 50 patients met the inclusion criteria of receiving the rhGH treatment for a year. The relevant anthropometric data at baseline and follow-up were recorded. A retrospective study that included 50 GHD children treated with rhGH was performed. Patients were divided into two groups according to treatment response: poor responders with average mean increase of height by < 3 cm/year and good responders with increase of height by ≥ 3 cm/year. Patients with idiopathic GHD constitute almost two-thirds of the pathogenesis of GHD (70 %). Forty-six patients (92%) showed good response (Δ height >3 cm after one year of therapy). The response to treatment were; 93% in the age group 3-5 years old, and 83% in the age group 10-12 years. The mean difference in the growth rate was ∆HV = 5.163 cm/year after one year of rhGH therapy. Our study demonstrated that the use of rhGH for one year has an promising effect on increasing the height of patients diagnosed with GHD. We highly recommend the early use of rhGH in with GHD

Growth hormone (GH) replacement unequivocally benefits growth, body composition, cardiovascular risk factors and quality of life. Less is known about the effects of GH on learning and memory. The recent paper on 'early onset - GH deficiency (GHD) results in spatial memory impairment in mid life - and is prevented by GH supplementation' by Nieves-Martinez importantly adds to this literature. Other data suggest that GH beneficially affects cognitive function in rats. In man, treatment of GHD has been associated with improvements in measures of memory and attention. There are also differences in verbal memory of patients with childhood onset GHD. Further questions remain, and the beneficial effects or otherwise of treating GHD in different age groups remain to be better defined. Certainly for reasons of maturation of neural connections and their development to young adulthood contemporaneous with rises in GH and IGF1 make these important areas for further study in man. Lastly because of what we already know in terms of cognitive effects of GHD, it is important to replace GH when studying other potential causes of adverse effects on cognition, for example, with radiotherapy.

TransCon growth hormone is a sustained-release human growth hormone prodrug under development in which unmodified growth hormone is transiently linked to a carrier molecule. It is intended as an alternative to daily growth hormone in the treatment of growth hormone deficiency. This was a multi-center, randomized, open-label, active-controlled trial designed to compare the safety (including tolerability and immunogenicity), pharmacokinetics and pharmacodynamics of three doses of weekly TransCon GH to daily growth hormone (Omnitrope). Thirty-seven adult males and females diagnosed with adult growth hormone deficiency and stable on growth hormone replacement therapy for at least 3 months were, following a wash-out period, randomized (regardless of their pre-study dose) to one of three TransCon GH doses (0.02, 0.04 and 0.08 mg GH/kg/week) or Omnitrope 0.04 mg GH/kg/week (divided into 7 equal daily doses) for 4 weeks. Main outcomes evaluated were adverse events, immunogenicity and growth hormone and insulin-like growth factor 1 levels. TransCon GH was well tolerated; fatigue and headache were the most frequent drug-related adverse events and reported in all groups. No lipoatrophy or nodule formation was reported. No anti-growth hormone-binding antibodies were detected. TransCon GH demonstrated a linear, dose-dependent increase in growth hormone exposure without accumulation. Growth hormone maximum serum concentration and insulin-like growth factor 1 exposure were similar after TransCon GH or Omnitrope administered at comparable doses. The results suggest that long-acting TransCon GH has a profile similar to daily growth hormone but with a more convenient dosing regimen. These findings support further TransCon GH development.

In clinical practice, every year approximately 150,000 children are referred with short stature (SS) based on a cut-off of fifth percentile. The most important endocrine and treatable cause of SS is growth hormone deficiency (GHD). The lack of reliable data on the prevalence of GHD in India limits estimation of the magnitude of this problem. The diagnosis and treatment of GHD are hurdled with various challenges, restricting the availability of growth hormone (GH) therapy to only a very limited segment of the children in India. This review will firstly summarize the gaps and challenges in diagnosis and treatment of GHD based on literature analysis. Subsequently, it presents suggestions from the members at advisory board meetings to overcome these challenges. The advisory board suggested that early initiation of the therapy could better the chances of achieving final adult height within the normal range for the population. Education and awareness about growth disorders among parents, regular training for physicians, and more emphasis on using the Indian growth charts for growth monitoring would help improve the diagnosis and treatment of children with GHD. Availability of an easy-to-use therapy delivery system could also be beneficial in improving adherence and achieving satisfactory outcomes.

To determine the impact of hypothalamic-pituitary (HP) disorders on health outcomes in children and adolescents who received conformal radiation therapy (RT) for central nervous system tumors. Cohort study including 355 patients (age ≤25 years at diagnosis) treated with high-dose (50.4-59.4 Gy) RT using photons for low-grade glioma or ependymoma. Patients (median age, 6.4 years at RT) received systematic endocrine follow-up (median duration, 10.1 years; range, 0.1-19.6). Associations between HP disorders and adverse health outcomes were determined by multivariable analysis. Prevalence was 37.2% for growth hormone deficiency (GHD), 17.7% for gonadotropin deficiency (LH/FSHD), 14.9% for thyroid-stimulating hormone deficiency (TSHD), 10.3% for adrenocorticotropic hormone deficiency (ACTHD), and 12.6% for central precocious puberty (CPP). Hypothalamus mean dose ≥ 36Gy was associated with higher odds of any deficiency. GHD was associated with short stature (OR 2.77; 95% CI 1.34-5.70), low bone mineral density (OR 3.47; 95% CI 1.16-10.40), and TSHD with dyslipidemia (OR 5.54; 95% CI 1.66-18.52). Patients with ACTHD and CPP had lower intelligence quotient scores, and memory scores were impaired in patients with GHD (P=0.02). Treatment of GHD was not associated with increased risk for tumor recurrence, secondary tumors, or mortality. HP disorders occur frequently in patients receiving high-dose RT and are related to physical and neurocognitive well-being. Future studies are needed to assess whether further optimization of endocrine management yields better health outcomes.

Introduction Long-acting growth hormone (LAGH) preparations have been developed to reduce the burden of daily injections and improve compliance in children and adults with growth hormone deficiency (GHD). Somapacitan is the only LAGH approved for both pediatric and adult GHD that has been in the market for nearly 2 years for these indications. It has now up to 4 years of follow up data from pediatric clinical trials. Areas covered In this article, we will review the rationale for developing somapacitan and other LAGH, the pharmacologic characteristics, pharmacokinetics, and pharmacodynamics of somapacitan. We will summarize the clinical trial results of safety, efficacy, and adherence of somapacitan in comparison to daily growth hormone (GH) in both adults and children. We will also provide practical recommendations on the initiation and monitoring of somapacitan, and discuss potential future uses of this LAGH. Expert opinion Continued somapacitan therapy in clinical trials in children with GHD has shown ongoing catch-up growth while having a similar safety profile to daily growth hormone. However, it will be important to capture real world data demonstrating ongoing safety, efficacy, and adherence in children and adults receiving somapacitan and other LAGH therapies.

Treatment Experience of Children with Growth Hormone Deficiency in the Phase 3 fliGHt Trial: Switching from Daily Growth Hormone to Once-weekly TransCon hGH

In Japan, treatment of growth hormone deficiency with pituitary-extracted human growth hormone (phGH) was covered by health insurance for the first time in 1975. However, because of the shortage of phGH, the Foundation for Growth Science (FGS) was founded in 1977 to control the use of the product by its registration system and to collect pituitary glands in Japan. In 1986, recombinant human growth hormone was first approved. Since then, the FGS has been involved in the harmonization of growth hormone measurement, assessment for treatment eligibility according to the diagnostic criteria by the research group of the Ministry of Health and Welfare, and database generation and its utilization.

The Insulin-Like Growth Factors in Adipogenesis and Obesity

PurposePediatric Cushing’s disease (CD) is rare and there are limited data on the long-term outcomes. We assessed CD recurrence, body composition, pituitary function and psychiatric comorbidity in a cohort of pediatric CD patients.MethodsRetrospective review of 21 CD patients, mean age at diagnosis 12.1 years (5.7–17.8), managed in our center between 1986 and 2010. Mean follow-up from definitive treatment was 10.6 years (2.9–27.2).ResultsFifteen patients were in remission following transsphenoidal surgery (TSS) and 5 were in remission following TSS + external pituitary radiotherapy (RT). One patient underwent bilateral adrenalectomy (BA). CD recurrence occurred in 3 (14.3 %) patients: 2 at 2 and 6 years after TSS and 1 7.6 years post-RT. The BA patient developed Nelson’s syndrome requiring pituitary RT 0.6 years post-surgery. Short-term growth hormone deficiency (GHD) was present in 14 patients (81 % patients tested) (11 following TSS and 3 after RT) and 4 (44 % of tested) had long-term GHD. Gonadotropin deficiency caused impaired pubertal development in 9 patients (43 %), 4 requiring sex steroid replacement post-puberty. Four patients (19 %) had more than one pituitary hormone deficiency, 3 after TSS and 1 post-RT. Five patients (24 %) had long-term psychiatric co-morbidities (cognitive dysfunction or mood disturbance). There were significant long-term improvements in growth, weight and bone density but not complete reversal to normal in all patients.ConclusionsThe long-term consequences of the diagnosis and treatment of CD in children is broadly similar to that seen in adults, with recurrence of CD after successful treatment uncommon but still seen. Pituitary hormone deficiencies occurred in the majority of patients after remission, and assessment and appropriate treatment of GHD is essential. However, while many parameters improve, some children may still have mild but persistent defects.