Inclusion and Withdrawal Criteria for Growth Hormone (GH) Therapy in Children with Idiopathic GH Deficiency—Towards Following the Evidence but Still with Unresolved Problems

According to current guidelines, growth hormone (GH) therapy is strongly recommended in children and adolescents with GH deficiency (GHD) in order to accelerate growth rate and attain normal adult height. The diagnosis of GHD requires demonstration of decreased GH secretion in stimulation tests, below the established threshold value. Currently, GHD in children is classified as secondary insulin-like growth factor-1 (IGF-1) deficiency. Most of children diagnosed with isolated GHD presents with normal GH secretion at the attainment of near-final height or even in mid-puberty. The most important clinical problems, related to the diagnosis of isolated GHD in children and to optimal duration of rhGH therapy include: arbitrary definition of subnormal GH peak in stimulation tests, disregarding factors influencing GH secretion, insufficient diagnostic accuracy and poor reproducibility of GH stimulation tests, discrepancies between spontaneous and stimulated GH secretion, clinical entity of neurosecretory dysfunction, discrepancies between IGF-1 concentrations and results of GH stimulation tests, significance of IGF-1 deficiency for the diagnosis of GHD, a need for validation IGF-1 reference ranges. Many of these issues have remained unresolved for 25 years or even longer. It seems that finding solutions to them should optimize diagnostics and therapy of children with short stature.

Effective GH replacement with once-weekly somapacitan vs daily GH in children with GHD: 3-year results from REAL 3

Context Current GH therapy requires daily injections, which can be burdensome. Somapacitan is a long-acting GH derivative in development for treatment of GH deficiency (GHD). Objective Evaluate the efficacy, safety, and tolerability of once-weekly somapacitan after 3 years of treatment. Design A multicenter, randomized, controlled, phase 2 study comparing somapacitan and once-daily GH for 156 weeks (NCT02616562). Setting Twenty-nine sites in 11 countries. Patients Fifty-nine children with GHD randomized (1:1:1:1) and exposed to treatment. Fifty-three children completed the 3-year period. Interventions Patients received somapacitan (0.04 [n=14], 0.08 [n=15] or 0.16 [n=14] mg/kg/week) or daily GH (n=14) (0.034 mg/kg/day, equivalent to 0.238 mg/kg/week) subcutaneously during the first year, after which all patients on somapacitan received 0.16 mg/kg/week. Main Outcome Measures Height velocity (HV) at year 3; changes from baseline in height standard deviation score (HSDS), HVSDS and IGF-I SDS. Results The estimated treatment difference (95% CI) in HV for somapacitan 0.16/0.16 mg/kg/week versus daily GH at year 3 was 0.8 cm/year (−0.4; 2.1). Change in HVSDS from baseline to year 3 was comparable between somapacitan 0.16/0.16 mg/kg/week, the pooled somapacitan groups, and daily GH. A gradual increase in HSDS from baseline was observed for all groups. At year 3, mean HSDS was similar for the pooled somapacitan groups and daily GH. Change from baseline to year 3 in mean IGF-I SDS was similar across treatments. Conclusions Once-weekly somapacitan in children with GHD showed sustained efficacy over 3 years in all assessed height-based outcomes with similar safety and tolerability to daily GH.

Patients with adult GH deficiency should receive GH replacement – Debate

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Diagnosis and Treatment of Adult Growth Hormone Deficiency

Adult growth hormone (GH) deficiency is associated with insulin resistance, elevated cardiovascular risk profile, increased fat mass, reduced muscle mass, skeletal fragility, and impaired quality of life. GH replacement therapy improves body composition, exercise capacity, skeletal health, cardiovascular outcomes, and quality of life, while reducing mortality. Prior to initiation of GH replacement therapy, it is essential to diagnose GH deficiency via a GH stimulation test in adults suspicious of such deficiency. Therapy should be started using (individualized) low dose of GH, followed by titration to the normal range of insulin-like growth factor-1. Clinical improvements should be monitored and side effects should be minimized.

Idiopathic combined adrenocorticotropin and growth hormone deficiency mimicking chronic fatigue syndrome

A 42-year-old man who had suffered from severe fatigue for 5 years was diagnosed as having chronic fatigue syndrome (CFS) and fibromyalgia. Endocrinological workup using combined anterior pituitary function tests showed that the patient had adrenocorticotropin hormone (ACTH) deficiency, with a normal pituitary MRI. Treatment with a physiologic dose of oral hydrocortisone replacement physically ameliorated his general fatigue. A secondary workup using a growth hormone-releasing peptide-2 test revealed that he also had growth hormone (GH) deficiency, and GH replacement therapy was started. His muscle pain and depression were improved by the therapy. Here, we present a rare case of combined deficiency of ACTH and GH in a middle-aged man with severe general fatigue. This case report aims to raise awareness of combined deficiency of ACTH and GH as a differential diagnosis of CFS and its mimics.

Xanthomatous Hypophysitis: A Case Report and Comprehensive Literature Review

PurposeXanthomatous hypophysitis (XHP) is an extremely rare form of primary hypophysitis for which there is a lack of clinical experience. A comprehensive understanding of its clinical characteristics, diagnosis and treatment is needed.MethodsHere, we report a case study and conduct a systematic review of XHP. Thirty-six cases were included, and their clinical manifestations, endocrine assessment, imaging features, treatment and follow-up data were collected and analyzed.ResultsThe mean age at diagnosis was 39.1 years, and females were predominant (75.0%). The most common symptom was headache (68.6%), and 66.7% of female patients presented menstrual disorders. The most common pituitary dysfunction was growth hormone (GH) deficiency. More than half of patients exhibited central diabetes insipidus (CDI). The majority of patients had an imaging presentation of a cystic lesion with peripheral enhancement. Pituitary stalk thickening was observed in half of the patients. Total lesion resection was achieved in 57.1% of cases. The recurrence rate after partial resection and biopsy was significantly higher than that after total lesion resection (57.1% vs. 0.0%, P = 0.0147). The most common pituitary hormone abnormalities to resolve after surgery were hyperprolactinemia (100.0%) and GH deficiency (91.7%). The typical pathological feature was inflammatory infiltration of foamy histiocytes, which showed positivity for CD68.ConclusionDiagnosis of XHP is difficult when relying on clinical symptoms and imaging features. Therefore, surgical histopathology is necessary. Based on the available evidence, total lesion resection is recommended for treatment. However, the long-term prognosis for this rare disease remains unclear.

Development and Internal Validation of a Predictive Model for Adult GH Deficiency Prior to Stimulation Tests

BackgroundThe diagnosis of adult GH deficiency (GHD) relies on a reduced GH response to provocative tests. Their diagnostic accuracy, however, is not perfect, and a reliable estimation of pre-test GHD probability could be helpful for a better interpretation of their results.MethodsEighty patients showing concordant GH response to two provocative tests, i.e. the insulin tolerance test and the GHRH + arginine test, were enrolled. Data on IGF-I values and on the presence/absence of other pituitary deficits were collected and integrated for the estimation of GHD probability prior to stimulation tests.ResultsAn independent statistically significant association with the diagnosis of GHD was found both for IGF-I SDS (OR 0.34, 95%-CI 0.18-0.65, p=0.001) and for the presence of other pituitary deficits (OR 6.55, 95%-CI 2.06-20.83, p=0.001). A low (<25%) pre-test GHD probability could be predicted when IGF-I SDS > +0.91 in the presence of other pituitary deficits or IGF-I SDS > -0.52 in the absence of other pituitary deficits. A high (>75%) pre-test GHD probability could be predicted when IGF-I SDS < -0.82 in the presence of other pituitary deficits or IGF-I SDS < -2.26 in the absence of other pituitary deficits.ConclusionThis is the first study that proposes a quantitative estimation of GHD probability prior to stimulation tests. Our risk class stratification represents a simple tool that could be adopted for a Bayesian interpretation of stimulation test results, selecting patients who may benefit from a second stimulation test and possibly reducing the risk of wrong GHD diagnosis.

Short and Long-Term Effects of Growth Hormone in Children and Adolescents With GH Deficiency

The syndrome of impaired GH secretion (GH deficiency) in childhood and adolescence had been identified at the end of the 19th century. Its non-acquired variant (naGHD) is, at childhood onset, a rare syndrome of multiple etiologies, predominantly characterized by severe and permanent growth failure culminating in short stature. It is still difficult to diagnose GHD and, in particular, to ascertain impaired GH secretion in comparison to levels in normally-growing children. The debate on what constitutes an optimal diagnostic process continues. Treatment of the GH deficit via replacement with cadaveric pituitary human GH (pit-hGH) had first been demonstrated in 1958, and opened an era of therapeutic possibilities, albeit for a limited number of patients. In 1985, the era of recombinant hGH (r-hGH) began: unlimited supply meant that substantial long-term experience could be gained, with greater focus on efficacy, safety and costs. However, even today, the results of current treatment regimes indicate that there is still a substantial fraction of children who do not achieve adult height within the normal range. Renewed evaluation of height outcomes in childhood-onset naGHD is required for a better understanding of the underlying causes, whereby the role of various factors - diagnostics, treatment modalities, mode of treatment evaluation - during the important phases of child growth - infancy, childhood and puberty - are further explored.

Mapping the journey of transition: a single center study of 170 childhood onset GH deficiency patients

Objective: To analyze metabolic parameters, body composition (BC) and bone mineral density (BMD) in childhood onset GH deficiency (COGHD) patients during transition period (TP). Design: Single center, retrospective study was performed on 170 consecutive COGHD patients (age 19.2±2.0 years, range 16-25) transferred after growth completion from two pediatric clinics to adult endocrine unit. Two separate analyses were performed: 1) cross-sectional analysis of hormonal status, metabolic parameters, BC and BMD at first evaluation after transfer from pediatrics to adult department; 2) longitudinal analysis of BC and BMD dynamics after 3 years of GH replacement therapy (rhGH) in TP. Results: COGHD was of a congenital cause (CONG) in 50.6% subjects, tumor related (TUMC) in 23.5% and idiopathic (IDOP) in 25.9%. TUMC patients had increased insulin and lipids levels (p<0.01) and lower Z score at L-spine (p<0.05) compared to CONG and IDOP groups. Patients treated with rhGH in childhood demonstrated lower fat mass and increased BMD compared to rhGH-untreated group (p<0.01). Three years of rhGH after growth completion resulted in significant increase in lean body mass (12.1%) and BMD at L-spine (6.9%), parallel with decrease in FM (5.2%). Conclusion: The effect of rhGH in childhood is invaluable for metabolic status, BC and BMD in transition to adulthood. Tumor related COGHD subjects are at higher risk for metabolic abnormalities, alteration of body composition and decreased BMD, compared to those with COGHD of other causes. Continuation of rhGH in transition is important for improving BD and BMD in patients with persistent COGHD.