Individualized Growth Hormone Treatment - Using Two Different Prediction Models in a Clinical Setting

BackgroundDiagnosing growth hormone deficiency (GHD) can be challenging; hence, prediction models on growth outcome from growth hormone (GH) treatment have shown to be useful. We aim to compare the accuracy of the more readily available KIGS (Pfizer International Growth Study) prediction model to the previously clinically validated Gothenburg model.MethodsPrepubertal children with GHD who started GH treatment at Queen Silvia Children’s Hospital between 2004 and 2016 were considered for the study. Exclusion criteria were short stature due to syndrome, chronic disease, oncology disease, or known bad adherence. Growth predictions were made according to the Gothenburg model and the KIGS model. Growth data from birth until one year after start of GH treatment were collected from medical charts. Predicted height and observed height were then compared. ResultsA total of 123 children, 47 girls (38%) and 76 boys (62%) were included, with a mean age of 5.71 (±1.81 SD) years at start of GH treatment. The Pearson correlation of predicted first-year growth versus growth outcome were r = 0.990 for the Gothenburg model and r = 0.991 for the KIGS model. Studentized residuals were 0.10 ± 0.81 SD and 0.03 ± 0.96 SD, respectively, for the models. The comparison between the two models showed r = 0.995.ConclusionThe Gothenburg model and the KIGS model are equally accurate at predicting height outcome from GH treatment for our study cohort. We therefore promote the use of either model in clinical settings.

Origin of the X-chromosome influences the development and treatment outcomes of Turner syndrome

Turner syndrome (TS) affects 1/2,500 live-born female infants. In the present study, we attempted to clarify the relationship between genetic factors (especially the X-chromosome origin), clinical features, body/sexual development, and treatment outcomes. We enrolled 39 female infants aged between 3 and 14 years. General demographic and clinical features were documented, and laboratory analysis of blood samples was performed. Subject karyotype was determined by G-banding of 50 peripheral white blood cells, and the parenteral origin of the retained X-chromosome was determined. Next, growth hormone (GH) treatment was prescribed for 12 months, with follow-ups performed as determined. For patient groups separated according to X-chromosome origin, the basal height, bone age, insulin-like growth factor (IGF)-1, and insulin-like growth factor binding protein-3 (IGFBP-3) levels were comparable; however, after the 12-month treatment, significant differences in the height increase and IGF-1 levels were observed. If the X-chromosome (or chromosomes) originated from both parents, the increase in height was less substantial, with lower serum IGF-1 levels. The uterine size, prolactin level, increased weight after treatment, and bone age difference after treatment negatively correlated with the mother’s age at the time of birth. The mother’s height at the time of birth demonstrated a negative correlation with the basal bone age difference and a positive correlation with the IGF-1 level. In summary, the retained X-chromosome derived from both parents is associated with poorer response to GH therapy. The mother’s age and height at the time of birth can strongly impact the patient’s body/sexual development and the response to GH treatment. Thus, the mother’s age and height at the time of birth and the parental origin of the X-chromosome should be carefully considered before developing a treatment plan for TS.

Cardiovascular safety of growth hormone treatment in Noonan syndrome: real-world evidence

Objective: To assess cardiovascular (CV) safety of growth hormone (GH) treatment in patients with Noonan syndrome (NS) in clinical practice. Design: Two observational, multicentre studies (NordiNet® IOS and the ANSWER Program) evaluating long-term effectiveness and safety of GH in >38,000 paediatric patients, of which 421 had NS. Methods: Serious adverse events, serious adverse reactions (SARs), and non-serious adverse reactions (NSARs) were reported by the treating physicians. CV comorbidities at baseline and throughout the studies were also recorded. Results: The safety analysis set comprised 412 children with NS (29.1% females), with a mean (standard deviation) baseline age of 9.29 (3.88) years, treated with an average GH dose of 0.047 (0.014) mg/kg/day during childhood. CV comorbidities at baseline were reported in 48 (11.7%), most commonly pulmonary valve stenosis and atrial septal defects. Overall, 22 (5.3%) patients experienced 34 safety events. The most common were the NSARs: headache (eight events in seven patients) and arthralgia (five events in three patients). Two SARs occurred in one patient (brain neoplasm and metastases to spine). No CV safety events were recorded in patients with NS. Five CV comorbidities in five patients were reported after initiation of GH treatment: three cases of unspecified CV disease, one ruptured abdominal aortic aneurysm and one pulmonary valve stenosis. Conclusions: GH treatment had a favourable safety profile in patients with NS, including those with CV comorbidities. Prospective studies are warranted to systematically assess the safety of GH treatment in patients with Noonan syndrome and CV disease.

Management of childhood-onset craniopharyngioma in Italy: A multicenter seven year follow-up study of 145 patients

Context Nationwide data on children diagnosed with craniopharyngioma (CP) are not available in Italy. Objective Identify patients’ characteristics, type of surgical approach, complications and recurrences, number of pituitary deficits and number of patients starting GH treatment. Methods Retrospective multicenter collection of 145 patients aged 0-18 years underwenting surgery for CP between 2000-2018, followed-up in 17 Italian centers of Pediatric Endocrinology. Results Age at diagnosis was 8.4±4.1 years. Duration of symptoms was 10.8±12.5 months and headache was most frequent (54%), followed by impaired growth (48%) and visual disturbances (44%). Most lesions were suprasellar (85%) and histology was adamantinomatous in all cases but two. Surgical approach was transcranic (TC) in 67.5% of cases and transphenoidal (TS) in 31.%. TC approach was prevalent in all age groups. Post-surgery complications occurred in 53% of cases with water-electrolyte disturbances most frequent. Radiotherapy was used in 39% of cases. All patients but one presented at least one hormone pituitary deficiency, with TSH deficit as most frequent (98.3%), followed by ACTH (96.8%), AVP (91.1%) and GH (77.4%). BMI significantly increased over time. A hypothalamic disturbance was present in 55% of cases. GH therapy was started during follow-up in 112 patients at a mean age of 10.6 years and 54 developed a recurrence or regrowth of the residual lesion. Conclusions CP is often diagnosed late also in Italy with TC more frequent than TS surgical approach. Post-surgery complications were not rare and hypopituitarism developed almost in all cases. BMI shows a tendency to increase overtime.

Growth hormone stimulation testing patterns contribute to sex differences in pediatric growth hormone treatment

Introduction: Males are twice as likely as females to receive pediatric growth hormone (GH) treatment in the United States, despite similar distributions of height z-scores in both sexes. Male predominance in evaluation and subspecialty referral for short stature contributes to this observation. This study investigates whether sex differences in GH stimulation testing and subsequent GH prescription further contribute to male predominance in GH treatment. Methods: Retrospective chart review was conducted of all individuals, age 2-16 years, evaluated for short stature or poor growth at a single large tertiary referral center between 2012-2019. Multiple logistic regression models were constructed to analyze sex differences. Results: Of 10,125 children referred for evaluation, a smaller proportion were female (35%). More males (13.1%) than females (10.6%) underwent GH stimulation testing (p<0.001) and did so at heights closer to average (median height z-score -2.2 [interquartile range (IQR) -2.6, -1.8] vs. -2.5 [IQR -3.0,-2.0], respectively; p<0.001). The proportion of GH prescriptions by sex was similar by stimulated peak GH level. Predictor variables in regression modeling differed by sex: commercial insurance predicted GH stimulation testing and GH prescription for males only, whereas lower height z-score predicted GH prescription for females only. Conclusions: Sex differences in rates of GH stimulation testing, but not subsequent GH prescription based on response to GH stimulation testing, seem to contribute to male predominance in pediatric GH treatment. That height z-score predicted GH prescription in females but not males raises questions about the extent to which sex bias—from children, parents and/or physicians—, as opposed to objective growth data, influence medical decision-making in the evaluation and treatment of short stature.

Growth hormone promotes hepatic gluconeogenesis by enhancing BTG2–YY1 signaling pathway

Growth hormone (GH) is one of the critical factors in maintaining glucose metabolism. B-cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are key regulators of diverse metabolic processes. In this study, we investigated the link between GH and BTG2–YY1 signaling pathway in glucose metabolism. GH treatment elevated the expression of hepatic Btg2 and Yy1 in primary mouse hepatocytes and mouse livers. Glucose production in primary mouse hepatocytes and serum blood glucose levels were increased during GH exposure. Overexpression of hepatic Btg2 and Yy1 induced key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6 phosphatase (G6PC) as well as glucose production in primary mouse hepatocytes, whereas this phenomenon was markedly diminished by knockdown of Btg2 and Yy1. Here, we identified the YY1-binding site on the Pck1 and G6pc gene promoters using reporter assays and point mutation analysis. The regulation of hepatic gluconeogenic genes induced by GH treatment was clearly linked with YY1 recruitment on gluconeogenic gene promoters. Overall, this study demonstrates that BTG2 and YY1 are novel regulators of GH-dependent regulation of hepatic gluconeogenic genes and glucose production. BTG2 and YY1 may be crucial therapeutic targets to intervene in metabolic dysfunction in response to the GH-dependent signaling pathway.

Real-World Treatment Patterns and Outcomes of Growth Hormone Treatment Among Children in Israel Over the Past Decade (2004–2015)

Objective: To assess a decade of growth hormone (GH) treatment patterns and outcomes in a real-world setting in Israel using a state-of-the-art computerized database.Methods: This large retrospective database study included 2,379 children initiating GH treatment in Maccabi Healthcare Services (between January 2004 and December 2014). Good adherence with therapy (proportion of days covered &gt;80%) was assessed during follow-up.Results: At GH treatment initiation: 62.1% were boys; height standard deviation score (SDS) was −2.36 ± 0.65 (mean ± SD); age was 9.8 ± 3.1 years; and time from short stature diagnosis to first GH purchase was 4.8 ± 3.3 years. Mean treatment period was 3.5 ± 0.95 years; 79.4% of children were treated for more than 3 years. The two main indications for GH therapy were idiopathic short stature (ISS) (n = 1,615, 67.9%) and GH deficiency (GHD) (n = 611, 25.7%). Children in the highest socio-economic-status (SES) tertile comprised 61.3% of ISS and 59.7% of GHD. After 3 years, mean height gain SDS was 1.09 ± 0.91 for GHD and 0.96 ± 0.57 for ISS (p = 0.0004). Adult height (age 15 for girls and 17 for boys) was recorded for 624 patients (26.2%) with better outcomes for GHD than ISS (−1.0±0.82 vs. −1.28±0.93, respectively; p = 0.0002). Good adherence was achieved in 78.2% of the cohort during the first year and declined thereafter to 68.1% during the third year of the treatment.Conclusions: Children who initiate GH therapy are predominantly male, belong mainly to the upper SES, commence treatment a long period after initial recognition of short stature, and have suboptimal adherence. Appropriate referral, diagnosis, and follow-up care may result in better treatment outcomes with GH therapy.

Safety of growth hormone (GH) treatment in GH deficient children and adults treated for cancer and non-malignant intracranial tumors—a review of research and clinical practice

Individuals surviving cancer and brain tumors may experience growth hormone (GH) deficiency as a result of tumor growth, surgical resection and/or radiotherapy involving the hypothalamic-pituitary region. Given the pro-mitogenic and anti-apoptotic properties of GH and insulin-like growth factor-I, the safety of GH replacement in this population has raised hypothetical safety concerns that have been debated for decades. Data from multicenter studies with extended follow-up have generally not found significant associations between GH replacement and cancer recurrence or mortality from cancer among childhood cancer survivors. Potential associations with secondary neoplasms, especially solid tumors, have been reported, although this risk appears to decline with longer follow-up. Data from survivors of pediatric or adult cancers who are treated with GH during adulthood are scarce, and the risk versus benefit profile of GH replacement of this population remains unclear. Studies pertaining to the safety of GH replacement in individuals treated for nonmalignant brain tumors, including craniopharyngioma and non-functioning pituitary adenoma, have generally been reassuring with regards to the risk of tumor recurrence. The present review offers a summary of the most current medical literature regarding GH treatment of patients who have survived cancer and brain tumors, with the emphasis on areas where active research is required and where consensus on clinical practice is lacking.