GH-deficient Patients Research Articles

Correlation of Increased Serum Adipsin with Increased Cardiovascular Risks in Adult Patients with Growth Hormone Deficiency

Objective: Adult growth hormone deficiency (AGHD) patients have an increased cardiovascular morbidity and mortality. Adipsin is an adipokine that is significantly correlated with metabolic disease, especially in people with obesity. The objective of our study was to compare AGHD patients with healthy subjects to evaluate whether adipsin levels are closely related to glycolipid metabolism and cardiovascular risks in AGHD patients. Methods: Our study included 88 AGHD patients and 88 age-, weight-, and body mass index (BMI)-matched healthy subjects. Anthropometric parameters such as BMI, waist circumference, and blood pressure were measured. Biochemical indicators such as serum adipsin, lipids, and fasting insulin levels were determined. Results: Adipsin levels in AGHD patients were significantly increased compared to levels of the control group (11,567.29 ng/mL, interquartile [9,856.46 to 13,360.60 ng/mL]) versus (9,127.86 ng/mL, interquartile [8,061.82 to 10,647.06 ng/mL], P = .000). Increased serum adipsin levels are correlated with cardiovascular risk factors such as a higher waist-to-hip ratio, serum lipids levels, and insulin resistance. Adipsin levels were inversely related to insulin-like growth factor 1 (IGF-1) (r = -0.6363, P<.0001) and insulin-like growth factor binding protein 3 levels (r = -0.498, P<.0001). The odds ratio (OR) for AGHD in the highest quartile was found to be 4.491 times the ratio in the lowest quartile (OR = 4.491, P = .048). Additionally, adipsin was found to be the most independent factor to influence IGF-1 levels in AGHD subjects. Conclusion: The serum levels of adipsin were significantly correlated with glucolipid metabolism disorder with a growth hormone deficiency status. Furthermore, serum levels of adipsin might be a good marker for the occurrence and development of cardiovascular diseases in AGHD patients. Abbreviations: AGHD = adult growth hormone deficiency; ASCVD = atherosclerotic cardiovascular disease; BMI = body mass index; DBP = diastolic blood pressure; FINS = fasting insulin; FPG = fasting plasma glucose; GH = growth hormone; HOMA-IR = homeostatic model to assess insulin resistance index; hsCRP = high-sensitivity C-reactive protein; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3; LAP = lipid accumulation products; LDL = low-density lipoprotein; SBP = systolic blood pressure; TC = total cholesterol; TG = triglycerides; WC = waist circumference; WHR = waist-to-hip ratio; OR = odds ratio.

The Relevance of Insulin-like Growth Factor-1 Concentration as a Screening Test for Diagnosis of Growth Hormone Deficiency

Objective: Growth hormone deficiency (GHD) is one of the most important endocrine and treatable causes of short stature. Insulin-like growth factor 1 (IGF-1) concentration is not recommended to establish the diagnosis of GHD. The aim of our study was to analyze the relevance of IGF-1 concentration as a screening test for the diagnosis of GHD. Materials and Methods: We retrospectively studied patients who were evaluated for short stature at the Endocrinology Department of King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia from January 2015 to December 2018. For IGF-1, laboratory reference ranges were based on age and sex. For all eligible patients, IGF-1 concentration was determined and an ITT was performed. Patients with a peak GH of ≤ 5.0 ng/ml were considered to be GHD and patients with a peak GH of ≥ 5.1 ng/ml were considered non-GHD (nGHD). Results: We retrospectively included 47 patients for analysis. Mean age was 14.7 ± 1.7 years. There were 38 males (80.9%) and 9 females (19.1%) and mean IGF-1 concentration was 146.4 ± 69.4 ng/dl. Results from the ITT indicated that 27 (57.4%) had GHD. Age was not significantly different between GHD and non-GHD (14.7 ± 1.8 vs. 14.8 ± 1.6 years, P = 0.9). There were non-significantly more males than females in GHD patients (59% vs. 50%, P = 0.7). Mean IGF-1 concentration was not significantly different (146.9 ± 70.4 ng/dl vs. 145.7 ± 69.8 ng/dl, P = 0.9). IGF-1 concentration below the reference ranges for age and gender was non-significantly higher in patients with GHD compared to non-GHD (53.8% vs. 46.2%, P = 0.8). The mean peak for GH concentration was significantly lower in patients with GHD (2.2 ± 1.3 ng/ml vs. 9.9 ± 5.6 ng/ml, P &lt; 0.0001). Peak GH concentration was not significantly correlated with IGF-1 concentration (r = 0.213, P = 0.2). We plotted a ROC curve of IGF-1 concentration according to the diagnosis of GHD as established using ITT. The AUC was 49%. An IGF-1 threshold of 154 ng/dl was selected to emphasize sensitivity rather than specificity. With a threshold of 154 ng/dl, sensitivity was 52% (95% confidence interval (95% CI); 32%, 71%), specificity was 40% (95% CI; 19%, 64%) and the negative predictive value for the diagnosis of GHD was 38% (95% CI; 24%, 54%). With a threshold of 105 ng/dl, the sensitivity was 41% and the specificity was 70%. A threshold of 74 ng/dl, gave a positive predictive value of 60% but a negative predictive value of 43%. 7 of the patients with IGF-1 concentration above the threshold of 154 ng/dl (N = 20) were normal and 13 had GH deficiency. These 13 GHD patients had IGF-1 concentration that differs significantly from those of their GH-sufficient counterparts (105 ± 35 vs. 222 ± 49 ng/dl, P &lt; 0.0001). If IGF-1 was used as a screening test (with a concentration threshold of 154 ng/dl) and ITT as a confirmatory test, 20 (43%) out of 47 ITT would not have been performed, leading to the misdiagnosis of 13 GH-deficient adults. Thus, in our study population, such a procedure would misdiagnose 13 out of 27 GHD patients (48%) and yield a sensitivity of 52%. Conclusion: Many reports have already reported that IGF-1 concentration is lower in patients with GHD than in the general population, our study demonstrated the poor negative predictive value of IGF-1 concentration for the diagnosis of GHD, making it the need of the use of the “gold standard” method ITT. This observation remains to be validated by population-based studies.

SUN-260 The Severity of GH Deficiency (GHD) Does Not Affect Adherence to Treatment in GHD Prepubertal Children Taking rh-GH via the Easypod Device

Introduction: The success of GH therapy, as in other chronic conditions, depends on the patient’s ability to maximally adhere to their treatment regimen. Low adherence to GH therapy has been reported in several studies, and shown to be correlated with age, socioeconomic status, treatment duration, the use of an injection device among others, although data are controversial. Recent studies have shown that GH deficient (GHD) patients naïve to treatment have better adherence rates than non-naïve ones, while no data exist on the effect of the severity of GHD on adherence to treatment. The Easypod Connect Observational Study (ECOS) is a prospective long-term observational study involving 24 countries aimed at evaluating the level of adherence in patients receiving growth hormone via the Easypod device. The Easypod device allows an automatic objective measure of adherence over time. The ECOS database provides adherence rates of a large number of patients receiving growth hormone via the Easypod device. Objective: to compare adherence to GH treatment in patients with high likelihood of being severe GHD (SGHD) with a group of non-severe GHD (NSGHD). Patients and methods: The group of SGHD included 17 naïve GHD prepubertal (aged 2 to 10 y in girls and 2 to 12 y in boys) patients (13 boys and 4 girls) with organic or genetic or congenital GHD. All had height-SDS <-2.5 at start of treatment and/or first year change in height >0.5 standard deviation score (SDS). The group of NSGHD included 49 naïve to treatment prepubertal (35 boys and 14 girls) with idiopathic GHD, and height SDS ≥-2.5 at start of treatment. After 2 and 3 y of treatment, respectively 15 and 12 patients were available in the SGHD group, and 37 and 22 in the NSGHD group. Differences in adherence rates between the groups were tested with the unpaired two-samples Wilcoxon test. Results: Mean (SD) height SDS at start was -2.7 (1.4) in SGHD and -2.1 (0.3) in NSGHD, and mean (SD) first year change in height SDS was 0.9 (0.5) in SGHD and 0.6 (0.3) in NSGHD. Adherence rates in the first three years of treatment were not significantly different (p>.1) between the two groups with medians of 92%, 88%, and 95% respectively in SGHD, and 93%, 90%, and 92% respectively in NSGHD. Conclusions: Our data confirm that naïve GHD children receiving GH treatment with the Easypod device have a good adherence to treatment up to three years. Our findings also show that the severity of GHD does not seem to affect adherence to treatment in prepubertal children.

MON-248 Impact of Body Mass Index on Peak Growth Hormone Response to Provocative Testing and Therapeutic Outcome in Children with Growth Hormone Deficiency

Introduction: The growth hormone (GH) stimulation test can be influenced by various factors, including type of GH stimuli, age, body mass index (BMI), and pubertal state. It is known that GH secretion is inversely related to BMI, but there is no available BMI - specific cut off value in children with growth hormone deficiency (GHD). The purpose of the study was to evaluate the therapeutic response according to obesity and relationship between GH secretion and BMI in children with GHD Methods: Among the GHD patients met the inclusion criteria, 460 patients conducted insulin stimulation test in common were enrolled for this study. Of these, the group were divided into idiopathic GHD (n=439), organic GHD (n=21), complete GHD (n=114), and partial GHD (n=325). We compared the variables including age, peak GH level, bone age, height standard deviation score (SDS), BMI SDS, and insulin-like growth factor-1 (IGF-1) SDS of each group. Results: Of the 439 patients with idiopathic GHD, 385 patients were normal (88%), 28 patients were overweight (6%), and 26 patients were obese (6%). The peak GH for the insulin stimulation test was 4.7 in obese group and 5.1 in non-obese group. The peak GH in organic GHD was 1.6 for obesity and 3.1 for non-obese group. According to the multiple regression analysis, the peak GH was significantly reduced by 1.06 as BMI SDS was increased by 1 in patients with complete GHD (p=0.03). The cutoff value of complete GHD in obese children was lower than that of non-obese group [response to insulin: obese group ≤ 4.7 (area under the curve AUC= 0.87, 95% CI 0.7-1.0), non-obese group ≤ 4.92 (AUC= 0.83, 95% CI 0.80-0.87); response to L-dopa: obese group ≤ 4.3 (AUC= 0.90, 95% CI 0.76-1.0), non-obese group ≤ 4.9 (AUC= 0.83, 95% CI 0.79-0.87)]. IGF-1 SDS and height SD at initiation of GH therapy of obese group were higher than those of non-obese group, but the height gain during GH therapy between two groups was similar. Regardless of obesity, therapeutic response of the first year of GH therapy was better than the second year of treatment. Conclusion: The BMI and GH peak of obese children with GHD shows inverse correlation, with a relatively low cutoff value. Further comparative research to better understand of the relationship between BMI and GH secretion with simple obese children is needed to expand clinical application.

Growth hormone of dried blood spot for the diagnosis of growth hormone deficiency

The diagnosis of growth hormone deficiency (GHD) is difficult to determine, and could be associated with severe complications, especially in the neonatal period. The stimulation test of growth hormone (GH) secretion is considered the gold standard for diagnosis, but it has methodological complications and is associated with adverse effects. Neonates present physiological increased secretion of GH, representing a diagnostic window. To evaluate if the dried blood spot on filter paper obtained in the neonatal period, as part of a neonatal screening for con genital hypothyroidism and phenylketonuria, allows differentiating patients with GHD from those who do not have it. Study of cases and controls by measuring the GH concen tration in dried blood spot on filter paper obtained in the neonatal period, comparing controls with GHD with cases with discarded deficiency. The sample was extracted from the filter paper, obtaining two 0.125 inch discs per each patient from the center of the blood spot on the paper, for a highly sen sitive ELISA assay for human GH based on the use of polyclonal antibodies against 22 kDa recom binant human GH. Seven cases of GHD and ten controls were obtained. The median GH concentration of the dried blood spot in the cases is 2.0 ng/ml (Interquartile range 3.6 ng/ml) and 2.05 ng/ml (Interquartile range 2.0 ng/ml) in the controls, Mann-Whitney U test 30.5 (p = 0.68). The two cases with multiple pituitary-hormone deficiency (MPHD) present concentrations lower than 1 ng/ml. The dried blood spot sample did not differentiate GHD patients from control cases, although MPHD cases present much lower concentrations compared to isolated growth hor mone deficiency (IGHD).

The Relevance of Insulin-Like Growth Factor-1 and Insulin-Like Growth FactorBinding Protein-3 Concentrations as a Screening Test for Diagnosis of Growth Hormone Deficiency

Background and objective: Growth hormone deficiency (GHD) is one of the most important endocrine and treatable causes of short stature. Reports regarding the sensitivity and specificity of insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-3) are not consistent. The aim of our study was to analyze the relevance of IGF-1 and IGFBP-3 concentrations as a screening test for diagnosis of GHD. Design: We retrospectively studied 40 patients whom were evaluated for short stature at the Endocrinology Department of King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia between January 2015 to December 2018. For IGF-1 and IGFBP-3 concentrations, laboratory reference ranges were based on age and sex. For all eligible patients, IGF-1 and IGFBP-3 concentrations were determined and an insulin tolerance test (ITT) was performed. Patients with a peak GH of ≤5.0 ng/ml were considered to be GHD. Results: We retrospectively included 40 patients evaluated for SS for analysis. Mean age was 14.7 ±1.7 years. There were 38 males (80.9%) and 9 females (19.1%) and mean IGF-1 concentration was 146.4 ±69.4 ng/dl. The observed male to female ratio was 4.2:1. Results from the ITT indicated that 27 (57.4%) had GHD. Age was not statistically significant different between GHD (14.7 ±1.8 years) and non-GHD (14.8 ±1.6 years), p=0.9. Moreover, there was non statistical significant more males (59%) than females (50%) in the GHD patients, P=0.7. In addition, there were not statistically significantly different between GHD and non-GHD patients in mean IGF-1 concentration (156.0 ±71.1 ng/dl vs. 140.8 ±68.1 ng/dl, p=0.5) and IGFBP-3 concentration (3752.9 ±1295.9mcg/L vs. 3816.8 ±867.0mcg/L, p=0.9). The mean peak for GH concentration was significantly lower in patients with GHD than without GHD (2.2 ±1.3 ng/ml vs. 9.9 ±5.6 ng/ml, p&lt;0.0001). Peak GH concentration was not significantly positively correlated with IGF-1 concentration (r=0.181, P=0.3) and IGFBP-3 concentration (r=0.103, P=0.5). With a threshold of IGF-1 concentration, sensitivity was 48% (95% confidence interval (95%CI); 26%, 70%), specificity was 37% (95%CI; 16%, 62%) and the negative predictive value for the diagnosis of GHD was 39% (95% CI; 24%, 57%). With a threshold of IGF-1+IGFBP-3 concentration, the sensitivity was 19% (95% CI; 5%, 42%) and the specificity was 89% (95%CI; 67%, 99%). A positive predictive value of 67% (95% CI; 29%, 91%) but a negative predictive value of 50% (95%CI; 44%, 56%). 17 of the patients with IGF-1+IGFBP-3 concentration above the threshold (N = 34) were normal and 17 had GH deficiency. These 17 GHD patients had IGF-1+IGFBP-3 concentration below the reference range for age and sex that did not differ significantly from those of their GH-sufficient counterparts (66.7% vs 50% , P=0.7) respectively. If IGF1+IGFBP-3 concentration was used as a screening test (with a concentration threshold below the reference range for age and sex) and ITT as a confirmatory test, 34 (85%) out of 40 ITT would not have been performed, leading to the misdiagnosis of 17 GH-deficient adults. Thus, in our study population, such a procedure would misdiagnose 17 out of 21 GHD patients (81%) and yield a sensitivity of 19%. Conclusion: Our study demonstrated the good negative predictive value of IGF-1+IGFBP-3 concentration for the diagnosis of GHD, making it possible to minimize the use of the “reference test” method ITT. This observation remains to be validated by population-based studies.

Characterization of a Novel POU1F1 Mutation Identified on Screening 160 Growth Hormone Deficiency Patients.

The objective of the study is the functional characterization of a novel POU1F1 c.605delC mutation in combined pituitary hormone deficiency (CPHD) and to report the clinical and genetic details of 160 growth hormone deficiency patients. Screening of GH1, GHRHR, POU1F1, PROP1, and HESX1 genes by Sanger sequencing was carried out in 160 trios and 100 controls followed by characterization of the POU1F1 c.605delC mutation by expression studies including site directed mutagenesis, co-transfection, protein degradation, and luciferase assays to compare the wild type and mutant POU1F1. In vitro studies showed that the POU1F1 c.605delC mutation codes for a truncated protein with reduced transactivation capacity on its downstream effectors, viz., growth hormone (GH) and prolactin (PRL) causing severe CPHD. Experiments using different protease inhibitors reveal rescue of the protein upon blockage of the lysosomal pathway that might be useful in novel drug designing using targeted approach thereby maintaining the milieu and preventing/delaying the disease. The study provides an insight into the disease causing mechanism of POU1F1 c.605delC mutation identified in a CPHD child with severe short stature and failure to thrive. It also shows mutation effect on the expression, function and turnover of protein and highlights mechanistic details by which these potent regulators may operate.

Circulating aryl hydrocarbon receptor-interacting protein (AIP) is independent of GH secretion.

BackgroundAryl hydrocarbon receptor-interacting protein (AIP) is evolutionarily conserved and expressed widely throughout the organism. Loss-of-function AIP mutations predispose to young-onset pituitary adenomas. AIP co-localizes with growth hormone in normal and tumorous somatotroph secretory vesicles. AIP protein is detectable in circulation. We aimed to investigate possible AIP and GH co-secretion, by studying serum AIP and GH levels at baseline and after GH stimulation or suppression, in GH deficiency (GHD) and in acromegaly patients.Subjects and methodsInsulin tolerance test (ITT) was performed in GHD patients (n = 13) and age-BMI-matched normal GH axis control patients (n = 31). Oral glucose tolerance test (OGTT) was performed in active acromegaly patients (n = 26) and age-BMI-matched normal GH axis control patients (n = 18). In-house immunometric assay was developed for measuring circulating AIP.ResultsSerum AIP levels were in the 0.1 ng/mL range independently of gender, age or BMI. Baseline AIP did not differ between GHD and non-GHD or between acromegaly and patients with no acromegaly. There was no change in peak, trough or area under the curve during OGTT or ITT. Serum AIP did not correlate with GH during ITT or OGTT.ConclusionsHuman circulating serum AIP in vivo was assessed by a novel immunometric assay. AIP levels were independent of age, sex or BMI and unaffected by hypoglycaemia or hyperglycaemia. Despite co-localization in secretory vesicles, AIP and GH did not correlate at baseline or during GH stimulation or suppression tests. A platform of reliable serum AIP measurement is established for further research of its circulatory source, role and impact.

Short- and long-term responsiveness to low dose growth hormone (GH) in adult GH deficiency: Role of GH receptor polymorphism.

In patients with growth hormone (GH) deficiency (GHD), low doses of recombinant human GH (rhGH) have a similar or better long-term clinical effect than higher doses. Pharmacogenetic studies suggest that GH receptor (GHR) polymorphism only influences some metabolic parameters. Nonetheless, there is no clear scientific evidence proving the effects of lower rhGH dose regimens on metabolic parameters. The aim of our prospective study was to evaluate the effects of GHR polymorphism in adult GHD patients treated with low rhGH dose during short- (6 and 12months) and long-term (5years) follow-up. Sixty-nine GHD adult patients were studied, before and during treatment with rhGH, using a standardised low-dose protocol calculated on the basis of body weight (0.01-0.03mgkg-1 week-1 ) and monitored by an insulin-like growth factor (IGF)-I plasma assay, as well as anthropometric and metabolic parameters. The GHR genotype (flfl, fld3 or d3d3) was determined from the peripheral blood. d3-GHR carriers showed a more effective short- and long-term response to low rhGH dose with respect to low-density lipoprotein reduction, body composition and blood pressure (homozygous patients only); d3-GHR homozygosity is related to a significant IGF-I increase during short-term follow-up. Regression analysis demonstrated that rhGH dose, age at diagnosis and GHR genotype are the major determinants of IGF-I increase at 6 and 12months of replacement therapy. The d3d3-GHR genotype may influence some metabolic effects during the short- and long-term follow-up of low rhGH dose and could be an independent determinant of the increase of IGF- I during short-term follow-up.

The association of +1150A polymorphism with low GH level in isolated growth hormone deficiency (IGHD) patients

Background and objectivesThe circulating level of growth hormone (GH) is necessary for normal development of skeletal and soft tissues. The growth hormone-1 (GH1) gene is responsible for GH production, any alteration in this gene causes growth hormone deficiency (GHD). We aimed to study the GH1 gene variants in a sample of Egyptian patients with isolated growth hormone deficiency (IGHD) and isolated short stature (ISS) and their possibility to be used as biomarker for GHD. MethodsForty-two short stature patients were selected and divided into two groups according to GH level, 33 patients with IGHD and 9 with ISS. Exon 4 and its flanking intronic region of GH1 were screened by Sanger sequencing. In silico analysis was used to determine the function of the detected variant. Results+1150A (rs2665802) polymorphism was detected in the studied fragment. +1150A Genotype was associated with short stature and low growth hormone levels in the two studied groups. ConclusionTo our knowledge this is the first molecular study on the IGHD and ISS in Egyptian patients. Our study sheds light on +1150A genotype may be a biomarker for IGHD and short stature.

The prevalence and volumetry of pituitary cysts in children with growth hormone deficiency and idiopathic short stature.

Background Pituitary cysts have been speculated to cause endocrinopathies. We sought to describe the prevalence and volumetry of pituitary cysts in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). Methods Six hundred and eighteen children evaluated for growth failure at the Division of Pediatric Endocrinology at New York Medical College between the years 2002 and 2012, who underwent GH stimulation testing and had a brain magnetic resonance imaging (MRI) prior to initiating GH treatment were randomly selected to be a part of this study. High resolution MRI was used to evaluate the pituitary gland for size and the presence of a cyst. Cyst prevalence, cyst volume and percentage of the gland occupied by the cyst (POGO) were documented. Results Fifty-six patients had a cyst, giving an overall prevalence of 9.1%. The prevalence of cysts in GHD patients compared to ISS patients was not significant (13.5% vs. 5.7%, p=0.46). Mean cyst volume was greater in GHD patients than ISS patients (62.0 mm3 vs. 29.4 mm3, p=0.01). POGO for GHD patients was significantly greater (p=0.003) than for ISS patients (15.3%±12.8 vs. 7.1%±8.0). Observers were blinded to patient groups. Conclusions GHD patients had a significantly greater volume and POGO compared to ISS patients. This raises the question of whether cysts are implicated in the pathology of growth failure.

Poor growth response during the first year of growth hormone treatment in short prepubertal children with growth hormone deficiency and born small for gestational age: a comparison of different criteria

BackgroundThere is no consensus on the definition of poor growth response after the first year of growth hormone (GH) treatment. We determined the proportion of poor responders identified by different criteria in children with GH deficiency (GHD) and born small for gestational age (SGA). The second aim was to analyze the IGF-1 response in poor growth responders.MethodsFirst-year height data of 171 SGA and 122 GHD children who remained prepubertal during the first GH treatment year were retrieved from the BESPEED database and analyzed. Criteria for poor first-year response/responsiveness were: change in height (∆Ht) SDS<0.3 or<0.5, height velocity (HV) SDS<0.5 or <1 based on the population reference, HV SDS<− 1 based on the KIGS expected HV curve (HV Ranke SDS), studentized residual (SR) <− 1 in the KIGS first-year prediction model.Results∆Ht SDS<0.5 gave the highest percentage poor responders (37% SGA, 26% GHD). Although % poor responders were comparable for ∆Ht SDS<0.3, HV SDS<+ 0.5, HV SDS<+ 1, SR<− 1, and HV Ranke SDS<− 1, these criteria did not always identify the same patients as poor responders. Among the poor growth responders 24% SGA and 14% GHD patients had an IGF-1 increase < 40%.ConclusionsThe different response criteria yield high but comparable percentages poor responders, but identify different patients. This study does not provide evidence that one criterion is better than another. A limited IGF-1 generation is not the major reason for a poor growth response in the first year of GH treatment in SGA and GHD children.Trial registrationRetrospectively registered.

Progression of pituitary tumours: impact of GH secretory status and long-term GH replacement therapy.

Most patients treated for hypothalamic-pituitary tumours develop GH deficiency. Long-term GH replacement treatment in adults with a previous history of hypothalamic-pituitary tumour could represent a concern about increasing the risk of tumour enlargement or recurrence. To assess the progression risk of hypothalamic-pituitary tumours according to the GH secretory status (normal GH secretion, non-treated and treated GH deficiency). and determine the predictors of neoplasm recurrence. We retrospectively reviewed 309 patients with tumours of the hypothalamic-pituitary region (294 subjects underwent neurosurgery while 81 radiotherapy) who were followed for 9.9 ± 8.3 years. Out of 309 patients, 200 were affected by severe GH deficiency; 90 of these underwent GH therapy. The tumour progression rate did not differ among GH-sufficient, not-treated and treated GH-deficient patients (16.5%, 16.4%. and 10.0%, respectively). In a multivariate analysis, previous radiotherapy (HR 0.12, CI 0.03-0.52, p < 0.005) and residual tumour (HR 8.20, CI 2.38-28.29, p < 0.001) were independent predictors of recurrence. After controlling for multiple covariates, the tumour recurrence risk in GH-sufficient and GH-treated patients was similar to that observed in not-treated GH-deficient patients. With limitations of retrospective analysis, GH therapy is not associated with an increased progression rate of tumours of the hypotalamic-pituitary region during long follow-up, thus supporting the long-term safety of GH treatment. The only predictors of tumour recurrence appear to be the presence of residual disease and the lack of radiotherapy.

Plasmatic free light chains as inflammatory marker in insulin resistance: comparison of metabolic syndrome with adult growth hormone deficiency.

Biological functions of immunoglobulin-free light chains (FLCs), other than in chronic inflammatory diseases, are still poorly defined; the field of insulin resistance (IR) has not been investigated, despite the strict relationships with oxidative stress (OS) and inflammation. Therefore, we evaluated FLCs levels and their relationships with metabolic parameters in adult growth hormone deficiency (GHD) and metabolic syndrome (MetS), both characterized by IR. One hundred subjects were enrolled: group A, patients with GHD [n =31, 24-69 years, mean ± SEM body mass index (BMI) 26.8 ± 1.5 kg/m2 ]; group B, patients with MetS (n = 29, 21-70 years, BMI 31.9 ± 1.3); group C, controls (N = 40, 21-62 years, BMI 21.6 ± 1.1). Groups were matched by age range and, for patients, by BMI. Morning blood sample was collected for metabolic parameters and FLCs, assessed by turbidimetric assay. GHD patients show levels of FLCs significantly higher than MetS and controls (mean ± SEM κ 37.21 ± 6.97, 15.27 ± 0.86, 12.34 ± 0.85 mg/l; λ 19.44 ± 2.61, 11.78 ± 0.72 and 11.67 ± 0.77 mg/l; κ/λ ratio 1.77 ± 0.13, 1.38 ± 0.09; and 1.10 ± 0.06, respectively); only κ were higher in MetS versus controls. Therefore, the ratio showed progressive declining values in GHD versus MetS versus controls. Our data show increased FLCs levels in GHD and MetS, with the highest values in the former. Both conditions show OS, but with different molecular patterns. FLCs may contribute to chronic inflammation, leading to OS, and cardiovascular complications of GHD. Prognostic and therapeutic implications require further investigation. © 2018 BioFactors, 44(5):480-484, 2018.

GH deficiency in patients with spinal cord injury: efficacy/safety of GH replacement, a pilot study.

ObjectiveGrowth hormone (GH) was shown to stimulate proliferation, migration and survival of neural cells in animal models. GH deficiency (GHD) was reported following traumatic brain lesions; however, there are not available data in spinal cord injury (SCI) patients. The aim of the study was to evaluate (1) the frequency of GHD in chronic SCI population; (2) the efficacy/safety of GH replacement in patients with SCI and suboptimal GH secretion.Design and methodsNineteen consecutive patients with chronic thoracic complete SCI (AIS-A) were studied. Patients with low GH secretion were randomized in a double-blind, placebo-controlled study to receive either subcutaneous placebo injections or GH combined with physical therapy, for 6 months. Baseline cranial MRI, AIS motor and sensory scale, quality of life (spinal cord impact measurement) and modified Ashworth spasticity scale, quantitative sensory testing and neurophysiological exploration were assessed at baseline, 1, 3 and 6 months following treatment.ResultsThirteen had GH deficiency. Seven received GH, five placebo and one dropped out. Both groups were similar according to clinical and demographical data at baseline, except for greater GH deficiency in the GH treatment group. At 6th month, patients treated with GH showed a significant improvement in SCIM-III score and in electrical perception threshold up to the 5th level below SCI, on both sides compared to baseline.ConclusionsGHD seems to be frequent in traumatic SCI and GH replacement is safe without side effects. GH combined with physical therapy can improve quality of life of SCI patients and, strikingly, the sensory perception below lesion level.

Growth hormone (GH) and triglyceride-rich lipoprotein (TRL) metabolism: Effect of one month of discontinued growth hormone treatment in growth hormone deficient patients

Aim: Growth hormone (GH) deficiency is associated with increased cardiovascular mortality. Insulin resistant states and lipid profile alterations with hypertriglyceridemia, decreased HDL cholesterol, increased small and dense LDL and postprandial hyperlipidemia are commonly observed in GH deficient patients but GH specific function in triglyceride-rich lipoprotein (TRL) metabolism regulation remains unclear.

Long-acting FC-fusion rhGH (GX-H9) shows potential for up to twice-monthly administration in GH-deficient adults.

Hybrid Fc-fused rhGH (GX-H9) is a long-acting recombinant human growth hormone (GH) under clinical development for both adults and children with GH deficiency (GHD). We compared the safety, pharmacokinetics and pharmacodynamics of weekly and every other week (EOW) dosages of GX-H9 with those of daily GH administration in adult GHD (AGHD) patients. This was a randomized, open-label, active-controlled and dose-escalation study conducted in 16 endocrinology centers in Europe and Korea. Forty-five AGHD patients with or without prior GH treatment were enrolled. Patients with prior GH treatments were required to have received the last GH administration at least 1 month prior to randomization. Subjects were sequentially assigned to treatment groups. Fifteen subjects were enrolled to each treatment group and randomly assigned to receive either GX-H9 or Genotropin (4:1 ratio). GX-H9 dosage regimens for Groups 1, 2 and 3 were 0.1 mg/kg weekly, 0.3 mg/kg EOW and 0.2 mg/kg EOW, respectively. All Genotropin-assigned subjects received 6 µg/kg Genotropin, regardless of treatment group. Main outcome analyses included measurements of serum insulin-like growth factor 1 (IGF-I), safety, pharmacokinetics, pharmacodynamics and immunogenicity. Mean GX-H9 peak and total exposure increased with an increase in dose after a single-dose administration. The mean IGF-I response was sustained above baseline over the intended dose interval of 168 h for the weekly and 336 h for the EOW GX-H9 groups. Safety profiles and immunogenicity were not different across the treatment groups and with Genotropin. GX-H9 has the potential for up to twice-monthly administration.

The Use and Abuse of Human Growth Hormone in Sports.

Context:Recombinant human growth hormone (rHGH) has become a target of abuse in the sporting world. Conversely, sports medicine clinicians may encounter athletes using rHGH to achieve normalcy in the context of growth hormone (GH) deficiency.Evidence Acquisition:Medline and PubMed databases were queried using the following keywords: GH, GH physiology, GH deficiency, acromegaly, GH athlete, GH sports, GH athletic performance, and GH deficiency concussion. Articles focusing on GH physiology, deficiency, excess, and its effects in both deficient and healthy patients were included.Study Design:Clinical review.Level of Evidence:Level 3.Results:GH is a naturally occurring hormone with important roles in human physiology. Patients with GH deficiency (GHD) present variably, and GHD has numerous etiologies. rHGH treatment has substantial therapeutic benefits for patients with GHD. The benefits of rHGH treatment in otherwise-healthy adults are uncertain. GH excess may cause health problems such as acromegaly. Professional, collegiate, and international sports leagues and associations have banned rHGH use to maintain athlete health, safety, and fair play. Athletes misusing GH may face prolonged suspensions from competition. Implementing GH abuse testing is challenging, but new methods, such as the biomarker testing procedure, are being finalized.Conclusion:rHGH is not only an important therapeutic agent for GH-deficient patients but also a target of abuse in competitive athletics. Its benefits in a healthy, adult population are uncertain. A safe exercise and competition plan, developed with a physician knowledgeable of GH use, physiology, and abuse potential, should be of benefit to a longitudinal clinician-patient relationship.

Correlation Between the Responses to Growth Hormone (GH) Treatment During Childhood and Adulthood in a Monocentric Cohort of GH-Deficient Patients.

Our aim was to analyze a cohort of patients with childhood-onset growth hormone deficiency (GHD) to evaluate if there is some correlation between the response to GH treatment during childhood and adulthood, respectively. This was an observational retrospective monocentric cohort study of 47 patients treated with GH during childhood and adulthood. Changes in growth parameters during childhood were compared with the increase of IGF-I z-score and other indexes of GH response (body composition, lipid profile) after 1 year of treatment in adulthood. The only significant positive correlation was observed between final growth velocity during the last year of childhood GH treatment and increase in IGF-I z-score in GH-treated adults (r=0.592, p=< 0.01). No correlation was observed between growth-promoting effects of GH as child and metabolic changes induced by GH as adult. We also observed a negative correlation between weight at the end of childhood GH treatment and the IGF-I response during first year of treatment in adults (r=- 0.335, p <0.05). No significant positive correlation could be observed between the main parameters that evaluate response to GH treatment in children and adults. However, the final growth velocity, which may be considered as one of the main criteria of end of GH treatment in children, was identified as parameter that could predict future response to GH treatment in adulthood.

Near final height in patients with idiopathic growth hormone deficiency: A single‐centre experience

We analysed near final height (NFH) data in children with growth hormone deficiency (GHD) treated with recombinant human GH (rhGH). We divided the idiopathic GHD patients into two groups, isolated GHD (IGHD) and multiple pituitary hormone deficiency, to evaluate NFH. Then, data were grouped according to gender, pre-pubertal/pubertal status and spontaneous or induced puberty. The trial was performed as a retrospective study. Median values are given, and measurements are expressed as standard deviation scores (SDSs). rhGH therapy was started at a median age of 12.1 (range 9.1-14.9) years in the IGHD group (n = 162, 83 males) and 9.1 (range 4.9-13.4) years in the multiple pituitary hormone deficiency group (n = 33, 22 males) at a median dose of 0.20 mg/kg/week. Height SDSs at the onset of therapy were -3.2 (range -4.4 to -2.6) and -3.9 (-6.8 to -2.8) in the two groups, respectively (P < 0.001). NFH SDSs were -1.8 (-2.9 to -1) and -1.6 (-3.1 to -0.4) (P = 0.139), and delta height SDSs (finish - start) were 1.4 (0.3-2.5) and 2.6 (1.5-4.6) (P < 0.001), respectively. Total delta height was 1.4 SDS (0.4-3.1) in patients who started rhGH treatment in the pre-pubertal period and 1.3 SDS (0.3-2.4) (P = 0.106) in those who started rhGH in the pubertal period. About 85% of the cases reached their genetic height potential. Delta height SDSs were higher than expected in cases that started treatment during the pubertal period. Therefore, it is possible to achieve NFH within the mid-parental height range in patients who start therapy during puberty.