GH-deficient Subjects Research Articles

Attenuation of gadolinium enhancement in pituitary gland on magnetic resonance imaging of patients with pediatric growth hormone deficiency

BackgroundAlthough it is generally thought that disturbance of perfusion in the anterior lobe of the pituitary gland leads to complete or partial hypopituitarism, the gadolinium (Gd) enhancement findings on Magnetic Resonance Imaging (MRI) of patients with growth hormone deficiency (GHD) remain unknown. The purpose of this study was to compare Gd enhancement of the pituitary gland on MRI of patients with GHD to that of healthy subjects.MethodsIn this retrospective study, we analyzed the data of 10 patients with clinically diagnosed GHD who underwent Gd-enhanced MRI of their pituitaries (age 8.3pm3.5 year, female 1, males 9), together with data of 5 patients with clinically normal growth hormone (GH) dynamics who also underwent Gd-enhanced pituitary MRI (age 6.2pm3.4 year, female 4, males 1). In each subject, a maximum-diameter region of interest (ROI) was drawn on the anterior pituitary gland of post Gd-enhanced coronal T1-weighted images, and the signal intensity ratio of the anterior pituitary gland to the white matter on the right temporal lobe of the same cross section was assessed.ResultsThe mean area of the ROI in the anterior pituitary gland and white matter of temporal lobe on the same cross section showed no significant differences between patients with GHD and those with normal GH (pituitary, 17.43 mm2pm8.24 vs. 21.08 mm2pm10.40, p = 1.00; white matter, 74.47mm2pm24.19 and 62.50 mm2pm17.90, p = 0.37), suggesting that the sizes of the pituitary glands were comparable. The ratios of Gd enhancement in the anterior pituitary gland showed significant differences between GHD and normal-GH subjects (pm0.716pm0.68pm0.26 vs.0.72pm0.16, p= 0.04).ConclusionsThese results suggested that the contrast effect on Gd-enhanced MRI is attenuated in the pituitary glands of patients with GHD compared to those with normal GH. These new clinical findings regarding Gd-enhanced MRI can assist the diagnosis of pediatric GHD.

Diagnosis of childhood and adolescent growth hormone deficiency using transcriptomic data.

Gene expression (GE) data have shown promise as a novel tool to aid in the diagnosis of childhood growth hormone deficiency (GHD) when comparing GHD children to normal children. The aim of this study was to assess the utility of GE data in the diagnosis of GHD in childhood and adolescence using non-GHD short stature children as a control group. GE data was obtained from patients undergoing growth hormone stimulation testing. Data were taken for the 271 genes whose expression was utilized in our previous study. The synthetic minority oversampling technique was used to balance the dataset and a random forest algorithm applied to predict GHD status. 24 patients were recruited to the study and eight subsequently diagnosed with GHD. There were no significant differences in gender, age, auxology (height SDS, weight SDS, BMI SDS) or biochemistry (IGF-I SDS, IGFBP-3 SDS) between the GHD and non-GHD subjects. A random forest algorithm gave an AUC of 0.97 (95% CI 0.93 - 1.0) for the diagnosis of GHD. This study demonstrates highly accurate diagnosis of childhood GHD using a combination of GE data and random forest analysis.

Efficacy of short-term induction therapy with low-dose testosterone as a diagnostic tool in the workup of delayed growth and puberty in boys

Constitutional delay of growth and puberty (CDGP) represents the most frequent cause of delayed puberty in males, sharing some clinical features with growth hormone deficiency (GHD) and isolated hypogonadotropic hypogonadism (IHH). Short-term induction therapy (SIT) has been approved for the induction of puberty in CDGP. We aim to investigate the efficacy of SIT with transcutaneous testosterone gel (TTG) or intramuscular testosterone therapy (IMTT) in a cohort of CDGP subjects, compared to clinical observation. Furthermore, we aim to evaluate the role of SIT as a diagnostic tool to differentiate CDGP from GHD and IHH subjects. The retrospective study included 246 male subjects with delayed puberty. The study population was divided into three groups: TTG, IMTT, and control group (CNT). At 6months observation, height velocity (HV) was significantly increased in both treated groups compared to CNT group, particularly higher in TTG than IMTT group. A significant testicular enlargement was revealed in both CNT and TTG group compared to IMTT group. Furthermore, LH value was significantly greater in TTG compared to IMTT group. IGF-1 values after SIT rose significantly in both treated groups compared to CNT group. Moreover, almost all GH provocative tests performed after SIT showed a normal GH response. SIT with TTG appears to be more effective to induce growth spurt, better tolerated and with a more physiological effect on pubertal induction compared to IMTT in CDGP population. Finally, TTG might be a useful tool in the diagnostic work up to discriminate CDGP from GHD or IHH.

The Long-Term Effects of Growth Hormone Replacement on Bone Mineral Density and Trabecular Bone Score: Results of the 10-Year Prospective Follow-up.

There are only few studies concerning about long-term effect of growth hormone (GH) replacement therapy on bone mineral density and bone microstructure. To assess effect of GH replacement therapy on bone mineral density (BMD) and trabecular bone score (TBS) in adult GH deficient (AGHD) subjects over period of 10 years. From 2005 to 2018, a prospective study of AGHD patients was conducted in national referral center for treatment of GHD. All patients received subcutaneous recombinant human GH in an IGF 1-normalizing regimen once a day. Lumbar spine (L-spine) and total hip (TH) BMD using Hologic densitometers were measured at baseline and every two years during treatment with rhGH. TBS was derived from L1-L4 DXA using iNsight® software (Medimaps, France) at each time point. Periods of measurement were baseline, year 2; 4; 6; 8 and 10. In total, 63 patients (38 males, 25 females, mean age 25.1±16 years) were included in the study. After 10 years of GH treatment, IGF-1 significantly increased (~35 %), with greatest increase at year 2. During 10-year follow-up, L-spine BMD increased approximately of 7 % (NS). TH BMD increase of 11 % during follow-up (p=0.0003). The greatest increment of BMD was achieved at year 6 on both sites, L-spine (+6 %) and TH BMD (+13 %) (p<0.05). There was no significant change of TBS during whole follow-up. In this study, sustaining positive effect of GH replacement therapy on bone density in subjects with adult GH deficiency over 10 years of follow-up was observed. The study did not show effect on TBS, as indirect measure of trabecular bone microarchitecture.

Circulating insulin-like growth factor 1 levels are reduced in very young children with Prader-Willi syndrome independent of anthropometric parameters and nutritional status.

Insulin growth factor-1 (IGF-1) is used to evaluate growth hormone (GH) sufficiency and is decreased in children with Prader-Willi syndrome (PWS). Although IGF-1 is negatively affected by body size and nutritional status, both of which are impaired in PWS children, these variables are typically not considered when assessing IGF-1 levels in these subjects. Here, we compared IGF-1 levels in PWS children to controls matched for age, sex, anthropometric parameters, and nutritional status. The retrospective analysis included genetically diagnosed PWS subjects (n = 65, median age; 14.0 months) and controls (n = 111, 14.3 months) matched for age, sex, anthropometric parameters (height-standard deviation score [SDS], weight-SDS, body mass index-SDS), and serum albumin levels, a marker for nutritional status. IGF-1 SDS was compared between PWS subjects and controls after adjustment for confounding variables. The GH provocation test was performed in 29 PWS subjects, and IGF-1 SDS was compared between GH-sufficient (n = 20) and GH-deficient (n = 9) subjects. Spearman's rank correlation coefficient was performed to investigate the association between age and IGF-1 SDS. None had received GH or levothyroxine treatment. After adjustment for confounding variables, IGF-1 SDS was significantly lower in PWS subjects than controls (-1.56 vs. -1.01, p = .003), while it was not different between GH-sufficient and GH-deficient PWS subjects. Correlation analysis failed to show an association between age and IGF-1 SDS both in control and PWS groups. IGF-1 SDS is lower in very young children with PWS independent of anthropometric parameters and nutritional status, suggesting the presence of hypothalamic dysfunction of GH secretion.

Circulating microRNA profile in humans and mice with congenital GH deficiency.

Reduced inflammation, increased insulin sensitivity, and protection against cancer are shared between humans and mice with GH/IGF1 deficiency. Beyond hormone levels, miRNAs are important regulators of metabolic changes associated with healthy aging. We hypothesized that GH deficiency in humans alters the abundance of circulating miRNAs and that a subset of those miRNAs may overlap with those found in GH‐deficient mice. In this study, subjects with untreated congenital isolated GH deficiency (IGHD; n = 23) and control subjects matched by age and sex (n = 23) were recruited and serum was collected for miRNA sequencing. Serum miRNAs from young (6 month) and old (22 month) Ames dwarf (df/df) mice with GH deficiency and their WT littermates (n = 5/age/genotype group) were used for comparison. We observed 14 miRNAs regulated with a genotype by age effect and 19 miRNAs regulated with a genotype effect independent of age in serum of IGHD subjects. These regulated miRNAs are known for targeting pathways associated with longevity such as mTOR, insulin signaling, and FoxO. The aging function was overrepresented in IGHD individuals, mediated by hsa‐miR‐31, hsa‐miR‐146b, hsa‐miR‐30e, hsa‐miR‐100, hsa‐miR‐181b‐2, hsa‐miR‐195, and hsa‐miR‐181b‐1, which target the FoxO and mTOR pathways. Intriguingly, miR‐181b‐5p, miR‐361‐3p, miR‐144‐3p, and miR‐155‐5p were commonly regulated in the serum of humans and GH‐deficient mice. In vitro assays confirmed target genes for the main up‐regulated miRNAs, suggesting miRNAs regulated in IGHD individuals can regulate the expression of age‐related genes. These findings indicate that systemic miRNAs regulated in IGHD individuals target pathways involved in aging in both humans and mice.

Diagnosis of Childhood and Adolescent Growth Hormone Deficiency Using Transcriptomic Data

Background: We have shown that gene expression (GE) data have promise as a novel tool to aid in the diagnosis of childhood growth hormone deficiency (GHD)1. Our previous study compared GE data in children with GHD to healthy control children of normal stature. The aim of this study was to assess the utility of GE data in the diagnosis of GHD in childhood and adolescence using non-GHD short stature children as a control group. Methods: GE data were obtained from patients undergoing growth hormone stimulation testing via a sample of blood taken at the start of the test. Arginine and glucagon stimulation tests with a cut-off for peak GH of <7mcg/L (IDS iSYS assay) were used for the diagnosis of GHD. GE was assessed in peripheral blood mononuclear cells via RNA-seq using the Illumina HiSeq 4000 platform. Data were taken for the 271 genes whose expression was utilised in our previous study. The synthetic minority oversampling technique was used to balance the dataset and a random forest algorithm applied to predict GHD status. Boruta was used to assess which of the genes were contributing to the predictive capacity. Results: Twenty-four patients were recruited to the study, with eight subsequently diagnosed with GHD. Of the eight patients diagnosed with GHD, three had two stimulation tests and five had one stimulation test with anterior pituitary hypoplasia (in addition one patient had an arachnoid cyst and another a thin stalk). Median (range) peak GH was 2.5 (0.1 - 5) mcg/L in the GHD group and 11.0 (7.4 - 31) mcg/L in the non-GHD group.There were no significant differences in gender, age, auxology (height SDS, weight SDS, BMI SDS) or biochemistry (IGF-I or IGFBP-3 SDS) between the GHD and non-GHD subjects. 82 of the 271 genes used in our previous study were above the threshold of detection for RNA-seq in this study. A random forest algorithm using these 82 genes gave an AUC of 0.97 (95% CI 0.93 - 1.0) for the diagnosis of GHD. Boruta was able to identify 65/82 genes with predictive capacity greater than permuted data within the dataset. Using a gene ontology approach the top fifty biological processes generated 16 clusters by affinity propagation which included regulation of TORC1 signalling and inositol phosphate metabolism. Conclusion: This study demonstrates highly accurate diagnosis of childhood GHD using a combination of GE data and random forest analysis and validates the findings of our original study. 1Murray etal (2018) JCI Insight 3(7): e93247

Gene polymorphisms in leptin and its receptor and the response to growth hormone treatment in patients with idiopathic growth hormone deficiency.

This study aimed to investigate the relationships between genetic polymorphisms of leptin/receptor genes and clinical/biochemical characteristics in children with growth hormone deficiency (GHD). Ninety-three GHD children and 69 age-matched normal controls were enrolled. Anthropometric measurements, bone age, and laboratory test results were obtained. Polymorphisms in the LEP gene promoter locus (LEP-2548, rs7799039) and LEPR genes (K109R, rs1137100 and Q223R, rs1137101) were analyzed using PCR-RFLP. The serum leptin levels were measured using an ELISA kit. The median height and BMI z-scores of all GHD subjects were -2.20 and -0.26, respectively, and those of normal controls were -0.30 and -0.13, respectively. The serum leptin levels were similar between GHD subjects and normal controls (p = 0.537), but those were different between the complete GHD (6.97 ng/mL) and partial GHD (4.22 ng/mL) groups (p = 0.047). There were no differences in the genotypic distributions of LEP-2548, LEPR K109R, and Q223R between GHD subjects and normal controls. However, GHD subjects with the G allele at LEP-2548 showed higher IGF-1 (p = 0.047) and IGFBP-3 SDSs (p = 0.027) than GHD subjects with the A allele. GHD subjects with the G allele at LEPR Q223R showed lower stimulated GH levels (p = 0.023) and greater height gain after 1 year of GH treatment (p = 0.034) than GHD subjects with the A allele. In conclusion, leptin/leptin receptor genes are suggested to have the role of growth-related factors, which can affect various growth responses in children who share the same disease entity.

Evaluation of oxidative stress effects on different macromolecules in adult growth hormone deficiency.

Adult growth hormone deficiency (GHD) is being increasingly recognized to cause premature mortality exacerbated by oxidative stress. A case-control observational study has been performed with the primary objective of evaluating new parameters of oxidative stress and macromolecular damage in adult GHD subjects: serum nitrotryptophan; Total Antioxidant Capacity expressed as LAG time; urinary hexanoil-lysine; urinary dityrosine and urinary 8-OH-deoxyguanosine. GHD was diagnosed using Growth Hormone-Releasing Hormone 50μg iv+arginine 0,5 g/Kg test, with a peak GH response <9 μg /L when BMI was <30 kg/m2 or <4 μg/L when BMI was >30 kg/m2. Patients affected by adult GHD were divided into three groups, total GHD (n = 26), partial GHD (n = 25), and controls (n = 29). Total Antioxidant Capacity, metabolic and hormonal parameters have been determined in separate plasma samples; nitrotryptophan in serum samples; hexanoil-lysine, dityrosine, 8-OH-deoxyguanosine in urine samples. Assessment of hexanoil-lysine exhibited a trend to increase in comparing total GHD vs partial and controls, although not significant. Values of 8-OH-deoxyguanosine did not significantly differ among the three groups. Significant lower levels of dityrosine in partial GHD vs total and controls were found. No significant difference in nitrotriptophan serum levels was found, while significantly greater values of Total Antioxidant Capacity were showed in total and partial GHD vs controls. Thus, our result confirm that oxidative stress is increased both in partial and total adult GHD. The lack of compensation by antioxidants in total GHD may be connected to the complications associated to this rare disorder.

Deficits in Bone Geometry in Growth Hormone-Deficient Prepubertal Boys Revealed by High-Resolution Peripheral Quantitative Computed Tomography

Introduction: Although growth hormone (GH) is essential for attainment of peak bone mass, bone health in prepubertal children with GH deficiency is not routinely evaluated. The objective of this study was to evaluate bone microarchitecture in GH-deficient (GHD) boys using high-resolution peripheral quantitative computed tomography (HR-pQCT). Methods: Fifteen control and fifteen GHD, GH naïve pre-pubertal boys were recruited for a case-control study at a major academic center. Subjects with panhypopituitarism, chromosomal pathology, chronic steroids, or stimulant use were excluded. Volumetric bone mineral density (vBMD; total, cortical, and trabecular), bone geometry (total, cortical and trabecular cross-sectional area, cortical perimeter), bone microarchitecture, and estimated bone strength of the distal radius and tibia were assessed by HR-pQCT. Areal BMD and body composition were assessed by DXA. Insulin-like growth factor 1 (IGF-1), osteocalcin, C telopeptide, and P1NP levels were measured. Results: GHD subjects had a significantly smaller cortical perimeter of the distal radius compared to controls (p < 0.001), with the difference in cortical perimeter persisting after adjusting for height z score, age, lean mass, and 25-hydroxyvitamin D level (p < 0.05).No significant differences were found in vBMD. No significant differences were found in microarchitecture, estimated strength, areal BMD, body composition, or bone turnover markers. Analysis showed significant positive correlations between IGF-1 levels and cortical parameters. Discussion/Conclusions: Prepubertal GHD boys had deficits in bone geometry not evident with DXA. Larger prospective/longitudinal HR-pQCT studies are needed to determine the extent of these deficits, the need for routine bone evaluation, and the timing of GH replacement for prevention or restoration of these deficits.

Long-term response to recombinant human growth hormone treatment: a new predictive mathematical method.

Recombinant GH has been offered to GH-deficient (GHD) subjects for more than 30years, in order to improve height and growth velocity in children and to enhance metabolic effects in adults. The aim of our work is to describe the long-term effect of rhGH treatment in GHD pediatric patients, suggesting a growth prediction model. A homogeneous database is defined for diagnosis and treatment modalities, based on GHD patients afferent to Hospital Regina Margherita in Turin (Italy). In this study, 232 GHD patients are selected (204 idiopathic GHD and 28 organic GHD). Each measure is shown in terms of mean with relative standard deviations (SD) and 95% confidence interval (95% CI). To estimate the final height of each patient on the basis of few measures, a mathematical growth prediction model [based on Gompertzian function and a mixed method based on the radial basis functions (RBFs) and the particle swarm optimization (PSO) models] was performed. The results seem to highlight the benefits of an early start of treatment, further confirming what is suggested by the literature. Generally, the RBF-PSO method shows a good reliability in the prediction of the final height. Indeed, RMSE is always lower than 4, i.e., in average the forecast will differ at most of 4cm to the real value. In conclusion, the large and accurate database of Italian GHD patients allowed us to assess the rhGH treatment efficacy and compare the results with those obtained in other Countries. Moreover, we proposed and validated a new mathematical model forecasting the expected final height after therapy which was validated on our cohort.

Disagreement in normative IGF-I levels may lead to different clinical interpretations and GH dose adjustments in GH deficiency.

Normative data for the iSYS IGF-I assay have been published both in the VARIETE cohort and by Bidlingmaier etal. To investigate whether normative data of the VARIETE cohort lead to differences in Z-scores for total IGF-I and clinical interpretation compared to normative data of Bidlingmaier etal. We used total IGF-I values previously measured by the IDS-iSYS assay in 102 GH-deficient subjects before starting GH treatment and after 12months of GH treatment. Z-scores were calculated for all samples by using the normative data of the VARIETE cohort and by the normative data reported by Bidlingmaier etal. Before GH treatment, Z-scores calculated by using the normative data of the VARIETE cohort were significantly lower than those calculated by the normative data of Bidlingmaier etal: -2.40 (-4.52 to +1.31) (mean [range]) vs. -1.41 (-3.14 to +1.76); P<.001). After 12months of GH treatment, again the Z-scores based on the normative data of the VARIETE cohort were significantly lower than those based on the normative data of Bidlingmaier etal: -0.65 (-4.32 to +2.79) vs 0.21 (-3.00 to +3.28); P<.001). IGF-I Z-scores in 102 GH-deficient subjects differed significantly when normative data from two different sources were used. In daily clinical practice, this would most likely have led to different clinical interpretations and GH dose adjustments.

Glucose homeostasis in GHD children during long-term replacement therapy: a case-control study.

To evaluate glucose homeostasis in children with growth hormone (GH) deficiency (GHD) receiving long-term replacement therapy. We evaluated glucose, insulin, HOmeostasis Model Assessment (HOMA-IR), and HbA1c in 100 GHD children at diagnosis and during 5 years of therapy. One hundred healthy children comparable to patients were evaluated at baseline and after 1 and 5 years. No difference was detected at baseline between GHD patients and controls in glucose (79.58 ± 9.96 vs. 77.18 ± 8.20 mg/dl), insulin (4.50 ± 3.24 vs. 4.30 ± 2.60 µU/ml), HbA1c (5.20 ± 0.31 vs. 5.25 ± 0.33%) levels, and HOMA-IR (0.93 ± 0.72 vs. 0.86 ± 0.61). One year of GH was associated with a significant increase in insulin (7.21 ± 4.84, p < 0.001) and HOMA-IR (1.32 ± 0.98, p < 0.001) in GHD children, which became different from controls (p < 0.001 and p = 0.004). These parameters did not change further during the following years of treatment in GHD subjects. In contrast, controls did not show significant changes in insulin (4.40 ± 2.60) and HOMA-IR (0.82 ± 0.60) during the first year; however, at the fifth year of the study a significant increase in insulin (6.50 ± 3.50, p = 0.004) and HOMA-IR (1.29 ± 0.54, p < 0.001) was documented, making these parameters comparable between patients and controls. Our results suggest that growth hormone (GH) treatment is not associated with significant impairment of insulin sensitivity in GHD children. The slight impairment observed in GHD adolescents after long-term GH is comparable to that physiologically occurring in healthy pubertal subjects.

The Impact of Growth Hormone Therapy on the Apoptosis Assessment in CD34+ Hematopoietic Cells from Children with Growth Hormone Deficiency.

Growth hormone (GH) modulates hematopoietic cell homeostasis and is associated with apoptosis control, but with limited mechanistic insights. Aim of the study was to determine whether GH therapeutic supplementation (GH-TS) could affect apoptosis of CD34+ cells enriched in hematopoietic progenitor cells of GH deficient (GHD) children. CD34+ cells from peripheral blood of 40 GHD children were collected before and in 3rd and 6th month of GH-TS and compared to 60 controls adjusted for bone age, sex, and pubertal development. Next, apoptosis assessment via different molecular techniques was performed. Finally, to comprehensively characterize apoptosis process, global gene expression profile was determined using genome-wide RNA microarray technology. Results showed that GH-TS significantly reduced spontaneous apoptosis in CD34+ cells (p < 0.01) and results obtained using different methods to detect early and late apoptosis in analyzed cells population were consistent. GH-TS was also associated with significant downregulation of several members of TNF-alpha superfamily and other genes associated with apoptosis and stress response. Moreover, the significant overexpression of cyto-protective and cell cycle-associated genes was detected. These findings suggest that recombinant human GH has a direct anti-apoptotic activity in hematopoietic CD34+ cells derived from GHD subjects in course of GH-TS.

The response to growth hormone treatment in prepubertal children with growth hormone deficiency in Japan: Comparing three consecutive years of treatment data of The Foundation for Growth Science in Japan between the 1990s and 2000s.

Growth hormone (GH) treatment for children with GH deficiency (GHD) is effective in improving adult height. To achieve favorable effects, GH treatment before puberty is very important, because prepubertal height gain is highly correlated with total height gain. However, no report has studied the effects by analyzing a nationwide data from recent GHD patients in Japan. We investigated the response to GH treatment using data compiled in the Foundation for Growth Science in Japan, and compared the effects between the 1990s and 2000s using analysis of covariance. We analyzed 534 prepubertal GHD subjects treated in the 2000s with three consecutive years of data from the start and investigated predictive factors for the effects. The cumulative height standard deviation score (SDS) change over three years of GH treatment was 0.91 ± 0.57 and 1.20 ± 0.62 in the 1990s and 2000s, respectively. Subjects in the 2000s were divided into three groups by severity, and the cumulative height SDS was 1.60 ± 0.93, 1.20 ± 0.54, and 1.00 ± 0.40 indicating severe, moderate, and mild GHD, respectively. Age and height SDS at the start and severity were identified as independent predictive factors. We also found a significant difference in the effects between the two cohorts after adjusting for the different factors (regression coefficient: -0.069, 95% confidence interval: -0.11 to -0.030, p = 0.0006), which might be due to the GH dose effect. We conclude that the effects of GH treatment in the 2000s had improved compared with those in the 1990s.

Infectious diseases and immunological responses in adult subjects with lifetime untreated, congenital GH deficiency.

Growth hormone is important for the development and function of the immune system, but there is controversy on whether growth hormone deficiency is associated to immune disorders. A model of isolated growth hormone deficiency may clarify if the lack of growth hormone is associated with increased susceptibility to infections, or with an altered responsiveness of the immune system. We have studied the frequency of infectious diseases and the immune function in adults with congenital, untreated isolated growth hormone deficiency. In a cross-sectional study, 35 adults with isolated growth hormone deficiency due to a homozygous mutation in the growth hormone releasing hormone receptor gene and 31 controls were submitted to a clinical questionnaire, physical examination serology for tripanosomiasis, leishmaniasis, HIV, tetanus, hepatitis B and C, and serum total immunoglobulin G, M, E and A measurement. The immune response was evaluated in a subset of these subjects by skin tests and response to vaccination for hepatitis B, tetanus, and bacillus Calmette-Guérin. There was no difference between the groups in history of infectious diseases and baseline serology. Isolated growth hormone deficiency subjects had lower total IgG, but within normal range. There was no difference in the response to any of the vaccinations or in the positivity to protein Purified Derived, streptokinase or candidin. Adult untreated isolated growth hormone deficiency does not cause an increased frequency of infectious diseases, and does not alter serologic tests, but is associated with lower total IgG levels, without detectable clinical impact.

Is retesting in growth hormone deficient children really useful?

Patients with childhood-onset GH deficiency (GHD) are usually retested after achievement of near final height, to verify whether they need to continue GH treatment. We investigated if GH stimulation test is necessary to confirm a persistent status of GHD or if other parameters could be a reliable predictor of GHD persistence. One-hundred and sixty-four children with idiopathic GHD (55 females and 109 males) were retested when they reached near final height using GH releasing hormone (GHRH)+arginine test or arginine alone. At diagnosis, 23.8% of patients showed severe GHD (GH peak at diagnosis <5 ng/mL) and 76.2% showed partial GHD (GH peak <10 ng/mL). At time of retesting, 82.1% of severe GHD and 82.4% of partial GHD patients showed transient GHD. IGF-I levels were not different between persistent (0.18±1.18 SDS) and transient GHD subjects (0.17±0.82 SDS). Furthermore, among persistent severe GHD patients only two showed very reduced levels of IGF-I (<-2.0 SDS). The majority of patients idiopathic GHD proved to be transient. IGF-I levels alone do not discriminate subjects with persistent from those with transient GHD. Therefore, after the end of GH substitutive treatment, a re-evaluation of GH secretion is mandatory to verify the persistence of GHD in adulthood.

A half-century of studies of growth hormone insensitivity/Laron syndrome: A historical perspective

A growth hormone (GH) dependent substance responsible for sulfate uptake by costal cartilage of hypophysectomized rats, labeled sulfation factor, was reported in 1957. In 1962 the radioimmunoassay for GH was described. The clinical picture of severe GH deficiency but with high serum concentrations of GH was reported in 3 siblings in 1966 and followed by a 1968 report of 22 patients belonging to 14 consanguineous oriental Jewish families in Israel. Defective sulfation factor generation was demonstrated in 15 of these individuals and in a 1971 report; FFA response to IV GH and growth response to GH injections suggested competitive saturation of peripheral tissue receptors by an abnormal GH. However, studies published in 1973 demonstrated normal fractionation of their circulating GH, and normal binding of GH from 22 patients to various antisera used for radioimmunoassay. In 1976, the Israeli investigators reported that circulating GH from 7 patients reacted normally in the recently developed radioreceptor assay for GH. In 1984, using hepatic microsome pellets, they demonstrated that the defect was a failure of GH binding to receptors. Characterization of the human GH receptor (GHR) gene, reported in 1989, included the initial description of a genetic defect of the GHR in 2 of 9 Israeli patients. At about the same time began the identification in Ecuador of what was to become the largest population of GH insensitivity in the world, ~100 individuals, and the only substantial population with a common mutation of the GH receptor. Treatment studies with recombinant IGF-I began in 1990. Growth response was modest compared to that of GH treated GH deficient subjects. The spectrum of GH insensitivity has expanded beyond GH receptor deficiency to include postreceptor abnormalities: IGF-I gene mutation (1996); IGF-I receptor mutation (2003); signal transducer and activator of transcription 5b mutation (2003); and mutation of the GH-dependent acid labile subunit (2004). ConclusionRare conditions of GH insensitivity caused by GH receptor and postreceptor abnormalities have provided insights into the processes of growth, body composition, and metabolism.

The introduction of the IDS-iSYS total IGF-1 assay may have far-reaching consequences for diagnosis and treatment of GH deficiency.

IGF-1 measurements are used for screening and monitoring GH deficiency (GHD) and acromegaly. Our objective was to study whether the introduction of the IDS-iSYS IGF-1 assay would lead to different clinical interpretations in GHD and acromegaly. In 106 GHD subjects and in 15 acromegalic subjects visiting our university hospital, total IGF-1 levels were measured before and during therapy by using the Immulite (IM) assay and IDS-iSYS (ID) assay. Z-scores were calculated by using assay-specific age-specific normative range values. All treatment decisions were based upon results obtained by the IM assay. In GHD subjects, absolute IGF-1 concentrations differed significantly between both IGF-1 assays before treatment (P < .001) but not during GH treatment (P = .32), and mean Z-scores for IGF-1 differed significantly before starting (IM, -2.23, vs ID, -1.43; P < .001) and during GH treatment (IM, -0.60, vs ID, +0.21; P < .001). In acromegalic subjects, absolute IGF-1 concentrations did not differ between both IGF-1 assays before treatment (P = .18) but were significantly different during treatment (P = 0.009), and mean Z-scores for IGF-1 were not different before starting (IM, 10.93, vs ID, 10.78; P = .41) or during treatment (IM, 3.60, vs ID, 3.18; P = .23). In GHD subjects, mean IGF-1 Z-scores significantly differed when measured by the IM assay compared with the ID assay irrespective of treatment. In contrast, in acromegaly, mean IGF-1 Z-scores did not differ significantly between both assays. Our study suggests that replacement of the IM assay by the ID assay may have far-reaching consequences for the clinical diagnosis and treatment of GHD.

Role of growth hormone in enchondroplasia and chondral osteogenesis: evaluation by X-ray of the hand

The process of growth and maturation of long (radius and ulna) and short (metacarpals and phalanges) bones of the hand (enchondroplasia) differs from that of the carpal cuboid bones (chondral osteogenesis). This study aimed to assess the impact of growth hormone (GH) on these two processes of bone maturation. Subjects of the study were 95 prepubertal children: 30 children with GH deficiency and 65 children with idiopathic short stature, aged 7.4 ± 1.9 y (mean ± SD) (trial registration number 98-0198-033). Bone maturation was assessed by the Greulich and Pyle method from X-rays obtained at the start and at 1 and 2 y of GH treatment, separately for carpals, long bones, and short bones, and was expressed as years of delay relative to chronological age. At GH start, the delay in bone maturation in the GH-deficient group was significantly greater for carpals (3.6 ± 1.3 y) than for long (3.0 ± 1.3 y) and short (1.7 ± 1.1 y) bones. The delay was nonsignificantly greater for carpal bones in GH-deficient subjects than in subjects with idiopathic short stature (3.6 ± 1.3 vs. 3.1 ± 1.1 y, respectively) and was normalized after 2 y of GH treatment. The dominant effect of GH was on chondral osteogenesis, with milder effect on enchondroplasia. A distinct delay in carpal and long-bone maturation, which normalizes during 2 y of GH treatment, was typical in GH-deficient children. Therefore, separate carpal bone assessment in bone age reading is needed.