Year Of rhGH Treatment Research Articles

Nutritional Status and Growth Outcomes in Pediatric Idiopathic Growth Hormone Deficiency: A Retrospective Study in Turkey

Objective: Growth and development in children are significantly influenced by nutritional status. Nutritional deficiencies such as low hemoglobin (Hb), ferritin, vitamin B12, and vitamin D have been linked to impaired growth. This study aims to evaluate the impact of these nutritional markers on growth outcomes in children with idiopathic growth hormone deficiency (IGHD) undergoing recombinant growth hormone therapy (rhGH). Material and Methods: A cross-sectional, retrospective study was conducted on 100 children with IGHD, aged under 16, diagnosed between 2000 and 2023. Data were collected from medical records, including height, body mass index (BMI), pubertal status, bone age, and nutritional markers [Hb, ferritin, vitamin B12, 25-hydroxy-vitamin D3 (25(OH)D3]. Growth parameters were assessed at the start and end of the first year of rhGH treatment. Results: The cohort had a median age of 11.3 years; 30% were female, and 50% were prepubertal. The median height standard deviation score (SDS) was -2.8, and median BMI SDS was -0.7. Prevalence of nutritional deficiencies included 23% with low Hb, 31% with low ferritin, 44% with low 25(OH)D3, and 15% with low vitamin B12. Despite these deficiencies, no significant differences were observed in height SDS or growth velocity when grouped by nutritional markers or supplementation status. Growth velocity showed a significant positive correlation with Hb levels and mid-parental height (MPH). Conclusion: Nutritional deficiencies were common among IGHD patients; there was no significant difference in terms of growth-related metrics in the first year of the rhGH therapy in comparisons between the groups with and without common nutritional deficiencies. This finding underscores the resilience of growth in the presence of these deficiencies. In contrast, growth velocity correlated positively with Hb levels and MPH, suggesting that these factors may play a significant role in influencing growth. Further research with larger samples and extended follow-up is needed to explore the long-term impact of nutritional supplementation on growth in IGHD.

IGF1 Haploinsufficiency: Phenotype and Response to Growth Hormone Treatment in 9 Patients.

The clinical features of bi-allelic IGF1 defects are well established, i.e., severe growth failure and microcephaly, delayed psychomotor development, and sensorineural deafness. However, information on clinical and endocrine consequences of heterozygous IGF1 variants and treatment options is scarce. We aimed at extending the knowledge base of the clinical presentation and growth response to recombinant human growth hormone (rhGH) of patients carrying such variants. Retrospective case series of patients with pathogenic heterozygous IGF1 variants. Nine patients from six families were included, harbouring five whole or partial gene deletions and one frameshift variant resulting in a premature stop codon (three de novo, one unknown inheritance). In the other two families, variants segregated with short stature. Mean (SD) birth length was -1.9 (1.3) SDS (n = 7), height -3.8 (0.6) SDS, head circumference -2.5 (0.6) SDS, serum IGF-I -1.9 (0.7) SDS, serum IGFBP-3 1.1 (0.4) SDS (n = 7), and GH peak range 5-31 μg/L (n = 4). Five patients showed feeding problems in infancy. Average height increased after 1 and 2 years of rhGH treatment by 0.8 SDS (range 0.3-1.3 SDS) and 1.3 SDS (range 0.5-2.0 SDS), respectively. Adult height in 2 patients was -2.8 and -1.3 SDS, which was, respectively, 1.3 and 2.9 SDS taller than predicted before start of treatment. Haploinsufficiency of IGF1 causes a variable phenotype of prenatal and postnatal growth failure, microcephaly, feeding difficulties, low/low-normal serum IGF-I values in contrast to serum IGFBP-3 in the upper-normal range. Treatment with rhGH increased growth in the first 2 years of treatment, and in 2 patients adult height after treatment was higher than predicted at treatment initiation.

Primary response in GHD children treatment as apredictor for long-term therapy effectiveness therapy effectiveness.

Short stature in growth hormone deficiency (GHD) can be treated with recombinant human growth hormone (rhGH), which is proven to be both safe and effective. However, aconsiderable number of patients does not achieve satisfying therapy outcomes. To evaluate the predictive effect of height increase in the first year of rhGH treatment on long-term therapy outcomes. 165 short-stature children (mean age 10.72 ±3.33 years; 63% males), diagnosed with GHD, treated with rhGH for at least one year (mean follow-up 4.32 ±1.80 years), divided into 2 groups according to the change in height standard deviation score (SDS) after the first year of rhGH treatment: good responders (GR) and poor responders (PR). Then, in one-year intervals, patient's chronological age, bone age, height, weight, insulin-like growth factor level, and rhGH dose were all assessed. In the GR group, mean height velocity SDS up to five years of observation was 1.19 ±0.41/year and in the PR group 0.59 ±0.38/year. The differences were statistically significant (p<0.05). The primary response to the rhGH treatment in GHD children seems to be agood predictor for long-term therapy outcomes.

Real life long-term efficacy and safety of rhGH therapy in children with SHOX deficiency.

This Italian survey aims to evaluate real-life long-term efficacy and safety of rhGH therapy in children with short stature homeobox-containing gene deficiency disorders (SHOX-D) and to identify potential predictive factors influencing response to rhGH therapy. This is a national retrospective observational study collecting anamnestic, anthropometric, clinical, instrumental and therapeutic data in children and adolescents with a genetic confirmation of SHOX-D treated on rhGH. Data were collected at the beginning of rhGH therapy (T0), yearly during the first 4 years of rhGH therapy (T1, T2, T3, T4) and at near-final height (nFH) (T5), when available. 117 SHOX-D children started rhGH therapy (initial dose 0.23 ± 0.04 mg/kg/week) at a mean age of 8.67 ± 3.33years (74% prepubertal), 99 completed the 1st year of treatment, and 46 reached nFH. During rhGH therapy, growth velocity (GV) SDS and height (H) SDS improved significantly. Mean H SDS gain from T0 was +1.14±0.58 at T4 and +0.80 ± 0.98 at T5. Both patients carrying mutations involving intragenic SHOX region (group A) and ones with regulatory region defects (group B) experienced a similar beneficial therapeutic effect. The multiple regression analysis identified the age at the start of rhGH treatment (β -0.31, p = 0.030) and the GV during the first year of rhGH treatment (β 0.45, p = 0.008) as main independent predictor factors of height gain. During rhGH therapy, no adverse event of concern was reported. Our data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless the wide variety of genotype.

Генетичний поліморфізм GHR-exon 3 в дітей з дефіцитом гормона росту

The effectiveness of the latest genetic technologies in advancing the diagnosis of growth hormone deficiency (GHD) and predicting growth response to recombinant human growth hormone (rHGh) therapy has been insufficiently studied. The genetic polymorphism of GHR-exon 3 has been considered as a possible predictor of growth response to replacement therapy, but the data obtained are contradictory. Purpose - to identify allelic variants of the growth hormone receptor gene (GHR-exon 3) in children with GHD; to identify the relationship of genetic polymorphism with other potential clinical and auxological predictors of growth response. Materials and methods. The study was conducted at the Odesa Regional Children’s Clinical Hospital of the Odesa Regional Council. The cohort of children with GHD included 92 children (69 boys and 23 girls). Genotyping of two alleles of GHR-exon 3 (d3 - exon 3 deletion; fl - full-length gene) was performed by the method of triprimer polymerase chain reaction. After determination of the GHR-exon 3 genotype (d3/d3; d3/fl; fl/fl), genetic data were coded based on the presence or absence of the d3 allele (d3-GHR, fl/fl-GHR, respectively). Results. Differences in growth potential in children with GHD associated with the d3-GHR genotype compared to the fl/fl-GHR genotype were found. In children without prior treatment, the d3-GHR genotype is associated with higher rates of «growth at baseline (SDS)», «growth (SDS) - target growth (SDS)» and stimulates an additional increase in growth rate by 2.2 cm in the first year of therapy. The results of the second year of rHGh treatment did not reveal a similar pattern of growth response. Taking into account the genetic polymorphism of GHR-exon 3 increases the sensitivity and accuracy of the mathematical model for predicting the growth response to replacement therapy in children with GHD. Conclusions. The d3-GHR genotype is associated with a better growth response in children with GHD in the first year of replacement therapy, but not in the second. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Follow-Up Study of Growth Hormone Therapy in Children with Kabuki Syndrome: Two-Year Treatment Results

Introduction: Kabuki syndrome (KS) is a genetic disorder with characteristic facial dysmorphisms, short stature, hypertension, and obesity later in life. The aim of this study was to evaluate catch-up growth and cardiovascular markers before and during growth hormone (rhGH) treatment in KS children. Methods: This prospective study included 18 children whose KS was genetically established. Each KS subject received rhGH for a period of 2 years. Several measurements were performed before and during treatment: anthropometry, glucose metabolism, lipid profile, markers for endothelial function, and low-grade inflammation. Results: This study found an increase in delta height standard deviation score (SDS) for the whole group of 1.1 SDS after 2 years of rhGH treatment. Baseline metabolic profiles showed no cardiometabolic abnormalities in these children. Although 4 out of 18 children were obese, there were no signs of the metabolic syndrome. During rhGH treatment, serum low-density lipoprotein cholesterol concentrations decreased significantly (2.16–1.91 mmol/L, p = 0.04). Apolipoprotein B100 concentrations also showed a reduction after 24 months of treatment, but the other lipid and (apo)lipoprotein parameters did not change. While other endothelial function markers were stable, only vascular cell-adhesion molecule-1 concentrations increased (1,084–1,161 pg/mL, p < 0.01) during rhGH therapy. Furthermore, BMI and waist circumference improved during treatment. There were no signs of hypertension. Conclusions: At baseline and during rhGH therapy, there were no signs of the metabolic syndrome. This is the first study demonstrating that rhGH treatment in KS children is a safe and effective therapy and that it positively influences linear height without exerting adverse effects on a wide array of cardiovascular risk markers.

Determinants of Final Height in Patients Born Small for Gestational Age Treated with Recombinant Growth Hormone

Introduction: About 8% of children born small for gestational age (SGA) do not reach a final height within the normal range. Recombinant human growth hormone (rhGH) has been shown to be effective in increasing the final height in children born SGA. Our objective was to identify predictive factors of final height in children born SGA treated with rhGH. Materials and Methods: In this retrospective study, conducted in a tertiary pediatric endocrinology referral center, we recruited all patients born SGA (defined as birth length or weight <10th percentile) treated with rhGH for more than 12 months for whom final height data were available. Some patients had received gonadotropin-releasing hormone (GnRH) analog therapy. Results: We included 252 patients with an average birth length of −2.0 ± 0.7 SD and birth weight of −1.7 ± 1.0 SD. After 4.6 ± 2.8 years of rhGH treatment, their height increased from −2.2 ± 0.9 SD to −1.5 ± 0.9 SD. In multivariate analysis, we identified 8 factors that predict 46% of the final height, namely, cause of SGA (p < 0.0001), GnRH analog therapy >2 years (p = 0.006), birth length (p < 0.02), height at the start of rhGH (p < 0.0001), IGF-1 level at the start of rhGH (p = 0.0002), growth velocity during the 1st year of treatment (p = 0.0002), and age and height at the onset of puberty (p < 0.0001, p = 0.0007, respectively). Conclusion: In this large cohort of SGA patients who had reached their final height, we were able to confirm that growth hormone increases final height in short SGA children. In addition, we identified several factors associated with a better response to growth hormone treatment.

SAT-096 Response to RHGH Therapy in Children with Isolated Short Stature with or Without an Identified Genetic Cause

Introduction: Children with isolated (former known as idiopathic) short stature (ISS) have been treated with rhGH with a variable response. Objectives: To evaluate the short-term response to rhGH therapy in children with ISS with or without a genetic diagnosis. Methods: We analyzed retrospectively the growth rate and height SDS change in the first year of rhGH treatment according to the presence or absence of defects in genes that regulate growth plate. The decision to start rhGH treatment was based on clinical features and the genetic results were obtained during the follow-up. Patients were enrolled in several previous genetic studies using gene candidate approach or multigene sequencing analysis. Results: A total of 51 prepubertal children (36 boys) with ISS were treated with rhGH. Thirteen of these children start puberty during the treatment and three of them were concomitant treated with GnRH analog. Basal characteristics of these children were 7.7 ± 3.2 years of age, height SDS -2.5 ± 0.8; sitting height/height (SH/H) SDS 1.2 ± 1.4; BMI SDS 0 ± 1.0 and mild delay of bone age (-1.6 ± 1.3 y). The mean target height SDS was -1.2 ± 0.9y, 18 (35%) of these children have at least one parent with height SDS < -2 and 3 (6%) both parents are short. Consanguinity was present in 3 (6%) cases. Among this cohort, fifteen children had pathogenic or likely pathogenic allele variants in genes that regulate growth plate: IHH (n = 4), SHOX (n = 9) and NPR2 (n = 2). Seven (47%) of these variants were inherited from a short stature parent. Children with or without an identified genetic cause have similar age and height SDS at the start of the treatment. A higher BMI and SH/H SDS were observed in children with genetic defects than in those without (BMI SDS 0.5 ± 1.1 vs. -0.15 ± 0.9, p = 0.02; SH/H SDS 2.0 ± 1.4 vs. 0.9 ± 1.3, p = 0.006). Additionally, children with genetic defects had a less marked bone age delay (-1.0 ± 1.3 vs. -1.9 ± 1.2; p = 0.02). Both groups were treated with similar rhGH dose (50 μg/kg/day). Patients with and without an identified genetic cause had similar improvement in growth velocity during the first year of therapy: 4.8 ± 1.6 to 8.9 ± 1.7 cm/y for patients with molecular diagnosis vs. 4.6 ± 1.2 to 8.5 ± 2.3 cm/y for those without. This resulted in similar height SDS change during this period for both groups (0.6 ± 0.3 vs. 0.6 ± 0.5 SDS for children with or without a genetic cause, respectively). Age at the start of treatment was the main variable that explains growth response variability during this first year (r2 = 0.17, p = 0.009). Conclusion: The presence or absence of an identified genetic cause, involving genes that regulate growth plate, did not significantly influence the short-term growth response to rhGH therapy of children with ISS. Long-term follow-up is still needed to assess the final height of these children and possibly to assess whether there is a different growth rate related to each known affected gene.

Effect of -202 A/C IGFBP-3 polymorphisms on growth responses in children with idiopathic short stature.

PurposeThis study evaluated the -202 A/C insulin-like growth factor binding protein 3 (IGFBP-3) promoter polymorphism as a predictor of serum IGFBP-3 concentration and growth velocity after recombinant growth hormone (rhGH) therapy in patients with idiopathic short stature (ISS).MethodsGenotyping and serial measurement of clinical parameters were performed in 69 children with a confirmed diagnosis of ISS. Restriction fragment length polymorphism analysis was performed to determine the genotype at the -202 IGFBP-3 locus. Serum insulin-like growth factor 1 (IGF-1) and IGFBP-3 levels were measured at baseline and after 1 year of rhGH treatment, as were height standard deviation score and growth velocity.ResultsThe -202 A/C IGFBP-3 genotype comprised 69.6% AA, 24.6% AC, and 5.8% CC. One year of treatment did not produce a meaningful difference in IGF-1 or IGFBP-3 levels between children in the AA group and those with at least one copy of the C allele (AC/CC group). Comparing the 2 groups after one year also revealed no significant difference in growth velocity (ΔHeight: 9.061±1.612 cm/yr in the AA group, 9.421±1.864 in the AC/CC group, P=0.419).ConclusionsrhGH treatment was effective and there were no significant differences in IGF-1, IGFBP-3, or growth velocity according to genotype. Thus, -202 IGFBP-3 genotype may not be a major factor affecting individual growth responses in Korean children with ISS.

Timing of GH Peak in Both Glucagon and Clonidine Tests is of Major Clinical Importance

Objective: To detect a possible correlation between timing of the peak value of growth hormone (GH) during stimulatory tests (STs) and the effectiveness of treatment with recombinant human growth hormone (rhGH) in children with idiopathic GH deficiency (iGHD). Methods: We retrospectively studied 92 patients with iGHD (57 boys; mean age at diagnosis: 9.93 years). Diagnosis was confirmed by 2 different STs, glucagon stimulation test (GST), and clonidine stimulation test (CST). Auxologic parameters were recorded, while observed and predicted (according to KIGS Prediction Model) height velocity during the first year of treatment and the index of responsiveness (IoR) were calculated for the prepubertal children (n = 65). Results: Atypical GST was defined as that with peak GH value at time 0 minutes, 30 minutes, 60 minutes, or 180 minutes, whereas atypical CST was defined as that with peak timing at 0 minutes, 30 minutes, or 120 minutes. Atypical GST was detected in 18 patients (19.57%). IoR was lower in the prepubertal children with atypical GST (-1.81 ± 0.67 versus -1.34 ± 0.85; P = .051). In the CST, the 18 children who had atypical timing, had significantly lower IoR (-1.86 ± 0.66 versus -1.35 ± 0.84; P = .047). When the patients were categorized according to the number of atypical tests, significant differences in the IoR were detected (-2.09 ± 0.68 with 2 atypical STs [n = 6], -1.64 ± 0.61 with 1 atypical ST [n = 16], and -1.29 ± 0.87 with no atypical ST [n = 43], P = .045). Conclusion: The presence of atypical peak GH timing during ST may be a factor that predicts lower growth hormone velocity during the first year of rhGH treatment in prepubertal children with iGHD. Abbreviations: CST = clonidine stimulation test; GH = growth hormone; GHD = growth hormone deficiency; GST = glucagon stimulation test; iGHD = idiopathic growth hormone deficiency; IoR = index of responsiveness; rhGH = recombinant human growth hormone; SDS = standard deviation scores; ST = stimulatory test.

SUN-258 Prediction of Height Two Years after Start Treatment in Children with Growth Hormone Deficiency

Background: Various prediction models for the growth response to recombinant human growth hormone (rhGH) have been published, but none of these have been able to incorporate data on adherence to rhGH treatment. Previous studies have shown that suboptimal adherence negatively affects the growth response in the first two years of rhGH treatment. The availability of the easypod electronic drug-delivery device which continuously assesses adherence, enables to develop a prediction model taking adherence into account. Aim: To develop a model for prediction of height standard deviation score (HSDS) two years after start treatment, using information available at the start of GH treatment and adherence in the first two years. Patients and Methods: We included prepubertal children with idiopathic isolated growth hormone deficiency (GHD) participating in the easypod connect observational study (ECOS), a 5-year, Phase IV open-label study to continuously assess real-world adherence via the easypod device. Inclusion criteria were GHD, naïve to rhGH treatment, age <10y in girls and <12y in boys, height and adherence available in the first and second year, target height, birth weight, gestational age, and information on GH dose. Linear regression analyses were performed to construct a prediction model for HSDS 2y after start treatment, with age at start, HSDS at start, target height (TH) SDS, birth weight SDS, GH dose, gestational age (<37 weeks vs ≥37 weeks), sex, and adherence in the first and second year as potential predictors. Stepwise backward regression analyses were performed to simplify the model without a statistically significant loss of fit with a model fit criterion of p<0.1 for each predictor. Results: In total, 132 patients complied with the inclusion criteria. Mean (SD) HSDS was -2.4 (0.9) and age at start 6.5 (2.0) yrs. The prediction model was: HSDS at 2y after start treatment = 0.4699 - 0.0627 x Age at start + 0.7904 x HSDS at start + 0.1216 x TH SDS + 0.0418 x birth weight SDS + 0.1659 x sex (male) + 0.0050 x adherence in the second year. P-values were <.001 for HSDS at start and adherence in the second year, .002 for Age at start, and .07 for TH SDS, birth weight SDS and sex. This model explained 76% of the total variance. For example, if a girl starts with GH treatment at 6.5y with a HSDS of -2.4, TH SDS of 0, birth weight SDS of 0 and 100% adherence in the second year, her predicted HSDS 2y after start treatment is -1.3 SD. If she misses 2 injections/week in the second year, the predicted HSDS 2y after start treatment is -1.5 SD. Conclusion: We have developed a prediction model for height two years after start treatment for children with GHD. This model can be used to study the impact of information available at the start of GH treatment and adherence in the second year. More research is needed to explore the effect of individual patterns of adherence on growth in real word settings.

Two-year recombinant human growth hormone (rhGH) treatment is more effective in pre-pubertal compared to pubertal short children with X-linked hypophosphatemic rickets (XLHR)

ContextTwenty-five to 40% of patients with well-controlled X-linked hypophosphatemic rickets (XLHR) have a final height under −2 SDS. Previous studies have shown that recombinant human growth hormone (rhGH) treatment improves linear growth in short children with XLHR. ObjectiveWe studied the effectiveness of rhGH treatment in children with XLHR in a larger cohort. DesignMonocentric, prospective, non-randomized trial. SettingUniversity hospital in France. Patients19 patients with XLHR and a mutation in the PHEX gene. Six male and 6 female Tanner stage 1 patients (age 6.1±2.4years) and 4 male and 3 female Tanner stage 2 patients (age 13.1±1years). At inclusion, height SDS was −2.35±0.8 SDS and growth velocity was −1.12±1.2 SDS. Intervention2years of treatment with 67mcg/kg/day of rhGH at initiation. Every three months rhGH dosage was adjusted using an IGF-1 dosing protocol. Main outcome measuresComparison in change from baseline to year 2 in height and growth velocity. ResultsHeight SDS improved from −2.35±0.8 SDS at baseline, to −1.62±0.8 SDS (p=0.01) after one and to −1.2±1 SDS (p=0.04) after two years of rhGH treatment. There was a strong correlation (r2=0.6104, p<0.0001) between the age of onset of rhGH treatment and the number of cm gained over the study period. Pre-pubertal patients height SDS improved compared to baseline height SDS after one (−1.5±0.7, p<0.03) and two (−0.96±1, p<0.03) years of rhGH treatment. In pubertal patients there was no significant improvement in height SDS after one year (−1.75±1) and after two years (−1.7±0.8) of rhGH treatment. ConclusionTwo-year rhGH treatment is effective to treat short stature in XLHR children. Pre-pubertal children responded better to rhGH. Clinical trial registration numberNCT02720770

Growth Hormone Therapy in Children with Kabuki Syndrome: 1-year Treatment Results

Background/Aims: Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children. Methods: In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year. Calculations for height, height velocity, BMI, sitting height, and subischial leg length were made. Bone age, insulin-like growth factor (IGF-I), and IGF binding protein 3 (IGFBP-3) were also measured. Results: This study showed an increase in height standard deviation score (SDS) for the whole group from –2.40 to –1.69 (p < 0.05) after 1 year of rhGH treatment. The change in height SDS within 1 year was >0.7 SDS for 10 subjects and >0.5 SDS for 3 subjects. The mean IGF-I SDS at the start of the study was –0.70 (±1.07), which increased after 12 months to 1.41 (±0.91) (p < 0.05). KS children who received rhGH at a younger age displayed significantly greater increases in height than those who started when they were older. The same was true for both gene mutation KMT2D versus KDM6A and for GH deficiency versus non-GH deficiency KS children (p < 0.05). Throughout the course of rhGH treatment, the subjects’ body proportions remained normal. Conclusions: All participants experienced catch-up growth during the year of rhGH treatment, but without an influence on body proportions.

Seven years of follow up of trabecular bone score, bone mineral density, body composition and quality of life in adults with growth hormone deficiency treated with rhGH replacement in a single center.

Adult growth hormone deficiency (AGHD) is characterized by impaired physical activity, diminished quality of life (QoL), weight and fat mass gain, decreased muscle mass and decreased bone mineral density (BMD). The aim of this study was to evaluate the effects of long-term treatment (7 years) with recombinant human growth hormone (rhGH) on metabolic parameters, body composition (BC), BMD, bone microarchitecture and QoL. In this prospective study, BMD and BC were assessed by dual-energy X-ray absorptiometry (DXA). Bone microarchitecture was assessed with the trabecular bone score (TBS). The QoL-AGHDA test was used to assess QoL. A total of 18 AGHD patients (mean age, 37.39 ± 12.42) were included. Body weight and body mass index (BMI) showed a significant increase after 7 years (p = 0.03 and p = 0.001, respectively). There was a significant tendency of body fat mass (BFM) (p = 0.028) and lean body mass (LBM) (p = 0.005) to increase during the 7 years of rhGH treatment. There was a significant increase in lumbar spine (LS) BMD (p = 0.01). TBS showed a nonsignificant decrease after 7 years of treatment, with a change of -0.86% ± 1.95. QoL showed a large and significant improvement (p = 0.02). Long-term rhGH treatment in AGHD patients induces a large and sustained improvement in QoL. Metabolic effects are variable with an increase in LBM as well as in BMI and BFM. There is a positive effect on BMD based on the increase in LS BMD, which stabilizes during long-term therapy and is not associated with a similar increase in bone microarchitecture.

Five-year response to growth hormone in children with Noonan syndrome and growth hormone deficiency.

BackgroundNoonan syndrome (NS) is an autosomal dominant disorder characterized by specific features including short stature, distinctive facial dysmorphic features, congenital heart defects, hypertrophic cardiomyopathy, skeletal anomalies and webbing of the neck. Molecular screening has shown that the majority of individuals with NS have a mutation in the PTPN11 gene. Noonan syndrome children may show an impaired growth hormone (GH)/insulin-like growth factor axis. Moreover, recombinant human GH (rhGH) has been shown to improve growth rate in patients with NS, although data are still limited.MethodsIn the present study, we assessed growth response following GH therapy (0.25 mg/Kg/week) in 5 (2 M and 3 F) GH-deficient NS patients (NSGHD, mean age 8.5 years) and in 5 (2 M and 3 F) idiopathic GH deficient (IGHD, mean age 8.6 years) patients. We also evaluated the safety of rhGH therapy in NS patients with GHD.ResultsAt the beginning of GH treatment, height and growth rate were statistically lower in NSGHD children than in IGHD ones. During the first three years of rhGH therapy, NSGHD patients showed a slight improvement in height (from −2.71 SDS to −2.44 SDS) and growth rate (from −2.42 SDS to −0.23 SDS), although the values were always significantly lower than in IGHD children. After five years of rhGH treatment, height gain was higher in IGHD children (mean 28.3 cm) than in NSGHD patients (mean 23.6 cm).During the first five years of rhGH therapy, regular cardiological and haematological check-ups were performed, leading to the conclusion that rhGH therapy was safe.ConclusionsIn conclusion, pre-pubertal NS children with GHD slightly increased their height and growth rate during the first years of GH therapy, although the response to rhGH treatment was significantly lower than IGHD children. Furthermore, the therapy appeared to be safe since no severe adverse effects were reported, at least during the first five years. However, a close follow-up of these patients is mandatory, especially to monitor cardiac function.

Growth hormone and the risk of atherosclerosis in growth hormone-deficient children

ObjectiveGrowth hormone-deficient (GHD) children have been found to have higher cardiovascular mortality rates and an increased carotid intima-media thickness (CIMT). This study investigated the risk of atherosclerosis and the effect of recombinant growth hormone (rhGH) replacement therapy on the lipid profile and CIMT in GHD children. DesignA total of 40 GHD children (mean age: 12.3±2.04years) were investigated before and after 1year of rhGH therapy at a dosage of 0.03mg/kg/day and 40 age- and sex-matched healthy children (mean age: 12.1±2.23years) were enrolled as a control group, in the same pubertal stage. Fasting blood samples were obtained for lipid profile, IGF-1, and IGFBP-3 analyses. The patients and controls underwent CIMT measurements before and after 1year of rhGH treatment. ResultsThe growth velocity and height standard deviation scores increased significantly over 1year of treatment in all patients. The total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, and atherogenic index (Ai) values were increased while the high-density lipoprotein (HDL) cholesterol value was decreased in the GHD children, as compared to the controls; however, the triglyceride (TG) level was comparable. After 1year of treatment, a significant decrease in the TC, LDL cholesterol, and Ai values as well as a significant increase in the HDL value were observed in the GHD patients, with the values becoming similar to those in the control group. The mean CIMT was significantly greater in the GHD subjects than in the controls. After 1year of therapy, the CIMT in the GHD subjects had decreased significantly; however, it was still greater than that in the control group. IGF-1 was negatively correlated with TC, LDL cholesterol, Ai, right CIMT, and left CIMT. ConclusionsGHD is associated with increased atherosclerotic risk in children. An improved lipid profile and CIMT were detected after 1year of hormone replacement therapy.

Effects of Growth Hormone (GH) Therapy Withdrawal on Glucose Metabolism in Not Confirmed GH Deficient Adolescents at Final Height

Context, objectiveGrowth hormone deficiency (GHD) is associated with insulin resistance and diabetes, in particular after treatment in children and adults with pre-existing metabolic risk factors. Our aims were. i) to evaluate the effect on glucose metabolism of rhGH treatment and withdrawal in not confirmed GHD adolescents at the achievement of adult height; ii) to investigate the impact of GH receptor gene genomic deletion of exon 3 (d3GHR).Design, settingWe performed a longitudinal study (1 year) in a tertiary care center.Methods23 GHD adolescent were followed in the last year of rhGH treatment (T0), 6 (T6) and 12 (T12) months after rhGH withdrawal with fasting and post-OGTT evaluations. 40 healthy adolescents were used as controls. HOMA-IR, HOMA%β, insulinogenic (INS) and disposition (DI) indexes were calculated. GHR genotypes were determined by multiplex PCR.ResultsIn the group as a whole, fasting insulin (p<0.05), HOMA-IR (p<0.05), insulin and glucose levels during OGTT (p<0.01) progressively decreased from T0 to T12 becoming similar to controls. During rhGH, a compensatory insulin secretion with a stable DI was recorded, and, then, HOMAβ and INS decreased at T6 and T12 (p<0.05). By evaluating the GHR genotype, nDel GHD showed a decrease from T0 to T12 in HOMA-IR, HOMAβ, INS (p<0.05) and DI. Del GHD showed a gradual increase in DI (p<0.05) and INS with a stable HOMA-IR and higher HDL-cholesterol (p<0.01).ConclusionsIn not confirmed GHD adolescents the fasting deterioration in glucose homeostasis during rhGH is efficaciously coupled with a compensatory insulin secretion and activity at OGTT. The presence of at least one d3GHR allele is associated with lower glucose levels and higher HOMA-β and DI after rhGH withdrawal. Screening for the d3GHR in the pediatric age may help physicians to follow and phenotype GHD patients also by a metabolic point of view.

Height Outcome of the Recombinant Human Growth Hormone Treatment in Subjects with Noonan Syndrome: A Meta-Analysis

Children with Noonan Syndrome (NS) present variable growth impairment associated to facial dysmorphology and cardiovascular anomalies. Mutations in several genes of RAS/MAPK signaling pathway have been identified, likely impairing Growth Hormone (GH) sensitivity. If untreated, these patients often remain short in adulthood. Although Recombinant Human GH (rhGH) treatment improves short-term linear growth, poor data on the Final Height (FHt) of rhGH-treated subjects with NS are available. After thorough search of the published literature for pertinent studies, a meta-analysis evaluation of the efficacy and safety of rhGH treatment in NS patients were performed. In total sample (n=885; 70.0% males), administration of rhGH progressively improved height pattern, but relevant catch-up growth was not shown. The rhGH-induced growth improvement appeared until FHt [n=168; –2.151 SDS (95%CI –2.792 to –1.511)]. During 1st year of rhGH treatment, height velocity gain meta-correlated with serum insulin-like growth factor 1 (IGF1) increment [n=31; r=0.685 (95%CI 0.419 to 0.843); P<0.0001] while negative meta-correlation was detected between age at rhGH start and height velocity [n=48; r=–0.608 (95%CI –0.765 to –0.383); P<0.0001]. Height gain after 1-yr rhGH treatment (dosage range 0.35-0.46 mg/kg/wk) was higher in NS patients without protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene mutation [n=33; 0.903 SDS (95%CI 0.552 to 1.254)] than that observed in subjects positive for PTPN11 mutations [n=62; 0.606 SDS (95% CI 0.274 to 0.938); P<0.0001]. While few serious adverse events were reported during rhGH treatment, causal relationship to rhGH therapy was unlikely. In conclusion, this meta-analysis indicates that rhGH treatment progressively improved height outcome of short children with NS. Future studies using carefully titrated rhGH protocols are need to optimize treatment protocols and establish possible risks, if any, leading to clear indications for practice and regulatory agencies.

Effect of the parental origin of the X-chromosome on the clinical features, associated complications, the two-year-response to growth hormone (rhGH) and the biochemical profile in patients with turner syndrome

BackgroundIt is possible that genes on the X chromosome are expressed differently depending of its parental origin. The objective of this study was to determine the influence of the parental origin of the X-chromosome on phenotypic variability, response to rhGH and on the biochemical profile of TS patients.MethodsThis was a cross-sectional multicenter correlational study carried out over three years in six Latin-American university hospitals. Unrelated 45,X TS patients (n = 93; 18.3 ± 8.5 years )) were evaluated. A subgroup (n = 34) of the patients were prospectively treated with rhGH over two years. DNA profiles of patients and their mothers were compared to determine the parental origin of the retained X-chromosome through 10 polymorphic X-chromosome-STRs. The association with clinical features, biochemical profiles and anthropometric data at the beginning and after two years of rhGH treatment was determined.ResultsSeventy two percent of patients retained the maternal X chromosome (Xm). A trend towards significance between maternal height and patients final height (p ≤ 0.07) in 45,Xm subjects was observed. There was no correlation between paternal height and patient height. No differences were detected between both groups in regard to dysmorphic features, classical malformations or increase in the height-SDS after rhGH. There were higher levels of triglycerides, total and LDL cholesterol in patients >20 years who retained the Xm.ConclusionsThe parental origin of the retained X chromosome may influence lipid metabolism in TS patients, but its effect on growth seems to be minimal. No parental-origin-effect on the phenotypic features, associated anomalies and on the growth response to rhGH was found in 45,X TS individuals.

Effect of growth hormone on bone status in growth hormone-deficient adults

Growth hormone deficiency (GHD) is associated with reduced bone mineral content and increased risk of osteoporotic fractures. Reduced peak bone mass might explain the low bone mineral density (BMD) among patients with childhood onset GHD (CO-GHD) whilst the cause of osteopenia in adult-onset GHD (AO-GHD) is not fully understood. Prospective multicentric study to asses bone status in GHD adults after two years of recombinant growth hormone replacement treatment. In 94 GHD adults (49 men; Ø 34.5 yrs) we have measured BMD and bone markers (CTX, osteocalcin) during two years of rhGH treatment (at baseline, after 3 and 6 months, and after 1 and 2 years). Patients were adequately substituted for GHD and other pituitary deficiencies. We have observed an increase in BMD-lumbar spine: n=42, 0.8155 →0.9418 g/cm2, p<0.0001; femoral neck n=41; 0.8468 →0.9031; p= 0.0004; BMD-whole body 1.0179 →1.0774; p=0.0003. We have compared gender difference: BMD-L-spine by 15.8 % in men (n=21) and by 5.6 % in women (n=19) (p= 0.008); BMD-femoral neck increased by 11.03 % in men and by about 3.0 % in women (p=0.032). In women, the initial decrease in BMD was recorded after 3 months. CO-GHD adults yielded a higher increase in BMD -L-spine (16.6 %, p=0.022). A correlation exists between IGF-I levels and BMD in lumbar spine (1st year: R=0.348, p=0.026; 2nd year: R= 0.33, p=0.0081) and between IGF-I and osteocalcin (1st year: R=0.383; p=0.0038). Two-year therapy with recombinant human growth hormone improved bone status. IGF-I appears to be a good indicator of rhGH effect on bone (Tab. 3, Fig. 9, Ref. 36). Text in PDF www.elis.sk.