GH-deficient Children Research Articles

Effects of Growth Hormone Treatment on Lipid Profiles

To assess the effects of growth hormone (GH) on lipid profiles in children and whether the effect is pharmacological. The authors determined serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and low-density lipoprotein cholesterol (LDL-C) every year during 3-y GH treatment in 48 GH deficient (GHD) short children and 22 children with short stature born small for gestational age (SGA). The abnormally high levels of TC, non-HDL-C, and LDL-C showed a high frequency in GHD short children compared with epidemiological studies in Japan. The high prevalence of high level of TC was also shown in SGA short children. Three-year GH treatment decreased serum TC, non-HDL-C, and LDL-C levels in both patient groups. GH treatment is clearly a pharmacological therapy in SGA short children and so may also be in GHD short children at the Japanese standard therapeutic dose. Taken together, GH improves lipid profiles, and its effect has the possibility of medical properties.

Growth Hormone Deficiency in Children: From Suspecting to Diagnosing.

Isolated Growth hormone deficiency is an important and treatable cause of short stature. However, it is often difficult to diagnose the condition with certainty due to the lack of a single robust diagnostic test. Short children, other than those with the classical phenotype of immature chubby facies, truncal obesity and micropenis in boys, or those with history of cranial lesions with known association with hypopituitarism, should be evaluated for growth hormone deficiency only after excluding the other more common conditions. These children typically have height markedly below that expected for their midparental height with low height velocity and delayed bone age. Growth hormone levels should be checked by provocative testing, after ensuring that the child is euthyroid, and after priming with sex steroids if indicated. Low levels of Insulin-like growth factor 1 and Insulin-like growth factor binding protein 3 and pituitary abnormalities on neuroimaging provide important corroborative evidence to the diagnosis.

Comparison of insulin tolerance test to arginine test for the diagnosis of growth hormone deficiency in children

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

One-year recombinant growth hormone therapy does not improve hemoglobin state and morphology of erythrocytes in growth hormone deficient children

An increase in growth rates of children suffering from growth hormone deficiency (GHD) subjected to recombinant growth hormone treatment (rGHT) was shown to be accompanied by acceleration of metabolic processes that may stimulate oxygen consumption in various organs and tissues. Therefore, oxygen-transporting properties of RBC should undergo considerable changes during the rGHT. The aim of this study was to examine the effects of rGHT on erythrocyte shape and hemoglobin state in GHD children. The level of oxyhemoglobin (Oxy-Hb) in RBC was analyzed by Raman spectroscopy. The RBC count, mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV) and other parameters were calculated. The blood of eleven treatment-naive prepubertal children with GHD (aged 3–9, median 5.7 years) was examined and compared with control group (aged 5–7; median 6.0 years) at three time points: 0, 3 and 12 months of rGHT. Before rGHT, the MI in GHD children was higher (median 0.48 vs 0.14 p=0.0018) and the RBC count was lower (median 4.20 vs 4.96 1012 cells/L p=0.0022) than in control group. After the treatment, cell count in GHD patients did not differ significantly from the control group, but Oxy-Hb level became higher (median 0.64 vs 0.41 p=0.0075). During rGHT, MCV decreased (median 80.3 vs 83.2μm3 p=0.0231). Morphological and functional characteristics of erythrocytes in GHD children were shown to differ significantly from the healthy control group. A twelve-month rGHT partially improved some of the studied parameters but Oxy-Hb level and echinocyte count remained high.

Геоэндемическая оценка клинико-эпидемиологических особенностей дефицита гормона роста у детей Одесского региона по результатам 15-летнего мониторирования

Геоэндемическая оценка клинико-эпидемиологических особенностей дефицита гормона роста у детей Одесского региона по результатам 15-летнего мониторирования

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.

Pathogenic and likely pathogenic genetic alterations and polymorphisms in growth hormone gene (GH1) and growth hormone releasing hormone receptor gene (GHRHR) in a cohort of isolated growth hormone deficient (IGHD) children in Sri Lanka

ObjectiveGenetic alterations in GH1 and GHRHR genes are known to cause isolated growth hormone deficiency (IGHD). Of these, GHRHR codon 72 mutation has been reported to be highly prevalent in the Indian subcontinent, but among Sri Lankans its prevalence was low compared to reports from neighboring countries. The present study was therefore carried out to identify genetic alterations in the GH1 gene and rest of the GHRHR gene in a cohort of Sri Lankan IGHD patients who tested negative for GHRHR codon 72 mutation. MethodsFifty five IGHD children negative for codon 72 (GHRHR) mutation were screened for gross GH1 gene deletion by polymerase chain reaction (PCR) and restriction fragment length polymorphism technique. The coding, intronic and promoter regions of the GH1 gene were sequenced in children who were negative for GH1 deletion (N=53). In a subset (N=40), coding, flanking intronic and promoter regions of the GHRHR gene were screened by single strand conformation polymorphism/sequencing. Identified coding region and intronic variants were subjected to in silico analysis to ascertain pathogenicity. Family members available were screened for the significant variants observed in the index child. ResultsGross GH1 gene deletions, 6.7kb and 7.0kb were observed in one child each. One novel and 24 reported single nucleotide variants (SNVs) were observed in the GH1 gene and its promoter. These included one reported pathogenic splice site mutation (c.172-2A>T) and one reported likely pathogenic missense mutation (c.406G>T). One large novel deletion of 5875 base pairs that included exon 1, one likely pathogenic novel SNV (c.211G>T) and 18 reported SNVs were observed in the GHRHR gene. Fourteen variants observed were of uncertain significance (8 in GH1 and 6 in GHRHR), twenty three variants were likely benign (11 in GH1 and 12 in GHRHR) and four variants were benign (4 in GH1 and none in GHRHR). ConclusionIn a cohort of IGHD children, six pathogenic or likely pathogenic genetic alterations of either GH1 gene or GHRHR gene were found. These affected a total of six children. Pathogenic status of four of these had been reported in the literature. Novel SNV in the GHRHR gene was predicted to be pathogenic through in silico analysis. The large novel deletion is likely to be pathogenic as it included exon 1 of GHRHR gene. Analysis of other genes will be needed to ascertain the genetic cause of IGHD in the remaining children.

Growth Hormone Improves Cardiopulmonary Capacity and Body Composition in Children With Growth Hormone Deficiency.

Growth hormone deficiency (GHD) in children may be associated with early cardiovascular risk factors and alterations in left ventricular (LV) structure and function; data on cardiopulmonary functional capacity are lacking. Aim of the study was to evaluate the effect of GHD and growth hormone (GH) therapy on cardiopulmonary functional capacity, left and right cardiac structure and function, and body composition in children and adolescents. Prospective, case-control study. Twenty-one untrained GHD children (11.3 ± 0.8 years) underwent cardiopulmonary exercise testing, echocardiography and dual-energy x-ray absorptiometry, before and after 12 months of GH therapy. Twenty-one controls matched for sex, pubertal status, body mass index, and physical activity (PA) were evaluated at baseline and after 1 year. At baseline, GHD patients showed reduced LV mass (LVM; 63.32 ± 7.80 vs 80.44 ± 26.29 g/m2, P = 0.006), peak oxygen consumption (VO2peak; 22.92 ± 4.80 vs 27.48 ± 6.71 mL/Kg/min, P = 0.02), peak workload (80.62 ± 29.32 vs 103.76 ± 36.20 W, P = 0.02), and O2 pulse (4.93 ± 1.30 vs 7.67 ± 2.93 mL/beat, P = 0.0003), compared with controls. GHD patients also exhibited lower lean body mass (LBM 65.36 ± 7.84% vs 76.13 ± 8.23%, P < 0.001), and higher fat mass (FM 30.84 ± 7.92% vs 22.19 ± 8.18%, P = 0.001) than controls. GH therapy resulted in a significant increase of LVM (72.01 ± 15.88, P = 0.03), VO2peak (26.80 ± 4.97; P = 0.01), peak workload (103.67 ± 32.24, P = 0.001), O2 pulse (6.64 ± 1.68, P = 0.0007), and LBM (75.36 ± 7.59%, P = 0.0001), with a reduction in FM (22.62 ± 7.73%, P = 0.001). No difference was found in either left or right ventricular function. Our results suggest that cardiac structure, body composition and cardiopulmonary functional capacity are impaired in children with untreated GHD and can be restored after short-term GH replacement therapy.

Correlation between adrenal function, growth hormone secretion, and insulin sensitivity in children with idiopathic growth hormone deficiency.

Patients with growth hormone deficiency (GHD) demonstrate an increased cortisol/cortisone ratio which could potentially explain the metabolic features of GHD, while GH treatment (GHT) could increase the cortisol metabolism. In 35 children (27M, mean age 10.1years) with idiopathic GHD at baseline and after 12months of GHT and in 25 controls, in addition to metabolic parameters, we assessed adrenal function by morning serum cortisol, its peak, and its area under the curve (AUCCOR) during insulin tolerance test (ITT). A cortisol peak <18µg/dl was shown in 22 and 31% of GHD children at baseline and after GHT, respectively. At baseline, GHD children had lower fasting glucose (p<0.001) and ISI-Matsuda (p=0.042), with concomitant higher Homa-IR (p=0.006) and morning cortisol (p=0.012) than controls. Morning cortisol was negatively correlated with GH (p<0.001), fasting glucose (p<0.001) and ISI-Matsuda (p<0.001) and positively with Homa-IR (p=0.010). Both cortisol peak and AUCCOR were negatively correlated with GH (all p<0.001) and ISI-Matsuda (p=0.016 and p=0.001, respectively). After 12months of GHT, a significant increase in fasting glucose (p<0.001), and Homa-IR (p=0.011) was documented, with a concomitant decrease in morning cortisol (p=0.002), AUCCOR (p=0.038), total (p=0.003) and LDL-cholesterol (p=0.016). No significant correlations were found among cortisol levels and all parameters were investigated. Cortisol levels correlate with GH secretion and with many metabolic parameters in GHD children, while the metabolic effects during GHT are mainly due to GHT per se and less to cortisol reduction.

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.

Early growth hormone treatment start in childhood growth hormone deficiency improves near adult height: analysis from NordiNet® International Outcome Study.

ObjectiveTo investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD).DesignNordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting.MethodsPatients (n = 172) treated to NAH (height at ≥18 years, or height velocity <2 cm/year at ≥16 (boys) or ≥15 (girls) years) were grouped by age (years) at treatment start (early (girls, <8; boys, <9), intermediate (girls, 8–10; boys, 9–11) or late (girls, >10; boys, >11)) and GHD severity (<3 ng/mL or 3 to ≤10 ng/mL). Multiple regression analysis was used to evaluate the effect of age at treatment start (as a categorical and continuous variable) on NAH standard deviation score (SDS).ResultsAge at treatment start had a marked effect on NAH SDS; NAH SDS achieved by patients starting treatment early (n = 40 (boys, 70.0%); least squares mean (standard error) −0.76 (0.14)) exceeded that achieved by those starting later (intermediate, n = 42 (boys, 57.1%); −1.14 (0.15); late, n = 90 (boys, 68.9%); −1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start.ConclusionsEarly initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.

Economic and social aspects of pituitary dwarfism treatment with recombinant growth hormone

Rationale. Pituitary dwarfism is an orphan disease requiring pathogenetic treatment. The domestic literature lacks studies devoted to the medical and economic effectiveness of treatment for growth hormone deficiency (GHD) using recombinant growth hormone (rGH) drugs.&#x0D; Aim. To analyze the cost effectiveness of rGH therapy in GHD children in the Russian Federation under the Program «7 High-Cost Nosologies».&#x0D; Material and methods. We analyzed data of 50 GHD children living in 4 regions of the Russian Federation and receiving rGH therapy under the Program «7 High-Cost Nosologies». We evaluated the amount of drug consumption and the economic component: the cost of treatment and monitoring for ≥ 6 years. The incremental cost was calculated as the difference between a program providing a GHD child with rGH treatment and monitoring and an alternative program providing a GHD child with financial and social assistance and medical examination.&#x0D; Results. The median cost of treatment of a single child with rGH at a dose of 0.033 mg/kg/day was 437.5 thousand rubles or 8.12 thousand US dollars for the entire analyzed period (mean, 6.95 years). The median cost of treatment per child per year was 63.6 thousand rubles/year or 1.09 thousand USD/year. Given the cost of treatment and monitoring, the integrated management of one patient cost 68.4 thousand rubles per year (470.7 thousand rubles for 6.95 years), on average, with monitoring accounting for 7.05%. The total cost of all benefits and examinations for one disabled child was 178.97 thousand rubles per year or 1,243.86 thousand rubles for 6.95 years (medical examinations accounted for 1.2%). Upon calculating the cost difference between the program providing a GHD child with treatment and monitoring and the alternative program when a GHD child was not provided with treatment, but received appropriate disability payments and medical examination, the incremental cost amounted to 110.6 thousand rubles per child per year (773.18 thousand rubles for 6.95 years).&#x0D; Conclusion. The study demonstrates that treatment of GHD children under Program «7 High-Cost Nosologies» is cost-effective for both the patient and society and the state in general. For example, the incremental cost between the two programs is 110.6 thousand rubles for a year or 773.18 thousand rubles for 6.95 years. The study results indicate the importance of thorough analysis of the effects and costs in assessing the effectiveness of medical programs, especially in the case of orphan diseases.

Molecular genetics of growth hormone deficient children: correlation with auxology and response to first year of growth hormone therapy.

With the paucity of available literature correlating genetic mutation and response to treatment, we aimed to study the genetic makeup of children with growth hormone (GH) deficiency in Western India and correlate the mutation with auxology and response to GH treatment at end of 1 year. Fifty-three (31 boys and 22 girls) children with severe short stature (height for age z-score <-3) and failed GH stimulation test were studied. Those having concomitant thyroid hormone or cortisol deficiencies were appropriately replaced prior to starting GH treatment. A magnetic resonance imaging (MRI) brain scan was done in all. Genetic mutations were tested for in GH1, GHRH, LHX3, LHX4 and PROP1, POU1F1 and HESX1 genes. Mean age at presentation was 9.7±5.1 years. Thirty-seven children (Group A) had no genetic mutation detected. Six children (Group B) had mutations in the GH releasing hormone receptor (GHRHR) gene, while eight children (Group C) had mutation in the GH1 gene. In two children, one each had a mutation in PROP1 and LHX3. There was no statistically significant difference in baseline height, weight and BMI for age z-score and height velocity for age z-score (HVZ). HVZ was significantly lower, post 1 year GH treatment in the group with homozygous GH1 deletion than in children with no genetic defect. Response to GH at the end of 1 year was poor in children with the homozygous GH1 deletion as compared to those with GHRHR mutation or without a known mutation.

MRI features of growth hormone deficiency in children with short stature caused by pituitary lesions.

We verified the advantages of using magnetic resonance imaging (MRI) for improving the diagnostic quality of growth hormone deficiency (GHD) in children with short stature caused by pituitary lesions. Clinical data obtained from 577 GHD patients with short stature caused by pituitary lesions were retrospectively analyzed. There were 354 cases (61.3%) with anterior pituitary dysplasia; 45 cases (7.8%) of pituitary stalk interruption syndrome (PSIS); 15 cases (2.6%) of pituitary hyperplasia due to primary hypothyroidism; 38 cases (6.6%) of Rathke cleft cyst; 68 cases (11.8%) of empty sella syndrome; 16 cases (2.8%) of pituitary invasion from Langerhans cell histiocytosis; 2 cases (0.3%) of sellar regional arachnoid cyst and 39 cases (6.8%) of craniopharyngioma. MRI results showed that the height of anterior pituitary in patients was less than normal. Location, size and signals of posterior pituitary and pituitary stalk were normal in anterior pituitary dysplasia. In all cases pituitary hyperplasia was caused by hypothyroidism. MRI results showed that anterior pituitary was enlarged, and we detected upward apophysis and obvious homogeneous enhancement. There were no pituitary stalk interruption and abnormal signal. We also observed that after hormone replacement therapy the size of pituitary gland was reduced. Anterior pituitary atrophy was observed in Rathke cleft cyst, empty sella syndrome, sellar regional arachnoid cyst and craniopharyngioma. The microstructure of hypophysis and sellar region was studied with MRI. We detected pituitary lesions, and the characteristics of various pituitary diseases of GHD in children with short stature. It was concluded that in children with GHD caused by pituitary lesions, MRI was an excellent method for early diagnosis. This method offers clinical practicability and we believe it can be used for differential diagnosis and to monitor the therapeutic effects.

Pharmacokinetic and Pharmacodynamic Modeling of MOD-4023, a Long-Acting Human Growth Hormone, in Growth Hormone Deficiency Children

Background/Aims: MOD-4023 is a long-acting human growth hormone (hGH) in clinical trials for the treatment of growth hormone deficiency (GHD). A key goal is maintenance of serum concentrations of insulin-like growth factor (IGF) 1 within normal range throughout GH dosing. The study aimed to develop a pharmacokinetic model for MOD-4023 and a pharmacodynamic model for the effect of MOD-4023 on IGF-1 to allow estimation of peak and mean IGF-1 and to identify the optimal IGF-1 sampling day. Methods: MOD-4023 (0.25, 0.48, or 0.66 mg/kg) was administered weekly for 12 months to 41 GH-naive GHD children (age 3–11 years). The control group (n = 11, age 4–9 years) received daily recombinant human growth hormone (r-hGH; 34 µg/kg). Sparse samples (4/subject) were obtained to determine serum concentrations of MOD-4023 or r-hGH and IGF-1. Results: A 2-compartment pharmacokinetic model with first-order absorption fit MOD-4023 data well; a 1-compartment model was appropriate for r-hGH. For both, weight-normalized systemic parameters were preferred over allometric scaling. For MOD-4023, an indirect model fit IGF-1 SDS data well; baseline IGF-1 increased over time. At steady state, samples obtained 4 days following dose administration predicted mean IGF-1 SDS during the dosing interval well. Conclusion: The IGF-1 profile is consistent with the weekly dosing interval. Sampling 4 days following dose administration allows estimation of mean IGF-1 SDS during the dosing interval in GHD patients.

Understanding burden of illness for child growth hormone deficiency

PurposeResearch demonstrates that children and adolescents with growth hormone deficiency (GHD) are impacted in multiple ways beyond their short stature; however, there are no disease-specific measures to assess these impacts. The purpose of this study was to examine the burden of GHD on children and adolescents, and to conduct concept elicitation to develop a model of the impact of GHD to support a disease-specific outcome measure.MethodsFour focus groups and 52 telephone interviews were conducted with children with GHD and parents/guardians of children with GHD to understand the experience and impacts from the child’s perspective, reported by children or parent-observers about the impact on the child. The interviews and focus groups were conducted in Germany, the United Kingdom, and the United States. Interview transcripts were analyzed thematically based on modified grounded theory principles.ResultsThere were 73 descriptions of patient’s experiences elicited from 70 respondents, as three respondents spoke for two children each. A majority of GHD descriptive narratives refer to boy children (n = 51, 69.9%) and a majority of children had taken GHD treatment (n = 64, 89%). Analysis identified four major areas of GHD impact: Signs and Symptoms (beyond short stature), Physical Aspects of Daily Life, Social Well-Being, and Emotional Well-Being.ConclusionsThe burden of GHD in children and adolescents is considerable and not limited to short stature. The severity of GHD impact on children and adolescents appears to be variable and individualized, but these data indicate that early identification and growth hormone treatment may lead to fewer impacts.

Effects of 1-year growth hormone replacement therapy on thyroid volume and function of the children and adolescents with idiopathic growth hormone deficiency.

There are different opinions about the effects of growth hormone replacement therapy (GHRT) on thyroid function and volume. This study aimed to assess the effects of GHRT on thyroid volume and function in the children and adolescents with growth hormone (GH) deficiency. A total of 29 patients diagnosed with GH deficiency were enrolled in the study. The control group consisted of 29 cases matched for age, gender and pubertal period with the patients. Thyroid function tests and insulin-like growth factor levels were measured, simultaneously thyroid volumes were assessed by ultrasonography at the initiation period and at the end of GHRT. Thyroid volumes of the patient group was -0.55±1.1 standard deviations (SDs) initially; whereas at the end of 1 year it was found to be -0.29±1.29 SDs and both SDs of thyroid volumes did not differ significantly. The SDs of thyroid volume of the control group was -0.85±1.03 SDs initially and -0.72±0.85 SDs at the end of 1 year; and they did not differ significantly. On the other hand, after GHRT of 1 year, thyroid stimulating hormone (TSH) and free thyroxine (T4) levels decreased. It was observed that SDs of thyroid gland volumes did not change in GH deficient children and adolescents after GHRT.

Effect of oxidative stress on major plasma carotenoid content and composition in prepubertal children with growth hormone deficiency

Objective and hypotheses. This study aimed at examining the effect of oxidative stress on amount and composition of major plasma carotenoids in prepubertal children with growth hormone deficiency (GHD).Material and methods. Thirteen prepubertal treatment-naive children (2 girls, 11 boys; aged 3.5—12.0 yr, median 8.0 years; bone age 1.5—8.0 yr; median 6.0 years,) with GHD and 7 prepubertal health children (7 boys; aged 6—11 years; median 9.3 years) were included in the study. The levels and composition of carotenoids (lutein with zeaxanthin, lycopene isomers, β-cryptoxanthin, β- and α-carotene and ketocarotenoids) were measured using reverse phase HPLC. Activity of the antioxidant system was assayed via thiobarbituric acid reactive substances (TBARS), ceruloplasmin (CP) levels and total antioxidant capacity (TAC) of plasma. Total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were also measured.Results. The levels of TBARS, TC and LDL-C in the GHD children were higher than in healthy children (median 5.6 vs 3.8 µM/L, 4.00 vs 4.37 and 2.40 vs 2.70 mM/L, respectively). Total carotenoid level did not significantly differ between control and the GHD groups. However, contents of lutein and β-cryptoxanthin were significantly lower in the GHD children in comparison with control group (21.34 vs 6.97 and 25.23 vs 10.08 mg/l, respectively). In contrast, levels of lycopene, α- and β-carotene did not significantly differ in the GHD and control groups. At the same time, the level of ketocarotenoids in the GHD children increases (35.67 vs 114.9 mg/l).Conclusions. We observed that the presence of mild oxidative stress leads to a changes in carotenoid profile of GHD children.

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.

Relationship between IGF-I Concentration and Metabolic Profile in Children with Growth Hormone Deficiency: The Influence of Children's Nutritional State as well as the Ghrelin, Leptin, Adiponectin, and Resistin Serum Concentrations.

Background Some, however not all, children with growth hormone deficiency (GHD) reveal a tendency towards metabolic disorders. Insulin-like growth factor I (IGF-I) is the main mediator of GH anabolic effects. Objective The aim of the study was to compare ghrelin, adiponectin, leptin, resistin, lipid, glucose, and insulin concentrations in GHD children, depending on the IGF-I bioavailability. Methods The analysis comprised 26 children with GHD, aged 5.7–15.3 yrs. Fasting serum concentrations of IGF-I, IGFBP-3, ghrelin, leptin, adiponectin, resistin, lipids, glucose, and insulin were measured. The GHD children were divided into two subgroups: (1) with lower IGF-I/IGFBP-3 molar ratio and (2) with higher IGF-I/IGFBP-3 molar ratio. The control group consisted of 39 healthy children, aged 5.1–16.6 yrs, of normal height and body mass. Results GHD children with lower IGF-I/IGFBP-3 molar ratio were found to have a significantly lower body mass and insulin and triglyceride concentrations, as well as significantly higher ghrelin and adiponectin concentrations than GHD children with higher IGF-I/IGFBP-3. Conclusions A better metabolic profile characterised GHD children with low IGF-I bioavailability. This phenomenon may be the result of high adiponectin and ghrelin concentrations in those children and their influence on adipose tissue, glucose uptake, and orexigenic axis.