GH-deficient Children Research Articles

Common Polymorphisms of the Growth Hormone (GH) Receptor Do Not Correlate with the Growth Response to Exogenous Recombinant Human GH in GH-Deficient Children

GH acts through the GH receptor (GHR), whose polymorphisms might affect the growth response to recombinant human GH (rhGH). The objective of this study was to investigate possible influences of GHR polymorphisms on the growth response to rhGH in GH-deficient (GHD) children. This was a 2-yr study (first year, spontaneous growth; second year, growth during rhGH treatment). This study was performed at a referral center. Fifty-four prepubertal GHD children (11 females; mean age, 7.8 yr; sd, 3.96) were studied. Patients were treated with rhGH (0.2 mg/kg.wk) for at least 1 yr after diagnosis. Growth velocity (GV) was measured 1 yr before treatment and during the first treatment year. GHR exons were amplified by PCR using pairs of intronic primers. The presence of single or multiple mismatches in the PCR products was revealed by denaturing high-pressure liquid chromatography. For exons in which mismatches were found by denaturing high-pressure liquid chromatography, direct sequencing was performed by automatic sequencer. Before the start of treatment, the mean height (Ht) sd score was -1.93 (sd, 0.70), and the mean GV sd score was -1.49 (sd, 1.26). The posttreatment (first 12 months) mean GV sd score was 3.55 (sd, 3.27). Molecular analysis revealed a high frequency of GHR polymorphisms; in particular: exon 3 deletion (Del 3) in 26 subjects (48%), polymorphism 504 A>G at codon 168 of exon 6 in 44 (82%), and polymorphism 1576 A>C at codon 526 of exon 10 in 35 (65%). In most patients, these different polymorphisms recurred in association. We found no significant differences in GV between the groups of subjects defined by the polymorphic genotypes. The most common GHR polymorphisms, alone or in association, do not appear to affect the growth response to rhGH in GHD children.

Discrepancies between Physician and Parent Perceptions of Psychosocial Problems of GHD Children Undergoing GH Therapy in Japan.

This study examined discrepancies between the perceptions of physicians treating short children with GH deficiency (GHD) using GH replacement therapy (GHRT) and the perceptions of the parents of these children and identified the major causes of parental anxiety. Three attending pediatric endocrinologists and the parents of 31 GHD children participated in this study. The physicians and parents completed a specially designed questionnaire to rate the types and degrees of psychosocial problems that GHD children might experience. For 6 of the first 11 questions, the physicians rated psychological problems differently than the parents did, tending to over- or underestimate parental concerns. This discrepancy did not disappear with treatment. However, the difference in the perception of anxiety between the physicians and parents changed for issues regularly discussed between them. Physicians and nurses were ranked as the most reliable providers of information. The parents of children who had previously undergone GHRT were a highly desired source of information. Psychosocial problems remain largely unaddressed by endocrinologists. Endocrinologists treating short stature are encouraged to be more involved in understanding parents’ anxieties, evaluation of misperceptions concerning parents’ expectations, and addressing these issues in future communication with parents. Support by experienced psychologists may help endocrinologists with this issue.

Three-Year Follow-up Study on Serum Leptin Levels in GH Deficient Children with GH Replacement Therapy.

Interactions between GH and leptin have been extensively studied. However, results of long-term GH therapy on serum leptin levels in GH-deficient children were not consistent. Moreover, no such reports were available in Japanese children with this disease. We studied 35 Japanese patients with GH deficiency (26 boys and 9 girls, mean age: 9.8 ± 6.2 yr old), of whom 6 patients with complete and 29 with incomplete GH deficiency were identified by GH provocation test. Serum leptin levels, percent of ideal body weight (%IBW) and percent fat (%fat) were determined at 0, 1, 3, 6, 12, 18, 24, and 36 mo after beginning GH therapy. Baseline levels of %fat and leptin were significantly higher in girls than boys (P<0.05), though serum leptin did not change throughout the study period in either group. Further, %IBW did not change significantly, whereas %fat exhibited significant changes after 6 mo in boys and remained virtually constant thereafter for up to 3 yr. In summary, serum leptin levels did not change in GH-deficient boys and girls during the 3-yr period after the start of GH replacement therapy, despite a decrease in %fat after 6 mo of therapy in the boys. Thus, it is conceivable that long-term GH replacement therapy can be employed without an effect on normal leptin secretion.

Recombinant human growth hormone (SMP-140) is effective for growth promotion in hypophysectomized rats

Growth hormone (GH) replacement therapy has been shown to have beneficial effects on linear growth enhancement in GH-deficient children over the past few decades. SMP-140 is a sterile liquid formation containing rhGH that is expected to improve patient compliance and accuracy of dosing, compared with the commercially available lyophilized form of GH. However, since there are no data showing that SMP-140 influences body elongation in animal models, we studied the effects of SMP-140 on body length in hypophysectomized (HPX) rats, which are used as animal models of GH deficiency. Consistent with the main feature of GH-deficient children, the body length of HPX rats was significantly shorter than that of sham-operated rats at the start of the study. SMP-140 (0.2, 1 and 5 mg/kg) was administered once daily to HPX rats for seven days, and resulted in a dose-dependent increase in body length and in the width of the growth plate cartilage. These results show that SMP-140 administration increases body length in an animal model of GH deficiency, and suggest that SMP-140 will be a useful agent for the treatment of growth-retarded children.

Increased Number and Affinity of Platelet Serotoninergic Receptors in Short, GH-Deficient Children

Increased Number and Affinity of Platelet Serotoninergic Receptors in Short, GH-Deficient Children

Changes of Thyroid Function During Long-term hGH Therapy in GHD Children. A Possible Relationship with Catch-up Growth?

Growth hormone (GH) treatment in patients with GH deficiency (GHD) can determine changes in the thyroid function. The clinical significance of these changes remains controversial, and all studies have so far covered rather a short period--usually no longer than one year. To determine the effect of long-term recombinant hGH treatment in children with idiopathic GHD on the thyroid function. Nineteen prepubertal children (12 boys and 7 girls, mean age 9.2 +/- 3.1 years) with idiopathic GHD were studied and followed for twenty-four months. None of the patients showed multiple pituitary hormone deficiencies. Nineteen healthy children matched for age and sex acted as controls. Patients with GHD showed a significant increase in TT (3) at twelve months and in FT (3) at six and twelve months after starting GH treatment, with a significant decrease at eighteen and twenty-four months. TT (4) level decreased significantly at twelve months and increased significantly at eighteen and twenty-four months. FT (4) also decreased, but only slightly, after twelve months of hGH treatment, and then increased significantly at twenty-four months. TSH levels did not vary significantly during the course of therapy. TT (3)/TT (4) and FT (3)/FT (4) ratios increased significantly after six and twelve months of therapy and significantly decreased later, approaching pre-therapy values. The SDS of Growth Velocity (SDS-GV) increased remarkably during the first year of therapy and then decreased significantly during the second year, although it remained significantly higher than the pre-therapy values. TT (3) and TT (3)/TT (4) ratio displayed a significant correlation with SDS-GV at twelve months of therapy. In a multiple regression analysis with age, bone age, parental height, GH dose, TT (3,) TT (3)/TT (4), and the SDS of IGF-I, only the TT (3)/TT (4) ratio at twelve months of therapy (p < 0.001) was identified as a significant predictor of SDS-GV. Our data confirm that changes in thyroid function are present in GHD children during long-term hGH therapy. These changes probably resulted from the effect of hGH on the peripheral metabolism of thyroid hormones and appear to be transitory, disappearing during the second year of hGH treatment. We speculate on the functional significance of these changes, and in particular, on their role in catch-up growth after hGH therapy.

IGF-I and IGF Binding Protein-3 Levels during Initial GH Dosage Step-Up Are Indicators of GH Sensitivity in GH-Deficient Children and Short Children Born Small for Gestational Age

Background: A stepwise increment of the GH dose is an approach aimed at avoiding adverse events. We investigated GH sensitivity by studying IGF-I and IGFBP-3 concentrations during the initial phase of GH treatment. Methods: Our investigation was part of the regular follow-up of prepubertal children with GH deficiency (GHD) (n = 31) and small for gestational age (SGA) (n = 23). Dosage was increased in three steps: one-third at the start, two-thirds after 14 days, and the full dose after 28 days (full dose: GHD = 28 µg/kg body weight (BW)/day; SGA = 60 µg/kg BW/day). Blood samples were taken on days 0, 14 and 28, as well as in conjunction with anthropometrical examinations after 3, 6 and 12 months. IGF-I and IGFBP-3 were measured by means of published in-house RIAs and age-related references were used to calculate standard deviation scores (SDS). Height velocity (cm/year) and Δ HT SDS were taken as growth response parameters. Results:Before GH treatment (GHD vs. SGA; median and p values): age (years) (6.6 vs. 6.0; n.s.), HT SDS (–2.6 vs. –3.2; p < 0.05); GH amount after stepping up (µg/kg BW/day) (28 vs. 60; p < 0.01); BW SDS (–0.5 vs. –2.9; p < 0.01); max. GH stimulated (µg/l) (5.6 vs. 10.8; p < 0.01); IGF-I SDS (–3.5 vs. –1.8; p < 0.01); IGFBP-3 SDS (–2.0 vs. 0.8; p < 0.01). After 1 year of GH therapy: HT velocity (cm/year) (9.8 vs. 9.6; n.s.), Δ HT SDS (0.9 vs. 0.9; n.s.); WT velocity (kg/year) (3.3 vs. 3.5; n.s.). Our results show that changes in growth similar to GHD could be induced in SGA by a dosage that was twice as high as the replacement dose given in GHD. GH dose and HT velocity did not correlate in both groups. IGF-I and IGFBP-3 increased as follows in GHD and SGA during stepping up of the dosage (ng/ml, GHD vs. SGA): at start, 54 vs. 89; at day 14, 78 vs. 132; at day 28, 90 vs. 167; at 3 months, 118 vs. 218. There was the same relationship between dose levels and absolute IGF-I concentrations in both groups. In terms of IGF-I SDS, the dose-response curve in SGA showed a shift to the right in comparison to GHD, thus indicating lower sensitivity to GH. The dynamics of IGF-I and IGFBP-3 differed, as IGFBP-3 peaked earlier (on day 28). In GHD, IGF-I SDS at 3 months was –0.7 vs. +0.9 in SGA. Near-identical levels were found for Δ IGF-I SDS and IGFBP-3 SDS above basal levels for each time-point investigated. First year HT velocity in GHD correlated negatively with basal IGF-I SDS (R² = 0.33; p <0.001) and basal IGFBP-3 (R² = 0.17; p <0.05) but did not correlate with the IGF-I increment during the 0- to 3-month period. Conversely, first year HT velocity correlated (+) in SGA with the IGF SDS increment during the 0- to 3-month period (R² = 0.26; p = <0.05). Height velocity in SGA, however, correlated neither with basal IGF-I and IGFBP-3 nor with the 0- to 3-month increments of IGFBP-3 SDS. Conclusions: IGFs increase during initial GH therapy, thus raising questions about short-term IGF generation tests. (I) In terms of IGF generation, substantially lower sensitivity to GH was observable in SGA. (II) Higher GH sensitivity during first year catch-up growth is associated with GHD, but in SGA it is attributable to increases in IGF. A wider range of GH dosages needs to be explored in order to gain further insight into the relationship between GH dose, IGF levels, and growth. Monitoring IGFs is a practical means for exploring GH sensitivity during dosage stepping up.

Alterations in the oxidant‐antioxidant status in prepubertal children with growth hormone deficiency: effect of growth hormone replacement therapy

Growth hormone deficiency (GHD) in adults is associated with increased oxidative stress determined by the underlying GH-IGF-1 axis alterations. Despite GHD being a common diagnosis in children with short stature, no data on the oxidant/antioxidant status are available in this age group. This study was designed to detect differences in oxidative stress parameters between prepubertal GH-deficient children and healthy controls. Furthermore, the effect of 12 months of conventional GH replacement (rGH) on oxidant-antioxidant status was evaluated in the GHD group only. Ten (nine males and one female) prepubertal children (mean age 9.1 +/- 1.3 years) with GHD were recruited and matched for sex and age (9.2 +/- 1.9 years) with 20 healthy controls (18 males and two females). At study entry, lag phase, an index of susceptibility of low density lipoprotein (LDL) to in vitro oxidation, malondialdehyde (MDA) and vitamin E were measured in all subjects. These parameters were also evaluated in GH-deficient children after 12 months of rGH treatment. The lag phase was significantly decreased in GH-deficient children compared to healthy controls (15.50 +/- 7.4 vs. 43.00 +/- 9.2 min; P = 0.0007), while MDA was significantly increased (1.33 +/- 0.38 vs. 0.46 +/- 0.10 nmol/mg; P = 0.0006). Vitamin E levels were significantly decreased (22.44 +/- 9.57 vs. 35.38 +/- 16.49 micromol/l; P = 0.001). IGF-1 and IGFBP-3 correlated directly to lag phase (r = 0.48; P = 0.01; r = 0.63, P = 0.002, respectively) and to vitamin E (r = 0.59, P = 0.003; r = 0.58, P = 0.006, respectively). By contrast, IGF-1 and IGFBP-3 correlated indirectly to MDA (r = -0.47, P = 0.01; r =-0.65, P = 0.002, respectively). After 1 year of rGH therapy, lag phase (39.32 +/- 15.24 min; P = 0.005) and vitamin E (34.9 +/- 7.7 micromol/l; P = 0.005) increased significantly, while MDA decreased significantly (0.71 +/- 0.42 nmol/mg; P = 0.005), reaching normal levels. These data show that children with GHD have substantially increased oxidative stress parameters compared to healthy controls and demonstrate a normalization of these parameters after 1 year of rGH therapy.

Effect of growth hormone therapy and puberty on bone and body composition in children with idiopathic short stature and growth hormone deficiency

The state of bone health and the effect of growth hormone (GH) therapy on bone and body composition in children with idiopathic short stature (ISS) are largely unknown. A direct role of GH deficiency (GHD) on bone density is controversial. Using dual-energy X-ray absorptiometry, this study measured total body bone mineral content (TB BMC), body composition, and volumetric bone mineral density (vBMD) at the lumbar spine (LS) and femoral neck (FN) in 77 children (aged 3–17 years) with ISS ( n = 57) and GHD ( n = 20). Fifty-five children (GHD = 13) receiving GH were followed over 24 months including measurement of bone turnover. At diagnosis, size-corrected TB BMC SDS was greater ( P ≤ 0.002) and LSvBMD SDS lower ( P < 0.03) than zero in both prepubertal ISS and GHD subjects, but FNvBMD SDS was reduced only in the GHD group ( P < 0.05). The muscle-bone relation, as assessed by the BMC/lean mass (LTM) ratio SDS was not different between groups. During GH therapy, prepubertal GHD children gained more height (1.58 [0.9] SDS) and LTM (0.87 [0.63] SDS) compared to prepubertal ISS children (0.75 [0.27] and 0.17 [0.25] SDS, respectively). Percent body fat decreased in GHD (−5.94% [4.29]) but not in ISS children. Total body BMC accrual was less than predicted in all groups accompanied by an increase in bone turnover. Puberty led to the greatest absolute, but not relative, increments in weight, LTM, BMI, bone mass, and LSvBMD. Our results show that children with ISS and GHD differ in their response to GH therapy in anthropometry, body composition, and bone measures. Despite low vBMD values at diagnosis in both prepubertal groups, size-corrected regional or TB bone data were generally within the normal range and did not increase during GH therapy in GHD or ISS children. Growth hormone had great effects on the growth plate and body composition with subsequent gains in height, LTM, bone turnover, and bone mass accrual, but no benefit for volumetric bone density over 2 years.

Congenital Growth Hormone Deficiency and Eye Refraction: A Longitudinal Study

The aim of this study was to study the influence of growth hormone deficiency (GHD) on emmetropization and to evaluate the effect of growth hormone replacement therapy on eye refraction. Twenty-eight children affected by congenital GHD and undergoing substitutive therapy (group 1), and 28 healthy subjects (group 2), were prospectively studied. All patients had a thorough eye examination, including cycloplegic refraction and axial length measurement (only GHD children). After 2 years, we found in both groups a reduction of the dioptric power of the eye. A t test for paired data showed statistically significant differences in both groups (p < 0.001), but the change of refraction was higher in group 2 (p < 0.01). Axial length showed a statistically significant increase, according to the myopic shift (p < 0.001). The change of the refraction found in GHD children could be related to the somatic growth and partially induced by growth hormone therapy. The difference between the two groups could be explained with the late beginning of the therapy in GHD children. It is possible to form the hypothesis that a correct and well-timed substitutive therapy could permit a normal emmetropization process.

Growth Hormone in T-Lymphocyte Thymic and Postthymic Development: A Study in HIV-Infected Children

Vigano A, Saresella M, Trabattoni D, et al. J Pediatr. 2004;145:542–548Growth hormone (GH) plays a role in thymic function, and decreased hormone secretion has been reported in HIV-infected children. Highly active antiretroviral therapy suppresses HIV replication and results in increases in CD4+ T cells in HIV-infected patients. The aim of this study was to determine if the level of immune reconstitution associated with antiretroviral therapy is influenced by the status of the GH insulin-like growth factor 1 axis.HIV-infected children (n = 26) were studied. Half of them had GH deficiency as defined by a reduced peak GH response to GH-releasing hormone and arginine-stimulation test. These patients were matched to 13 patients of similar age, pubertal status, and clinical findings but with normal GH-response tests.Thymic volume was measured with magnetic resonance imaging. Peripheral blood lymphocyte subsets were evaluated with standard monoclonal antibody techniques. Serum interleukin 7 levels were measured with an enzyme-linked immunosorbent assay.The 2 patient populations did not differ in age, weight, height, body mass index, pubertal status, clinical or immunologic stage of disease, or number and percentage of CD4+ T cells before beginning antiretroviral therapy. After antiretroviral therapy, children with GH deficiency had reduced CD4+ T-cell numbers and percentages, reduced interleukin 7 concentrations, and reduced thymic volumes. “Naive” CD4+ T cells were lower in the GH-deficient children, as were central memory T cells. In contrast, effector memory CD4+ T cells and effector CD8+ T cells were increased in the GH-deficient children.Thymic and postthymic lymphocyte pathways are impaired in HIV-infected children, and antiretroviral therapy–associated immune reconstitution is often incomplete. GH might be useful in the management of HIV-infected children with GH deficiency and incomplete immune reconstitution with antiretroviral therapy.The reasons why some patients respond to antiretroviral therapy more effectively than others is generally unknown. However, this study suggests that some of this variation may be related to the GH axis of the infected patients. Whether GH-replacement therapy will improve the immune reconstitution in GH-deficient subjects awaits clinical trials. Of interest, also, would be the effect of GH treatment on subjects with incomplete immune reconstitution but normal GH-stimulation studies.

The role of growth hormone in determining birth size and early postnatal growth, using congenital growth hormone deficiency (GHD) as a model

The role of GH in early human growth is unclear. Congenital GH deficiency (CGHD) provides a useful tool to explore this putative role. We have assessed the effects of CGHD on birth size and early postnatal growth, and the further impact of the presence of additional pituitary hormone deficiencies and midline brain defects on these parameters. Weight, length and BMI expressed as standard deviation scores (SDS), over the first two years of life, were retrospectively compared in 44 GH-deficient children (M:F 26 : 18). Thirty-eight of 44 patients underwent GH provocation testing and all patients had neuro-imaging of the brain. The patients were divided into three groups of increasing phenotypic complexity {group A [n = 12, isolated GHD, no midline defects], group B [n = 10, combined pituitary hormone deficiency (CPHD); no midline defects], group C (n = 22, CPHD with midline defects)}. Mean birth weight, length and BMI SDS were -0.4, -0.9 and +0.1 SDS, respectively. The differences were significant for weight (P = 0.03) and BMI (P = 0.003), but not length (P = 0.3) SDS, between groups A and C. Of the three groups, group A had a lower weight and BMI SDS than group C. The prevalence of postnatal complications (n = 25) was significantly different in the three groups [group A (8%), group B (80%), group C (73%); P < 0.001] and particularly between patients with isolated GH deficiency (IGHD) (group A) and CPHD (groups B and C; P < 0.0001). No patients in group A presented with neonatal hypoglycaemia as compared with 70% of those in group B and 59% in group C (P = 0.001). A reduced length SDS was observed in all patients within 6 months of birth and the reduction was greatest in group B (P = 0.03). Group C remained significantly (P < 0.05) heavier at 12, 18 and 24 months compared to group A. BMI SDS was significantly (P < 0.05) greater at all study points in CPHD patients (groups B and C) as compared with IGHD. Serum GH concentrations at testing did not correlate significantly with birth length (r = -0.08, P = 0.7), birth weight (r = -0.08, P = 0.6) or the age at induction of GH treatment (r = 0.12, P = 0.5). There were no significant differences between peak serum GH concentrations in patients in groups A (7.8 +/- 6.3 mU/l), B (3.9 +/- 4.8 mU/l) or C (8.7 +/- 5.4 mU/l). Length, weight and BMI data from our study groups suggest that GH per se has a minimal effect on intrauterine growth but a significant effect during the infancy period. Early growth may also be influenced by the complexity of the hypopituitary phenotype reflected by the presence of additional pituitary hormone deficiencies and midline forebrain defects.

A brief review of the use and utility of growth hormone stimulation testing in the NCGS: Do we need to do provocative GH testing?

True growth hormone deficiency (GHD) in childhood, while rare, has major clinical consequences. GHD is often associated with other pituitary hormone deficiencies, so these children may require multiple hormonal replacement and close clinical follow-up to optimize their outcome. Growth hormone stimulation testing (GHST), as currently conducted, is not a reliable diagnostic tool. Both changes in growth hormone assay methodologies and increases in the diagnostic threshold contribute to the incorrect labeling of a substantial proportion of normal children as having idiopathic GHD. Fortunately, newer imaging technologies and laboratory tests form a more rational basis to diagnose true GHD. The use of GHST among GH-naive subjects (<20 years of age) enrolled in the National Cooperative Growth Study has declined over the past two decades, from a high of 89% between 1987 and 1989 to only 52% in 2002. Given that GH stimulation testing does not meaningfully aid in distinguishing those few children with true growth hormone deficiency from the much more common short normal child and that alternatives are now available, it is time to discontinue the routine use of GHST in children.

Endothelial Function, Carotid Artery Intima-Media Thickness, Epicardial Adipose Tissue, and Left Ventricular Mass and Function in Growth Hormone-Deficient Adolescents: Apparent Effects of Growth Hormone Treatment on These Parameters

The purpose of this study was to determine whether GH-deficient (GHD) adolescents have abnormalities of cardiac and vascular function detectable during the teenage years. Ten GHD children on GH treatment with a chronological age (CA) of 14.6 +/- 1.7 yr and 12 untreated GHD adolescents with a CA of 15.0 +/- 3.0 yr were studied. Cardiac mass and function, carotid artery intima-media thickness, flow-mediated endothelium-dependent vasodilation (percent change from baseline diameter during hyperemia), and hyperemia-induced blood flow increase of the brachial artery (percent change from baseline) and epicardial adipose tissue were evaluated by echocardiography. Fourteen healthy adolescents served as controls. Untreated GHD adolescents present with a reduced left ventricular mass when compared with controls (P < 0.05) and a lower flow-mediated endothelium-dependent increase in the diameter of the brachial artery during hyperemia than both controls and treated GHD subjects (P < 0.02), whereas their epicardial adipose tissue is significantly higher than that of healthy controls (P < 0.02). Interventricular septum thickness, posterior wall thickness, left ventricular ejection fraction, and carotid artery intima-media thickness were similar in all three groups. Hyperemia-induced blood flow increase was greater in treated GHD adolescents than both untreated subjects and controls (P < 0.001). Body mass index correlated positively with epicardial adipose tissue in all three groups and with carotid intima-media thickness in treated and untreated GHD adolescents. GHD adolescents have a reduced left ventricular mass and vascular abnormalities manifested by lower flow-mediated endothelium-dependent vasodilation. These findings together with an increase in epicardial adipose tissue, a good indicator of abdominal/visceral fat, may contribute to an increased cardiovascular risk in the long term. An improvement in endothelial function and a reduction in arterial stiffness appear to occur after GH replacement.

Adult Height in Patients Treated for Isolated Growth Hormone Deficiency: Role of Birth Weight

To evaluate the effect of growth hormone (GH) administration on adult height (AH) in two groups of isolated GH-deficient (IGHD) children born either small (birth weight below –2 SD) or appropriate (birth weight above –2 SD) for gestational age (GA). Out of 35 prepubertal IGHD children, 14 small for GA (SGA, group A) and 21 appropriate for GA (AGA, group B) were examined. All patients received continuous GH treatment at a median dose of 0.028 mg/kg/day (range 0.023–0.032) in group A and 0.024 (range 0.023–0.028) in group B. GH treatment was administered for a period of 67.0 months (range 42.37–96.05) in group A and 54.31 months (range 47.14–69.31) in group B. All children were measured using a Harpenden stadiometer every 6 months until they reached AH (growth velocity <1 cm/year). The patients underwent a retesting a few months after stopping GH therapy. A significant difference was found between group A and B as expected for birth weight SD, –2.70 (range –2.87 to –2.29) and –0.73 (range –1.30 to 0.14) respectively (p < 0.000001) and interestingly also for body mass index SDS (BMI SDS) at retesting, 0.08 (range 0.30 to –1.51) and 0.61 (range 0.73 to –1.10) respectively (p < 0.04). We observed no significant differences between groups A and B in height (expressed as the SDS for chronological age, height SDS) at diagnosis (p = 0.75), height SDS at start of puberty (p = 0.51), height SDS at retesting (p = 0.50), target height SDS (TH SDS) (p = 0.47), AH SDS (p = 0.92), corrected height SDS (height SDS – TH SDS) (p = 0.60), BMI SDS at diagnosis (p = 0.25), GH dosage (p = 0.34) and therapy duration (p = 0.52). GH treatment with a standard dose in short IGHD children leads to a normalization of AH without any significant difference between SGA and AGA patients.

Growth hormone treatment in non-growth hormone-deficient short children

The unlimited availability of GH obtained by recombinant DNA technology has allowed optimization of treatment in GH-deficient (GHD) children. At the same time it has prompted a number of studies in conditions not characterized by GHD such as Turner syndrome, intrauterine growth retardation, chronic renal failure and other chromosomal and genetic abnormalities associated with short stature. Several controlled and uncontrolled studies have now reported the adult height of patients with short stature and normal GH secretion. Critical reviewing of the data shows that some short non-GHD children may benefit from a prolonged treatment with GH. However, further studies are needed in order to be able to identify the subjects for whom treatment is really beneficial.

Serum cytokine levels in GH-deficient children during substitutive GH therapy

The aim of the present study was to investigate the effect of exogenously administered human GH (hGH) on serum levels of interleukin (IL)-4, IL-6, IL-12 and tumour necrosis factor (TNF)-alpha in GH-deficient (GHD) children. We evaluated 13 short prepubertal GHD children, aged between 2 and 13 years, and 13 age-matched healthy subjects as controls. Circulating cytokine values were evaluated in basal conditions in all children, and 6 and 24 h following the 1st hGH injection (0.23 mg/kg per week), and then after 3 months of hGH treatment in GHD patients. Serum levels of IL-4, IL-6, IL-12 and TNF-alpha were measured by commercially available ELISAs. No significant differences were found between controls and GHD children in basal values of serum IL-4, IL-6, IL-12 and TNF-alpha (P > 0.05 by Mann-Whitney U test). Analysis of cytokine levels during hGH treatment showed significant changes over time in TNF-alpha and IL-6 levels (P = 0.0014 and P = 0.00 024 respectively), with the more pronounced effect observed at 6 h following the first administration of hGH (i.e. increase in IL-6 (Wilcoxon matched pairs test, P = 0.0015) and TNF-alpha levels (P = 0.0015)). No significant changes over time were observed in IL-4 and IL-12 serum levels. In vivo release of the pro-inflammatory cytokines IL-6 and TNF-alpha can be affected by hGH treatment in GHD children, suggesting a direct effect of GH on the immune function.

Final adult height of patients who received hematopoietic cell transplantation in childhood

AbstractGrowth impairment and growth hormone (GH) deficiency are complications after total body irradiation (TBI) and hematopoietic cell transplantation (HCT). To determine the impact of GH therapy on growth, the final heights of 90 GH-deficient children who underwent fractionated TBI and HCT for malignancy were evaluated. Changes in height standard deviation (SD) from the diagnosis of GH deficiency to the achievement of final height were compared among 42 who did and 48 who did not receive GH therapy. At HCT, GH-treated patients were younger (P = .001), more likely to have undergone central nervous system irradiation (P = .007), and shorter (P = .005) than patients who did not receive GH therapy. After HCT, GH deficiency was diagnosed at 1.5 years (range, 0.8-9.5 years) for GH-treated and 1.2 years (range, 0.9-8.8 years) for nontreated patients. GH therapy was associated with significantly improved final height in children younger than 10 years at HCT (P = .0001), but GH therapy did not impact the growth of older children. Girls (P = .0001) and children diagnosed with acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), or myelodysplastic syndromes (MDS) (compared with acute lymphoblastic leukemia [ALL] or non-Hodgkin lymphoma [NHL]; P = .02) also showed more rapid growth than their counterparts. These data demonstrate that GH therapy improves the final height of young children after fractionated TBI.

The impact of idiopathic childhood‐onset growth hormone deficiency (GHD) on bone mass in subjects without adult GHD

Despite seemingly adequate growth hormone (GH) treatment during childhood, children with GH deficiency (GHD) have reduced bone mineral density (BMD) at final height. The aim was to evaluate BMD and bone mineral content (BMC) in adults treated for idiopathic childhood-onset (CO) GHD, 18 years after stopping GH treatment. Twenty-six (11 females) patients with idiopathic CO GHD participated. All patients but two had been treated for isolated GHD in childhood. The childhood diagnosis was established by an insulin tolerance test (ITT) and reassessed in adulthood by an ITT (N = 21) or arginine test (n = 5), revealing that 10 patients had GHD according to adult criteria. Accordingly, the patient group was divided into (1) patients who did not have persistent GHD in adulthood and (2) patients who did have persistent adult GHD. Twenty-six healthy subjects acted as age-, gender- and body mass index (BMI)-matched controls. The patients who did not have persistent GHD had significantly lower IGF-I values and whole-body, femoral neck and lumbar spine BMD compared to controls [0.994 +/- 0.10 vs. 1.114 +/- 0.11 g/cm2 (P = 0.003), 0.842 +/- 0.12 vs. 0.962 +/- 0.11 g/cm2 (P = 0.006) and 1.026 +/- 0.14 vs. 1.127 +/- 0.13 g/cm2 (P = 0.004), respectively]. Femoral neck BMD was significantly reduced in the patients who had persistent GHD, compared to controls (0.842 +/- 0.09 vs. 0.938 +/- 0.11, P = 0.04). Significant correlations were observed between all bone variables and IGF-I in all subjects, whereas no correlations were observed between bone variables and GH peak levels in the 26 patients. In conclusion, we found that (1) patients with idiopathic CO GHD, who at retest in adulthood did not have GHD according to adult criteria, had reduced serum IGF-I and BMD/BMC compared to controls. (2) This observation was also made in the patients who did have persistent GHD in adulthood. The findings may reflect the fact that the present diagnostic criteria for adult GHD (i.e. response to the ITT) do not reflect the clinical consequences of disordered GH-IGF axis in CO GHD young adults who were treated with GH in childhood. Alternatively, despite seemingly adequate GH treatment in childhood an optimal peak bone mass in adolescence may never have been reached in either of the groups. (3) IGF-I levels correlated with clinical signs of the adult GHD syndrome. We believe that further studies on the indications and diagnostic procedures for GH treatment after cessation of linear growth are necessary.

Peripheral inflammatory and fibrinolytic markers in adolescents with growth hormone deficiency: Relation to postprandial dyslipidemia

To determine whether peripheral inflammatory and fibrinolytic markers are elevated in growth hormone-deficient (GHD) adolescents and associated with increased postprandial lipoproteins. Fifteen GHD children on GH treatment with a chronologic age of 12.7 +/- 2.5 years and 10 untreated GHD adolescents with a chronologic age of 13.0 +/- 2.6 years were studied. Triglycerides (TG), C-reactive protein (CRP), fibrinogen, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were measured in the fasting state and 4 hours after ingesting a high-fat meal; 15 healthy adolescents served as controls. Fasting and postprandial TG of untreated GHD children were higher than those in treated subjects and healthy controls. Fasting TNF-alpha, CRP, and fibrinogen concentrations of untreated GHD adolescents were higher than those in healthy controls, but similar to those of GH-treated GHD adolescents. Although fibrinogen levels increased after a high-fat meal in GHD adolescents, CRP, TNF-alpha, and IL-6 concentrations did not increase further. Fasting and postprandial TG of untreated GHD adolescents were positively associated with fasting and postprandial CRP, and with postprandial TNF-alpha and IL-6 concentrations. Fasting TG also correlated positively with fasting fibrinogen concentrations in untreated and treated GHD adolescents. The pronounced inflammatory response seen in GHD adolescents seems to be associated with the presence of elevated levels of fasting and postprandial TG, which may result in an increased susceptibility for premature atherosclerosis.