Steven D. Chernausek

Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome

Seventy girls with Turner syndrome, verified by karyotype, were randomly assigned to observation or treatment with human growth hormone (hGH), oxandrolone, or a combination of hGH plus oxandrolone for a period of 12 to 24 months, to assess the effect of treatment on growth velocity and adult height. Subsequently, all subjects received either hGH alone or hGH plus oxandrolone. Data are presented for 62 subjects treated for a period of 3 to 6 years. When compared with the anticipated growth rate in untreated patients, the growth rate after treatment with hGH, both alone and in combination with oxandrolone, showed a sustained increase for at least 6 years. Treatment is continuing in over half of the subjects; at present, 14 (82%) of 17 girls receiving hGH alone and 41 (91%) of 45 girls receiving combination therapy exceeded their expected adult heights. Thirty girls have completed treatment; mean height for these 30 patients is 151.9 cm, compared with their mean original projected adult height of 143.8 cm. We conclude that therapy with hGH, alone and in combination with oxandrolone, can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome.

Three-year results of a randomized prospective trial of methionyl human growth hormone and oxandrolone in Turner syndrome

Seventy girls with Turner syndrome, 4 to 12 years of age, participated in a prospective, randomized study to determine the effects on growth of methionyl human growth hormone (met-hGH) or oxandrolone. Subjects were randomly assigned to receive either no treatment (control) or met-hGH (0.125 mg/kg three times per week), oxandrolone (0.125 mg/kg/day), or combination met-hGH plus oxandrolone. At the end of an initial period of 12 to 20 months, patients in the original control and oxandrolone groups were given combination met-hGH plus oxandrolone. At that time the dosage of oxandrolone was lowered to 0.0625 mg/kg/day. Sixty-five subjects have now completed the first 3 years of the study. Compared with the control growth rate for year 1 (3.8 cm/yr), significant increases in growth rate were seen in all 3 years of combination therapy (9.8, 7.4, and 6.1 cm/yr, respectively) and in the first 2 years of treatment with met-hGH alone (6.6, 5.4, and 4.6 cm/yr). When growth velocity was expressed as standard deviation for age in girls with Turner syndrome, significant increases relative to the control group for year 1 (-0.1 SD) were seen in all three years of both combination therapy and met-hGH alone (combination, +6.6, +4.3, +3.0 SD; met-hGH, +3.1, +2.0, +1.4 SD). After 3 years of treatment, predicted adult height by the method of Bayley-Pinneau increased 4.5 cm in the met-hGH group and 8.2 cm in the combination group.

Modulation of insulin-like growth factor actions in L6A1 myoblasts by insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5: A dual role for IGFBP-5

We have previously shown that the insulin‐like growth factors (IGFs) stimulate both proliferation and differentiation of skeletal muscle cells in culture, and that these actions in L6A1 muscle cells may be modulated by three secreted IGF binding proteins (IGFBPs), IGFBP‐4, ‐5, and ‐6. Since we found that the temporal expression pattern of IGFBP‐4 and IGFBP‐5 differed dramatically during the transition from proliferating myoblasts to differentiated myotubes, we undertook the current study to examine the effects of purified IGFBP‐4 and IGFBP‐5 on IGF‐ stimulated actions in L6A1 muscle cells. As has been shown for other cell types, we found that IGFBP‐4 had only inhibitory actions, inhibiting IGF‐I and IGF‐II‐ stimulated proliferation and differentiation. In contrast, IGFBP‐5 exhibited both inhibitory and stimulatory actions. When added in the presence of 30 ng/ml IGF‐I, IGFBP‐5 (250 ng/ml) inhibited all markers of the early proliferative response: the tyrosine phosphorylation of the cytoplasmic signaling molecules IRS‐1 and Shc, the activation of the MAP kinases, ERK1 and 2, the elevation of c‐fos mRNA, the early inhibition of the elevation in myogenin mRNA, and the increase in cell number. In contrast, IGFBP‐5 stimulated all aspects of the myogenic response to IGF‐I: the later rise in myogenin mRNA, the elevation of creatine kinase activity, and the fusion of myoblasts into myotubes. This dual response to IGFBP‐5 was greatest when it was added at a molar ratio of IGFBP‐5 to IGF‐I of 2:1. In contrast, when IGFBP‐5 was added in the presence of IGF‐II, it inhibited both proliferation and differentiation. Neither IGFBP had any effect when added in the presence of R3 IGF‐I, an analog with substantially reduced affinity for IGFBPs. Our results suggest that the role of IGFBP‐4 is mainly to sequester excess IGFs, and thus inhibit all actions. IGFBP‐5, however, is capable of eliciting a dual response, possibly due to its unique ability to associate with the cell membrane. J. Cell. Physiol. 177:47–57, 1998.

Growth response of children with non-growth-hormone deficiency and marked short stature during three years of growth hormone therapy

Short-term administration of human growth hormone to children with idiopathic short stature can improve mean growth rate and predicted adult height. It is yet unknown whether therapy would alter pubertal development or affect final height. Three-year treatment results in a group of children with idiopathic short stature are reported. For year 1 of the study, 121 prepubertal children were randomly selected to receive somatotropin, 0.3 mg/kg per week, administered subcutaneously three times weekly (n = 63), or to be nontreatment control subjects (n = 58). After 1 year, all subjects were again randomly selected to receive either three-times-weekly or daily dosing at the same total dose. For the 92 subjects who completed 36 months of treatment, mean growth rate increased from a mean of 4.6 cm/yr before treatment to a mean of 8.0 cm/yr in the first year of treatment. Daily dosing resulted in a significantly faster mean growth rate (9.0 cm/yr) than three-times-weekly dosing (7.8 cm/yr) (p = 0.0005). Mean growth rates were 7.6 and 7.2 cm/yr during years 2 and 3, respectively, and did not differ by dosing group. Mean standardized height for all subjects improved from -2.7 to -1.6 after 3 years. When the growth rate was standardized for bone age, however, subjects who remained prepubertal had a significantly greater gain in mean height SD score than subjects who became pubertal during that 3-year period (p < 0.02). Mean standardized Bayley-Pinneau predicted adult height SD score increased from -2.7 to -1.6 and was independent of the timing of pubertal onset, but for individuals this score was more variable. Year-1 growth response, expressed as growth rate or change in height SD score, was the best predictor of growth in subsequent years. Responses to therapy could not be reliably predicted from baseline anthropometric variables, plasma insulin-like growth factor I SD score, growth hormone levels. Final height assessment will be needed to determine the ultimate benefit of therapy.

Paracrine overexpression of IGFBP-4 in osteoblasts of transgenic mice decreases bone turnover and causes global growth retardation.

Insulin‐like growth factor binding protein 4 (IGFBP‐4) is abundantly expressed in bone and is generally believed to function as an inhibitor of IGF action. To investigate the function of locally produced IGFBP‐4 in bone in vivo, we targeted expression of IGFBP‐4 to osteoblasts using a human osteocalcin promoter to direct transgene expression. IGFBP‐4 protein levels in calvaria of transgenic (OC‐BP4) mice as measured by Western ligand blot were increased 25‐fold over the endogenous level. Interestingly, levels of IGFBP‐5 were decreased in the OC‐BP4 mice, possibly because of a compensatory alteration in IGF‐1 action. Morphometric measurements showed a decrease in femoral length and total bone volume in transgenic animals compared with the controls. Quantitative histomorphometry at the distal femur disclosed a striking reduction in bone turnover in the OC‐BP4 mice. Osteoblast number/bone length and bone formation rate/bone surface in OC‐BP4 mice were approximately one‐half that seen in control mice. At birth, OC‐BP4 mice were of normal size and weight but exhibited striking postnatal growth retardation. Organ allometry (mg/g body weight) analysis revealed that, whereas most organs exhibited a proportional reduction in weight, calvarial and femoral wet weights were disproportionally small (∼70% and 80% of control, respectively). In conclusion, paracrine overexpression of IGFBP‐4 in the bone microenvironment markedly reduced cancellous bone formation and turnover and severely impaired overall postnatal skeletal and somatic growth. We attribute these effects to the sequestration of IGF‐1 by IGFBP‐4 and consequent impairment of IGF‐1 action in skeletal tissue.

Methionyl human growth hormone and oxandrolone in Turner syndrome: Preliminary results of a prospective randomized trial

Seventy girls with Turner syndrome, 4 to 12 years of age, were randomly assigned to receive either no treatment (control) or methionyl human growth hormone (0.125 mg/kg three times per week), oxandrolone (0.125 mg/kg/day), or combination hGH plus oxandrolone therapy. Baseline growth rates averaged 4.3 cm/yr, and all were within 2 SD of mean growth velocity for age in girls with Turner syndrome. Sixty-seven girls remained in the study for a minimum of 1 year. Growth rates and growth velocity (in standard deviations for age in girls with Turner syndrome) were control 3.8 cm/yr (-0.1 SD), hGH 6.6 cm/yr (+2.3 SD), oxandrolone 7.9 cm/yr (+3.7 SD), and combination therapy 9.8 cm/yr (+5.4 SD). Mean bone ages advanced 1.0 years (hGH), 1.3 years (oxandrolone), and 1.6 years (combination). However, median increments in height age/bone age (delta HA/delta BA) ratios ranged from 1.0 to 1.1 for treatment groups, compared with 0.8 for the controls. Predicted adult height by the method of Bayley-Pinneau increased 2.5 cm for hGH or oxandrolone alone, and 3.2 cm for combination treatment. These data indicate that both hGH and oxandrolone can significantly stimulate short-term skeletal growth in patients with Turner syndrome, and potentially increase final adult height.

Resistance to the growth-promoting and metabolic effects of growth hormone in children with chronic liver disease

Because growth failure is a frequent complication of chronic liver disease in childhood, we examined the growth hormone/insulin-like growth factor type I axis and its relationship to growth disturbances, nutritional status, and carbohydrate metabolism in nine children (2.1 to 18.6 years of age) with chronic cholestatic liver disease. Seven had cholestasis associated with splenomegaly and histologic findings of cirrhosis; two patients had Alagille syndrome. Stature was less than or equal to 15th percentile in all except the youngest subject and less than 5th percentile in five subjects. Ten-hour, nocturnal, integrated serum concentrations of growth hormone were considerably higher in patients with cholestasis than in control subjects (mean +/- SD) 9.7 +/- 3.8 vs 4.7 +/- 1.9 ng/ml; p less than 0.02). Serum concentrations of insulin-like growth hormone type I were less than 95th percentile confidence intervals for age- and sex-matched norms in five patients and at the lower limits of normal in the remaining four patients. Insulin sensitivity, determined with the minimal model intravenous glucose tolerance test, was not decreased in five patients despite elevated levels of circulating growth hormone. The estimated mean caloric and protein intake exceeded the recommended dietary allowance and the weight-for-height index was greater than 90% for six of nine patients. Triceps and subscapular skin-fold thicknesses, indicators of body fat stores, were greater than 25th percentile for five of nine and eight of nine patients, respectively, suggesting deficient lipolytic action of GH. We conclude that children with cholestatic liver disease have a resistance to the growth-promoting, diabetogenic, and lipolytic properties of growth hormone.

Linear growth in response to growth hormone treatment in children with short stature associated with intrauterine growth retardation: the National Cooperative Growth Study experience.

Short stature commonly follows intrauterine growth retardation (IUGR). Most patients are not growth hormone (GH)-deficient, but GH therapy has been used in IUGR. Early studies found a heterogeneous increase in initial growth rate that could not be maintained. Results of more recent studies with higher doses are more encouraging but do not establish whether final height is increased. Data from a large number of patients in the National Cooperative Growth Study were reviewed to evaluate the response to GH treatment in patients with IUGR-associated short stature. Two hundred seventy such patients were identified and were categorized as those with unclassified IUGR and those with Russell-Silver syndrome/primordial short stature (RSS/PSS). Patients were treated with standard doses of recombinant human GH (approximately 0.3 mg/kg per week) and were assessed periodically for up to 4 years. The height SD score at baseline in patients with unclassified IUGR was -3.49 +/- 1.16, and their relative height improved with each year of therapy. Patients who completed 4 years of treatment reached a height SD score of -1.32 +/- 0.79. Results were similar in patients with RSS/PSS; their baseline height SD score was -3.83 +/- 1.05 and improved to -2.10 +/- 0.99 by year 4. Despite these encouraging results, no change occurred in predicted adult heights. Furthermore the number of patients who remained in treatment for 4 years decreased substantially, thus limiting the interpretation of the data. These data suggest that a beneficial response to GH occurs in some patients with IUGR-associated short stature and that little difference exists in the responses in patients with RSS/PSS compared with those in patients with unclassified IUGR.

Effect of insulinlike growth factor-1 treatment in children with cystic fibrosis.

Objectives Malnutrition is common in cystic fibrosis (CF) and adversely affects survival. Because insulinlike growth factor-1 (IGF-1) has insulinlike effects in terms of carbohydrate metabolism and is growth promoting, the authors hypothesized that its use would increase linear growth rate and decrease insulin requirements in children with CF. Methods The authors used a double-blind placebo-controlled crossover design. Seven prepubertal children aged 9.6 to 13 years (5 boys and 2 girls) were treated with placebo or IGF-1 for 6 months. After a 6-month washout period, patients received the alternative therapy for 6 months. The primary outcome measure was linear growth rate. Secondary outcome measures were changes in body mass index, body composition determined by dual energy x-ray absorptiometry, forced expiratory volume (FEV 1 ), and the blood glucose/insulin ratio. Results The mean height z score at baseline was −1.5 ± 0.8. At entry, the mean serum IGF-1 level was 124 ± 25 ng/mL (normal range, 110–771 ng/mL). With treatment, mean serum IGF-1 levels increased twofold to threefold for all patients. The half-life for IGF-1 was 10.3 hours. We observed no significant difference in linear growth rate, weight gain, rate of accretion of lean body mass, or mean FEV 1 during treatment with IGF-1 compared with placebo. The glucose/insulin ratio, an indirect index of insulin sensitivity, was significantly increased with IGF-1 treatment compared with placebo (P < 0.02). No adverse events related to IGF-1 were detected. Conclusions Treatment with IGF-1 for 6 months did not promote linear growth in prepubertal children with CF. However, the glucose/insulin ratio was increased without changing blood glucose levels with IGF-1 treatment suggesting increased insulin sensitivity.

Growth hormone insensitivity in children with biliary atresia

Malnutrition is a critical predictor of mortality and morbidity in children with biliary atresia who undergo orthotopic liver transplantation. Growth hormone (GH) enhances nitrogen retention in patients with chronic obstructive lung disease, sepsis, and in fasted adult volunteers. The goal of this study was to assess the acute response to recombinant human GH (rhGH) treatment in children with biliary atresia to determine whether GH therapy was likely to improve pretransplant nutritional status. Five children, aged 10-32 months, with biliary atresia and persistent cholestasis despite surgical attempts to reestablish bile flow, were studied. All five children had portal hypertension, conjugated hyperbilirubinemia, and decreased serum albumin concentrations. Length, weight, and growth velocity were decreased in all five children. Despite adequate energy and protein intake, fat stores were depleted in all five subjects, and somatic protein stores were diminished in all except one child. Baseline serum concentrations of insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) were low (8.4 +/- 2 ng/ml and 0.2 +/- 0.1 mg/l respectively). In the four children who completed the study, serum IGF-I and IGFBP-3 levels did not change after treatment with rhGH (0.1 mg/kg/day) for 4 days. Our findings indicate that children with biliary atresia awaiting liver transplantation are insensitive to GH and that treatment with GH is unlikely to promote anabolism. A rationale exists for examining the effect of treatment with IGF-I, which mediates the anabolic effects of GH.