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Objective: To carry out a multicenter, prospective, randomized trial of human growth hormone (GH), alone or in combination with oxandrolone (OX), in patients with Turner's syndrome (TS)., Methods: In an initial phase lasting 12 to 24 months, 70 girls with TS, verified by karyotype, were randomly assigned to one of four groups: (1) observation, (2) OX, (3) GH, or (4) GH plus OX. After completion of the first phase, group 3 subjects continued to receive GH only. All other subjects were treated with GH plus OX. Subjects were followed up until attainment of adult height and/or cessation of treatment. Data from this trial were compared with growth characteristics of 25 American historical subjects with TS (matched for age, height, parental target height, and karyotype) who never received either GH or androgens., Results: Of the 70 subjects enrolled, 60 completed the clinical trial. The 17 subjects receiving GH alone all completed the trial and reached a height of 150.4+/-5.5 cm (mean +/- SD), 8.4+/-4.5 cm taller than their mean projected adult height at enrollment (95% confidence interval [CI]: 6.3 to 10.6 cm). The 43 subjects receiving GH plus OX attained a mean height of 152.1+/-5.9 cm, 10.3+/-4.7 cm taller than their mean projected adult height (95% CI: 8.9 to 11.7 cm). The historical control subjects had a mean adult height of 144.2+/-6.0 cm, precisely matching their original projected adult height of 144.2+/-6.1 cm., Conclusions: GH, either alone or in combination with OX, is capable of stimulating short-term growth and augmenting adult height in girls with TS. With early diagnosis and initiation of treatment, an adult height of more than 150 cm is a reasonable goal for most girls with TS.

Mutations in the GHR locus may play a role in the cause of idiopathic short stature (ISS) by impairing growth-hormone (GH) receptor (GHR) function. At one extreme, mutations that nullify the function of the GH receptor are linked to complete GH insensitivity syndrome, or Laron syndrome, and we hypothesized that less-disruptive mutations could contribute to partial GH insensitivity syndrome. Low levels of GH binding protein may indicate mutations in the extracellular domain of the receptor, and by focusing on 14 children with ISS who had low GH binding protein and insulin-like growth factor I levels, we found three heterozygotes and one compound heterozygote for mutations in the extracellular domain of the receptor. We have since extended our study to a broader spectrum of patients, adding 76 patients with ISS who were treated with GH in a phase II study of the safety and efficacy of recombinant human GH in ISS and also adding 10 patients who were ascertained as having ISS by pediatric endocrinologists in private practice. The GHR gene has thus been analyzed in 100 patients with ISS, eight of whom were found to carry mutations: four in our original study and four with normal or elevated levels of GH binding protein. The latter group consists of three carriers of heterozygous extracellular domain mutations and one carrier of a heterozygous intracellular domain mutation. Family data suggest that the carriers of these mutations have a range of phenotypes, supporting our hypothesis that the expression of these heterozygous mutations as partial GH insensitivity syndrome depends on the genetic makeup of the person.

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.

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.

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.

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.

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.

To define further the alterations in growth hormone (GH) secretion that occur in childhood hypothyroidism, we quantified spontaneous nocturnal secretion in seven patients with primary hypothyroidism. We examined the relationship between plasma insulin-like growth factor I (IGF-I) and GH secretory profile in each patient before and during therapy with L-thyroxine. In contrast to the results of previous studies that used pharmacologic tests of GH release, spontaneous GH secretion was consistently attenuated in the hypothyroid state. Mean nocturnal GH levels were reduced by 58% (1.48 +/- 0.38 ng/ml, mean +/- SEM) in comparison with values obtained during L-thyroxine therapy (3.54 +/- 0.71 ng/ml, p less than 0.01). Coincident with the reduced levels of GH, plasma IGF-I concentrations were lower in patients before therapy (0.46 +/- 0.20 U/ml) compared with concentrations during therapy (1.50 +/- 0.34 U/ml, p less than 0.01). In treated, euthyroid patients, GH and IGF-I levels were equivalent to those of normal children. The excellent correlation (r = 0.77) between plasma IGF-I and mean nocturnal GH concentrations indicates that reduced plasma IGF-I levels in hypothyroidism probably result from suppressed GH secretion.

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.