Acceleration of growth in Turner syndrome patients treated with growth hormone: summary of three-year results. Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height. Psychological aspects of the Canadian randomized controlled trial of human growth hormone and low-dose ethinyl oestradiol in children with Turner syndrome. The Canadian Growth Hormone Advisory Group. The growth and cardiovascular effects of high dose growth hormone therapy in idiopathic short stature. Low-dose recombinant human growth hormone increases body weight and lean body mass in patients with short bowel syndrome. High dose growth hormone treatment induces acceleration of skeletal maturation and an earlier onset of puberty in children with idiopathic short stature. Randomised trial of growth hormone in short normal girls. Prospective randomised treatment with recombinant human growth hormone in cystic fibrosis. Recombinant human growth hormone treatment, using two dose regimens in children with chronic renal failure--a report on linear growth and adverse effects.
In 1983, a multicenter, collaborative, prospective study was begun to investigate the efficacy of human growth hormone (hGH), alone and in combination with oxandrolone, in girls with Turner syndrome. While subjects in the control group grew 3.8 cm/yr (-0.1 SD for untreated Turner patients), subjects receiving hGH alone grew 6.6, 5.4 and 4.6 cm/yr in years 1-3, respectively (+3.1, +2.0, +1.4 SD). Subjects in the combination therapy group grew 9.8, 7.4 and 6.1 cm/yr (+6.6, +4.3, +3.0 SD). Turner subjects in both treatment groups showed increased in Bayley-Pinneau predicted adult heights and in Turner projected adult heights. A cardinal clinical feature of Turner syndrome (TS) is linear growth failure resulting in extreme short stature: the median adult height of untreated women with TS is 143 cm, 20 cm (8 in.) below that of the general female population. In the largest multicenter, randomized, long-term, dose-response study conducted in the United States, 232 subjects with TS received either 0.27 or 0.36 mg/kg.wk of recombinant human GH with either low dose ethinyl E2 or oral placebo. The study was placebo-controlled for both GH and estrogen for the first 18 months and remained placebo-controlled for estrogen for its duration. The near-final height of the 99 subjects whose bone age was at least 14 yr was 148.7 +/- 6.1 cm after 5.5 +/- 1.8 yr of GH started at a mean age of 10.9 +/- 2.3 yr; this represents an average increase of 1.3 +/- 0.6 SD scores from baseline (TS standard). Height was greater than 152.4 cm (60 in.) in 29% of subjects compared with the expected 5% of untreated patients. Mean near-final heights of subjects who received the lower GH dose, with or without estrogen, were 145.1 +/- 5.4 and 149.9 +/- 6.0 cm, respectively; those who received the higher GH dose with or without estrogen achieved mean near-final heights of 149.1 +/- 6.0 and 150.4 +/- 6.0 cm, respectively. Factors that most impacted outcome were younger age, lower bone age/chronological age ratio, lower body weight, and greater height SD score at study entry. This study demonstrates significant GH-induced improvement in height SD score, with correction of height to within the normal channels for a significant number of patients, and provides evidence of a GH dose-response effect. These data also indicate that early administration of estrogen, even at relatively low doses, does not improve gain in near-final height in patients with TS. Preliminary results are presented after 2 years of the Canadian long-term multicentre study on the impact of hormone therapy on the final height, sexual development and psychological status of girls with Turner syndrome. Girls entering the study were randomized either to be treated with recombinant human growth hormone or to act as controls. Both groups received oestrogen replacement therapy in the same dose and format at the age of 13 years. However, for the purposes of the psychological study at this time, children receiving oestrogen were excluded from analysis. Girls treated with GH for a period of 2 years showed a significant increase in growth rate, which declined with continued treatment, while the growth rate in the control group remained constant throughout. There was a correlation between the higher growth rate and the girls' perceptions of themselves as more intelligent, more attractive, having more friends, greater popularity and experiencing less teasing than the untreated group. Growth rate was not correlated with family or school functioning. It is possible that high dose GH treatment may have beneficial effects on growth but important adverse effects on cardiac function. We have therefore investigated the efficacy and cardiovascular effects of high dose biosynthetic human GH (r-hGH) treatment in children with idiopathic short stature and a normal pretreatment height velocity.
                Randomized controlled study.
                Twenty-nine short (height SDS < 1.5), normally growing (height velocity SDS > -1.5), prepubertal children referred to two specialist growth clinics.
                Children were randomly assigned to an observation group or to receive 'standard' (20 IU/m2/week) or 'high' (40 IU/m2/week) dose r-hGH by daily subcutaneous injection. At the end of 1 year the observation group were randomly assigned to 'standard' or 'high' dose r-hGH therapy for the second year of the study. Regular growth, biochemical and echocardiographic monitoring were performed throughout the study period.
                Changes in height velocity, HtSDS for bone age (HtSDSBA), left ventricular mass index (LVMI) and left ventricular function (fractional shortening) during 2 years treatment.
                Twenty-seven children completed the study. Ht velocity SDS increased with r-hGH therapy in a dose dependent fashion. First-year height velocity SDS was +5.7 in the high dose r-hGH group compared with +2.7 in the standard dose r-hGH group and -0.5 in the observation group (P < 0.001). In those children treated for 2 years HtSDSBA was -0.5 in the high dose group but had not changed significantly in the standard dose group (-1.7) (P = 0.01). After one year r-hGH treatment LVMI was 71 g/m2 (observation group), 73 g/m2 (20 IU/m2/week group) and 74 g/m2 (40 IU/m2/week group) (P = 0.77). LVMI increased significantly from baseline to 76 g/m2 after 2 years therapy with 40 IU/m2/week r-hGH (P = 0.04) but nevertheless remained within the normal range. Fractional shortening did not change significantly over 2 years of r-hGH therapy.
                High dose (40 IU/m2/week) r-hGH treatment of children with idiopathic short stature resulted in a greater short-term acceleration in growth rate than 'standard' dose therapy without an excessive advance in skeletal maturity and probably represents the optimal growth promoting dose for short, normally growing children. Whether continued high dose r-hGH therapy increases final height requires further study. Left ventricular morphology and function remained within the normal range during r-hGH therapy but regular monitoring of cardiovascular status should continue in non-GHD children receiving r-hGH in high doses over a longer time period. The authors investigate the effects of low dose recombinant human growth hormone (rhGH) on body composition and absorptive capacity in patients with short bowel syndrome from Crohn's disease.
                Patients with short bowel syndrome usually are malnourished because of malabsorption. The anabolic effects of high doses of rhGH have been tested in different clinical catabolic conditions, recently including patients with short bowel syndrome. The authors have investigated the effects of low-dose rhGH in short bowel syndrome in a placebo-controlled crossover clinical trial.
                Ten patients were treated with daily subcutaneous doses of rhGH/placebo (0.5 international units/kg-1 per week-1 = 0.024 mg/kg-1 per day-1) for 8 weeks in a randomized, double-blind, placebo-controlled crossover clinical trial with a minimum of 12 weeks wash-out. Absorptive capacity and biochemical parameters were investigated in a metabolic ward before treatment and during first and last week of treatment. Body composition was determined by DEXA-Scan (Lunar DPX, Scanexport Medical, Helsingborg, Sweden), impedance analysis, and whole body potassium counting.
                Low-dose rhGH doubled serum levels of insulin-like growth factor-1 (IGF-1) and increased body weight, lean body mass, and total body potassium by 5% (p < 0.05). Fat-free mass and total body water increased by 6% (p = 0.008). Increases in IGF-1 levels correlated with increases in fat-free mass (r = 0.77, p < 0.02). No significant changes in absorptive capacity of water, energy, or protein were detected.
                Eight weeks of low-dose rhGH treatment leads to increases in body weight, lean body mass, and fat-free mass in patients with short bowel syndrome, correlated to increases in IGF-1 levels. Long term growth hormone (GH) treatment in children with idiopathic short stature (ISS) results in a relatively small mean gain in final height of 3-9 cm, which may not justify the cost of treatment. As it is unknown whether GH treatment during puberty adds to final height gain, we sought to improve the cost-benefit ratio, employing a study design with high dose GH treatment restricted to the prepubertal period.
                To assess the effect of short term, high dose GH treatment before puberty on growth, bone maturation, and pubertal onset.
                Five year results of a randomised controlled study are reported. Twenty six boys and nine girls were randomly assigned to a GH treatment group (n = 17) or a control group (n = 18). Inclusion criteria were: no signs of puberty, height less than -2 SDS, age 4-8 years for girls or 4-10 years for boys, GH concentration >10 micro g/l after provocation, and normal body proportions. To assess GH responsiveness, children assigned to the GH treatment group received GH treatment for two periods of three months (1.5 IU/m2/day and 3.0 IU/m2/day), separated by three month washout periods, during the first year of study. High dose GH treatment (6.0 IU/m2/day) was then started and continued for at least two full years. When puberty occurred, GH treatment was discontinued at the end of a complete year's treatment (for example, three or four years of GH treatment).
                In response to at least two years on high dose GH treatment, mean (SD) height SDS for chronological age increased significantly in GH treated children from -2.6 (0.5) to -1.3 (0.5) after two years and -1.4 (0.5) SDS after five years of study. No changes in height SDS were observed in controls. A rapid rate of bone maturation of 3.6 years/2 years in treated children compared to 2 years/2 years in controls was observed in response to two years high dose GH treatment. Height SDS for bone age was not significantly different between groups during the study period. GH treated children entered into puberty at a significantly earlier age compared to controls.
                High dose GH treatment before puberty accelerates bone age and induces an earlier onset of puberty. This may limit the potential therapeutic benefit of this regimen in ISS. There are few data on the long-term outcome of growth-hormone treatment in short normal children. We assessed the impact of growth-hormone treatment on pubertal development and near-final height in girls.
                In a randomised controlled trial, we studied ten girls, with a mean age of 8.07 years and height 2 SDs or more below the mean for their age, and eight short untreated controls matched for age, and 20 short untreated girls who did not give consent for randomisation. The girls received either 30 IU/m2 somatropin per week as daily subcutaneous injections or no treatment. We assessed pubertal staging and height gain every 6 months.
                Eight treated girls completed a mean of 6.2 years' therapy. By a mean age of 16.4 years, their mean height SD score had changed significantly from -2.42 to -1.14 (p=0.008) and they were, on average, 7.5 cm taller than the girls in the control group (height SD scores did not change significantly from -2.55) and 6.0 cm taller than the non-consent group. The timing of each pubertal stage, and the age and amplitude of peak height velocity were similar for all groups.
                Growth-hormone therapy effectively increased height SD score among short normal girls started on treatment in early to mid childhood, with no untoward effect on pubertal progression. To evaluate the efficacy and safety of treatment with recombinant growth hormone (rGH) in patients with cystic fibrosis (CF).
                Twenty patients with CF (aged 10-23 years) were randomised to age and sex matched treatment and control groups. The treatment group received daily subcutaneous injections of 1 IU/kg/wk rGH for 12 months. Pulmonary function (forced expiratory volume in one second (FEV1) and airway resistance), exercise capacity measured with a bicycle ergometer, body composition (dual energy x ray absorptiometry), and weight were assessed at the beginning of the study and after 6 and 12 months.
                rGH treatment did not improve weight and pulmonary function, but lean body mass increased significantly in the treatment group. Exercise capacity increased in the treatment group from 143 (16) W (mean (SD)) to 164 (19) W after 12 months of rGH treatment.
                Treatment of CF patients with rGH for one year improved the exercise capacity significantly but not pulmonary function. The improved exercise capacity needs confirmation in a larger population before such an expensive treatment is justified. The aim of this study was to study the efficiency and the adverse effects of 2 or 4 IU/m2/day of growth hormone (GH) in the first year and 4 IU/m2/day in the second. Of 29 growth-retarded children with chronic renal failure (CRF) (aged 3.4-15.1 years), 23 completed the first year of therapy, and 16 completed the second year. Height velocity SDS (HVSDS) increased in the first year in the low-dose group with 3.0, and 3.8 in the high-dose group. In the second year, HVSDS increased by 1.3 in the low-dose group and by 2.1 in high-dose group (p < 0.05). The IGF-I/IGFBP-3 ratio rose identically during the first year (p < 0.01). The retarded bone age did not advance inappropriately. The integrated insulin levels (AUC) increased significantly after 1 year of therapy in both groups. HbA1c, levels did not change. The number of adverse events was highest in the low-dose group, in which one patient developed overt insulin dependent diabetes mellitus. In conclusion, glucose metabolism should be monitored in children with CRF during rhGH-treatment. GH therapy in our patients resulted in a significant increase in height velocity with no inappropriate bone age progression and few serious adverse effects, all without relation to the dose of rhGH. The low start dose (2 IU/m2/ day) was of no advantage compared to the high dose.
Recombinant human growth hormone (hGH) doses between 0.3 to 0.375 mg/kg/wk increase short-term growth in girls with Turner syndrome by approximately three (two) cm in the first (second) year of treatment. Treatment in one trial increased final height by approximately six cm over an untreated control group. Despite this increase, the final height of treated women was still outside the normal range. Additional trials of the effects of hGH carried out with control groups until final height is achieved would allow better informed decisions about whether the benefits of hGH treatment outweigh the requirement of treatment over several years at considerable cost.