Utility of the National Cooperative Growth Study database for safety reporting.

The National Cooperative Growth Study (NCGS) maintains the largest database in the world, collecting information on patients with growth disorders treated with growth hormone (GH). More than 24,000 children have been monitored during its first decade (1985 through 1995). The database provides unique opportunities to learn about effectiveness of GH therapy in a real-world context. Its size also makes it possible to investigate rare adverse reactions, which is not reasonable in a randomized controlled trial (RCT). The frequency of adverse experiences reported in an observational study like the NCGS is lower than in an RCT, because the investigators in an observational study typically do not report events that they believe are clearly unrelated to the study drug. Nevertheless the NCGS has greatly facilitated collecting adverse-event data; approximately 75% of all adverse-event reports for GH received by the manufacturer are through NCGS data-collection forms. The NCGS has thus amassed a repository of GH safety data that is unparalleled. Furthermore, in contrast to an RCT, the NCGS database reflects real-world experience with long-term GH therapy in North America. Although the advantages of an observational study such as the NCGS must be recognized, such a study does differ from an RCT in important ways. For example, because the NCGS protocol allows customized patient treatment and individualization of GH therapy, it may be difficult to use the database to address questions (e. g., estimation of dose-response relationships, true incidence of adverse events) that require RCT designs.

Heterologous humoral immune response in patients treated with human growth hormone from different sources.

The existence of homologous anti-human growth hormone (anti-hGH) and heterologous anti-bovine growth hormone (anti-bGH) humoral immune responses in hypopituitary patients under hGH therapy has been reported previously. In order to study the influence of the hormone source, both responses were compared by radiobinding assays performed with [125I]hGH or [125I]bGH as tracers. Fifty-seven hypopituitary patients treated with extractive hGH, recombinant methionyl hGH or authentic recombinant hGH were studied. A very low incidence of heterologous antibodies was found in patients under recombinant hGH therapy, contrary to the high incidence observed in patients treated with extractive hGH preparations. In addition, immunochemical studies performed with a synthetic peptide (hGH 44-128) indicated that this peptide exhibited, in the anti-bGH/[125]bGH radioimmunoassay system, higher reactivity than the native hGH, suggesting that such a fragment resembled an altered conformation of the hormone. The high heterologous response elicited only by the extractive hGH along with the behaviour of the hGH 44-128 fragment supports the fact that the extraction and purification procedures in extractive preparations may alter slightly the structure of the hGH molecule and trigger a heterologous immune response.

Effects of nightly clonidine administration on growth velocity in short children without growth hormone deficiency: a double-blind, placebo-controlled study.

Children with short stature, slowed linear growth velocity, and delayed skeletal maturation may secrete growth hormone (GH) normally in response to provocative stimuli but may also have spontaneous undersecretion of GH. Orally administered clonidine, an alpha 2-adrenergic agonist, is a potent acute stimulator of growth hormone releasing hormone-mediated pituitary GH release. We performed a double-blind, placebo-controlled crossover study of nightly oral clonidine therapy (0.1 mg/m2) in 10 short, slowly growing, non-GH-deficient (stimulated GH level > 15 micrograms/L) prepubertal boys (range, 6.1 to 12.2 years; mean height standard deviation score, -2.3 +/- 0.4). Results of 6 months of clonidine therapy were compared with the results of 6 months of placebo therapy; GH responsiveness was subsequently assessed in 7 of 10 patients. Growth velocity (4.9 +/- 0.6 cm/yr baseline) was not improved by clonidine (4.6 +/- 1.2 cm/yr) or placebo (5.2 +/- 1.2 cm/yr), but it increased (p < 0.001) with GH therapy (8.2 +/- 1.3 cm/yr). Clonidine therapy similarly did not significantly affect plasma levels of insulin-like growth factor I or bone age maturation. Diminution in clonidine-stimulated peak GH levels was not observed after long-term oral clonidine therapy. Thus, in contrast to previous non-placebo-controlled studies, nightly clonidine therapy did not increase growth velocity or plasma insulin-like growth factor I levels. Subsequent acceleration in growth velocity during GH therapy suggests that a proposed increase in clonidine-induced endogenous GH secretion does not result in an effective growth-promoting stimulus.

Clinical response of alopecia, trichorrhexis nodosa, and dry, scaly skin to zinc supplementation.

Two unrelated patients had dry brittle hair, alopecia, trichorrhexis nodosa, dry scaly skin, pigment dyschromia, short stature, and neurosecretory growth hormone deficiency. By means of the zinc tolerance test, patient 1 was shown to have zinc deficiency, whereas no clear zinc deficiency could be demonstrated in patient 2. In both patients, hair and the skin abnormalities responded to oral zinc therapy.

Effect of growth hormone treatment on serum creatinine concentration in patients with cystinosis and chronic renal disease.

Three patients with nephropathic cystinosis and chronic renal disease, treated since early childhood with orally administered cysteamine, had an accelerated rate of rise of serum creatinine values after receiving recombinant human growth hormone. During 18 to 24 months of growth hormone treatment, each patient had a twofold to fourfold increase in growth velocity. The slope of the plot of reciprocal serum creatinine values versus age for each patient after growth hormone treatment was significantly steeper than the pretreatment slope. Growth hormone treatment had no effect on the rate of change of the uncorrected 24-hour renal creatinine clearance. We conclude that these patients gained body size but failed to compensate for their increased creatinine production with an increase in glomerular filtration rate. The result was an accelerated rate of rise of their serum creatinine values, hastening renal transplantation in one patient and the anticipated need for transplantation in another.

Long-term treatment with growth hormone of children with short stature and normal growth hormone secretion.

Children with short stature but normal growth rate and/or normal growth hormone response to sleep and secretagogues were treated with recombinant methionyl human growth hormone, 0.3 mg/kg per week. In each year of treatment, about 80% of the subjects maintained an increase in growth rate greater than the defined limit (greater than 1 cm/yr above pretreatment growth rate) for continuation of human growth hormone treatment. Comparison of the group that continued to respond to human growth hormone with the group that did not maintain an accelerated growth rate did not reveal differences in bone age delay, sleep or secretagogue-stimulated human growth hormone secretion, degree of short stature either absolute or relative to target height, and somatomedin C concentration before or after initiation of therapy. The group that failed to respond to the human growth hormone treatment in the first year of treatment was younger and had a higher pretreatment growth rate. Review of the longitudinal growth curves revealed five patterns of response to human growth hormone treatment: (1) failure to increase growth rate in two subjects with height SD scores within 1 SD of target height, (2) failure to increase growth rate in five subjects with height SD scores greater than 1 SD less than the target height, (3) acceleration in growth rate in three subjects that was not maintained until achievement of a height within 1 SD of the target height, (4) acceleration of growth rate in five subjects that was maintained until achievement of a height within 1 SD of the target height, and (5) acceleration in growth rate that was maintained during the 3 years of treatment in 15 subjects who had not attained a height within 1 SD of the target height. We conclude that human growth hormone treatment of some but not all short children with "normal" growth hormone secretion will result in sustained acceleration of growth rate and attainment of prepubertal heights that are closer to but do not exceed their genetic height potential. A clinical trial of human growth hormone may be necessary to determine which subjects will benefit from the treatment.

[The null effect of Somatrem during typhoid fever]. / Efecto nulo de Somatrem durante fiebre tifoidea.

The simultaneous occurrence of typhoid fever in a child with an idiopathic growth hormone insufficiency treated with Somatrem, produced a lack of response to the recombinant hormone, evidenced by a lack of growth during the acute disease. It is concluded that the administration of Somatrem should be suspended during the simultaneous occurrence of any severe illness.

[Clinical and biochemical evaluation of the administration of growth hormone]. / Evaluación clínica y bioquímica de la administración de hormona de crecimiento.

Ten children with isolated growth hormone deficiency were treated for 1 year with 0.5 UI/kg week with Somatrem (recombinant human growth hormone), given as intramuscular injections three times weekly. Before treatment the children had a chronological age of 7-12.4 years (mean 10.4 years), with a bone age at least 25% below the chronological age. There was no radiological evidence of an intra or suprasellar mass in any child, and no response to provocative growth hormone tests (with exercise or arginine-insulin injection). Informed written consent for treatment was obtained from the parents of each child. Clinical signs were registered every month; triiodothyronine, thyroxine, thyrotropine, glucose, urea, creatinine, blood cells count, and hemoglobine, glycosylated hemoglobine, glutamic-piruvic and glutamic-oxalacetic transaminases, alkaline phosphatase, anti-human growth hormone and, E. coli antibodies, insulin like growth factor 1, and bone age were assessed every 3 months. The mean height velocity was 0.27 +/- 0.1 cm/month before treatment, and increased throughout treatment to a value of 0.62 +/- 0.16 cm/month after 12 months. Within the first year eight of the 10 children had a height increase of 8.4 +/- 0.98 cm. The other two children showed no significant difference; one of them with a very low socioeconomic status, and the other developed typhoid fever. All of the children showed an advance in bone age, but none reached a bone age appropriate for their chronological age; without modifications in the laboratory parameters. Insulin like growth factor 1 increased in 9 children. Pain at the injection site was the only side effect reported.

[Results of the treatment of growth hormone deficiency with methionine-somatotropin or recombinant somatotropin]. / Resultados del tratamiento de la deficiencia de hormona de crecimiento con metionina-somatotropina o con somatotropina-recombinante.

Sixteen children with hGH deficiency were treated for a year with methionyl-somatotropin (Somatonorm) or recombinant-somatotropin (Genotropin). The hormone was administrated subcutaneously 3 time/week, 0.45-0.6 IU/kg/week. After a year of treatment, the mean growth rate in those who received Somatonorm increased from 3.96 +/- 0.8 cm/yr to 9.08 +/- 2.7 cm/yr, and in those who received Genotropin from 3.6 +/- 0.6 cm/yr to 8.58 +/- 1.1 cm/yr with no significant difference. No adverse effects were observed, but four children that received Somatonorm developed antihGH antibodies with a very low binding capacity, of less than 0.1 mg/L. All the children that received Genotropin were negative for antihGH antibodies.

Growth hormone treatment in the United States: demographic and diagnostic features of 2331 children.

Demographic, diagnostic, and baseline clinical data were collected for a large cohort (N = 2331) of children who started treatment with biosynthetic human growth hormone (GH) between October 1985 and October 1987. Eighty-one percent met classic criteria for GH deficiency and were classified as having idiopathic GH deficiency (59%), organic GH deficiency (18%), or septo-optic dysplasia (4%). The remaining 19.8% had short stature of varied causes. Height standard deviation score at diagnosis, maximum GH response to stimulation, and heights of parents were examined according to gender, race, age at diagnosis, and previous treatment history. The predominance of boys in all subgroups except septooptic dysplasia, and the observation that girls with idiopathic GH deficiency were comparatively shorter than boys at diagnosis, suggest ascertainment bias. Black children with idiopathic GH deficiency were shorter than white children at diagnosis, and their low overall representation (6.0%) compared with their percentage in the at-risk population (12.9%) also suggest ascertainment bias among races. These data provide a profile of GH deficiency as it is currently defined and expose possible inherent biases in the diagnostic process. Now that GH supply is no longer limited, criteria for its use should be formulated to avoid apparent underascertainment or late diagnosis of GH deficiency in girls and black children.

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.

Ovine prolactin and human growth hormone derivatives. Specific modification of their alpha-amino groups.

The alpha-amino group of ovine prolactin (oPRL) and human growth hormone (hGH) was selectively modified by transamination with glyoxylic acid. No difference was found in the binding capacity of transaminated oPRL to rat liver lactogenic receptors with respect to its control, although both samples showed a decrease in its binding capacity with reference to the native hormone. This decrease was due to conformational changes caused by the reaction conditions and not by the transamination itself, as shown by the circular dichroism spectra. Transaminated hGH retained the full binding capacity of the hormone. These results suggest that the alpha-amino group is not relevant for the binding to lactogenic liver receptors in both lactogenic hormones.

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.