RESUMEN
Long-term GH replacement therapy is indicated for children with growth failure due to GH deficiency (GHD). We evaluated the feasibility of administering a long-acting GH preparation [Nutropin Depot (somatropin, rDNA origin) for injectable suspension] to prepubertal children with GHD by examining pharmacokinetic and pharmacodynamic response parameters after single or multiple doses. Data were collected from three studies involving 138 children treated with Nutropin Depot 0.75 mg/kg once per month, 0.75 mg/kg twice per month, or 1.5 mg/kg once per month. Twenty-two patients underwent intensive sampling to estimate mean peak serum GH concentrations (C(max)) and time to achieve C(max) for GH and IGF-I. Thereafter, weekly serum concentrations were measured and compared with baseline. C(max) and area under the curve were approximately proportional to the dose administered. Fractional area under the curve data indicate that at least 50% of GH exposure occurs during the first 2 d after administration. Serum GH levels remained above 1 microg/liter for 11-14 d. IGF-I levels remained above baseline for 16-20 d, but increases were not proportional to dose. After multiple doses over a 6-month period, peak and trough concentrations showed no progressive accumulation of GH, IGF-I, or IGF binding protein-3. Nutropin Depot administration once or twice per month provides serum levels of GH and IGF-I expected to promote growth, without accumulation of GH, IGF-I, or IGF binding protein-3, in children with GHD.
Asunto(s)
Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/farmacocinética , Niño , Preescolar , Preparaciones de Acción Retardada , Esquema de Medicación , Femenino , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Errores Innatos del Metabolismo/sangre , Errores Innatos del Metabolismo/tratamiento farmacológicoRESUMEN
A pharmacokinetic-pharmacodynamic study of a long-acting GH [Nutropin Depot; somatropin (rDNA origin) for injectable suspension] was performed in 25 patients with adult GH deficiency. Single doses of 0.25 mg/kg and 0.5 mg/kg, based on ideal body weight, were administered sc. After either dose, serum GH concentrations rose rapidly in both sexes. In men, the lower dose maintained serum IGF-I levels within 1 SD of the mean for age and sex for 14-17 d; the higher dose raised IGF-I levels 2 SD above the mean. In most women, all of whom were receiving oral estrogen, the lower dose did not normalize IGF-I levels; the higher dose maintained IGF-I near the mean for approximately 14 d. Increases in IGF binding protein-3 and acid-labile subunit levels were observed in both sexes; however, a sex-related difference was not obvious. Fasting glucose and insulin concentrations were transiently elevated in men receiving the higher dose. Patients tolerated the injections well. We concluded that a single injection of Nutropin Depot at these doses in patients with adult GH deficiency increased serum IGF-I to within normal limits for 14-17 d. Estrogen-treated women required approximately twice the dose needed in men to produce comparable IGF-I concentrations.
Asunto(s)
Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/farmacocinética , Adulto , Anciano , Glucemia/análisis , Proteínas Portadoras/sangre , Preparaciones de Acción Retardada , Ayuno , Femenino , Glicoproteínas/sangre , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/farmacología , Humanos , Insulina/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Cinética , Masculino , Persona de Mediana Edad , Caracteres SexualesRESUMEN
Treatment of naive children with GH deficiency has relied upon long-term replacement therapy with daily injections of GH. The daily schedule may be inconvenient for patients and their caregivers, possibly promoting nonadherence with the treatment regimen or premature termination of treatment. We studied a new sustained release GH formulation, administered once or twice monthly, to determine its efficacy and safety in this population. Seventy-four prepubertal patients with documented GH deficiency were randomized to receive sustained release recombinant human GH at either 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by sc injection in a 6-month open-label study. Efficacy was determined by growth data from 69 patients completing 6 months and 56 patients completing 12 months in an extension study. Growth rates were significantly increased over baseline and were similar for the two dosage groups. The mean (+/-SD) annualized growth rate (pooled data) was 8.4 +/- 2.1 cm/yr at 6 months, and the growth rate was 7.8 +/- 1.8 at 12 months compared with 4.5 +/- 2.3 at baseline. Standardized height, bone age, and predicted adult height assessments demonstrated catch-up growth without excessive skeletal maturation. Injection site-related events (including pain, erythema, and nodules) were the most commonly reported adverse events; no serious adverse events related to treatment were reported. Laboratory studies documented no accumulation of trough GH or IGF-I levels during treatment, nor did glucose intolerance or persistent hyperinsulinism develop. Sustained release recombinant human GH is safe and effective for long-term GH replacement in children with GH deficiency. Patients achieved similar growth velocities when sustained release GH was given once or twice monthly. The enhanced convenience of this dosage form may result in greater long-term adherence to the treatment regimen.
Asunto(s)
Hormona del Crecimiento/administración & dosificación , Hormona de Crecimiento Humana/deficiencia , Anticuerpos/sangre , Niño , Preescolar , Femenino , Crecimiento/efectos de los fármacos , Hormona del Crecimiento/efectos adversos , Hormona del Crecimiento/inmunología , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , MasculinoRESUMEN
Growth hormone (GH) plays an important role in longitudinal bone growth in childhood, accrual of peak bone mass, and bone preservation in adults. GH deficiency (GHD) is associated with reduced bone turnover and decreased bone mineral density (BMD), especially in patients with childhood-onset GHD. GH replacement therapy stimulates bone remodeling and causes an initial decrease in BMD due to bone resorption and expansion of the remodeling space. This is followed by increased bone formation and a significant increase in BMD that continues with prolonged GH therapy. The effect appears to be dose-dependent. GH dose should be individualized based on factors such as age, oral estrogen therapy, and IGF-I levels. Young GH-deficient adults with low BMD measurements by dual-energy X-ray (DEXA) scan should be considered for GH replacement therapy to reduce future fracture risk.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Hormona del Crecimiento/uso terapéutico , Adulto , Animales , Remodelación Ósea , Ensayos Clínicos como Asunto , Hormona del Crecimiento/deficiencia , Hormona del Crecimiento/farmacología , HumanosRESUMEN
GH production rates markedly increase during human puberty, mostly as an amplitude-modulated phenomenon. However, GH-deficient children have been dosed on a standard per kg BW basis similar to prepubertal children. This randomized study was designed to compare the efficacy and safety of standard recombinant human GH (rhGH) therapy (group I, 0.3 mg/kg x week) vs. high dose therapy (group II, 0.7 mg/kg x week) in GH-deficient adolescents previously treated with rhGH for at least 6 months. Ninety-seven children with documented evidence of GH deficiency (peak GH in response to stimuli, <10 ng/mL), with either organic or idiopathic pathology, were recruited. Both groups were matched for sex (group I, 42 males and 7 females; group II, 41 males and 7 females), age [group I, 14.0+/-1.6 (+/-SD) yr; group II, 13.7+/-1.6], standardized height (group I, -1.4+/-1.1; group II, -1.2+/-1.1), bone age (group I, 13.1+/-1.3 yr; group II, 13.1+/-1.3) etiology, maximum stimulated GH, previous growth rate, and midparental target height. All subjects were in puberty (Tanner stage 2-5) at study entry. Of the 97 subjects enrolled, 45 were treated for 3 yr or more; 48 completed the study. Of the subjects who discontinued the study, the most common reason was satisfaction with their height, although others discontinued for adverse events or personal reasons. The frequency of patients who discontinued was the same in both groups. The primary efficacy analysis was the difference between dose groups for near-adult height, defined as the height attained at a bone age of 16 yr or more in males and 14 yr or more in girls; all subjects who qualified were included in the analysis. This difference was statistically significant at 4.6 cm by analysis of covariance (ANCOVA; P < 0.001; n = 75). For subjects who received at least 4 yr of rhGH treatment, the difference between dose groups at that time point was 5.7 cm (by ANCOVA, P = 0.024; n = 20). The mean height SD score at near-adult height was -0.7+/-0.9 in the standard dose group and 0.0+/-1.2 in the high dose group. At 36 months the cumulative change in height (centimeters) was 21.5+/-5.3 cm (group I) vs. 25.1+/-4.9 (group II; P < 0.001, by ANCOVA); the change in Bayley-Pinneau predicted adult height was 4.8+/-4.2 cm (group I) vs. 8.4+/-5.7 (group II; P = 0.032). Median plasma IGF-I concentrations at baseline were 427 microg/L (range, 204-649) in group I and 435 microg/L (range, 104-837) in group II; at 36 months they were 651 microg/L (range, 139-1079) in group I vs. 910 microg/L (range, 251-1843) in group II (P = NS). No difference in change in bone age was detected between groups at any interval. High dose rhGH was well tolerated, with a similar safety profile as standard dose treatment and no difference in hemoglobin A1c or glucose concentrations between groups. In summary, compared to conventional treatment, high dose rhGH therapy in adolescents 1) increased near-adult height and height SD scores significantly, 2) did not increase the rate of skeletal maturation, and 3) appears to be well tolerated and safe. In conclusion, high dose rhGH therapy may have a beneficial effect in adolescent GH-deficient patients, particularly those who are most growth retarded at the start of puberty.
Asunto(s)
Estatura/efectos de los fármacos , Hormona del Crecimiento/uso terapéutico , Hormona de Crecimiento Humana/deficiencia , Pubertad/efectos de los fármacos , Adolescente , Índice de Masa Corporal , Densidad Ósea , Desarrollo Óseo , Metabolismo de los Hidratos de Carbono , Niño , Femenino , Crecimiento/efectos de los fármacos , Hormona del Crecimiento/administración & dosificación , Hormona del Crecimiento/efectos adversos , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , MasculinoRESUMEN
Idiopathic short stature (ISS) refers to a heterogeneous group of children with marked growth failure of unknown cause, and encompasses familial short stature and constitutional delay of growth. It has been postulated that specific genetic mutations may explain certain cases of growth failure. Some patients with growth hormone (GH) deficiency have mutations in the GH-releasing hormone receptor or GH gene, whereas patients with GH insensitivity syndrome have mutations in the GH receptor or insulin-like growth factor-I gene. It appears that heterozygous mutations of the GH receptor may cause partial GH insensitivity in a subset of patients with ISS. Defects in the short stature homeobox-containing gene (SHOX) in the pseudoautosomal region of the sex chromosomes may cause the growth failure seen in the Leri-Weill and Turner syndromes, and in some familial cases of ISS. Further research into stature-related genes will likely contribute to our understanding of this population.
Asunto(s)
Estatura/genética , Trastornos del Crecimiento/genética , Hormona de Crecimiento Humana/genética , Estatura/fisiología , Femenino , Hormona Liberadora de Gonadotropina/metabolismo , Hormona de Crecimiento Humana/deficiencia , Humanos , Masculino , Mutación , Fenotipo , Receptores de Factores de Crecimiento/genética , Síndrome de Turner/genética , Cromosoma X/genética , Cromosoma Y/genéticaRESUMEN
Clinical trials of recombinant human GH therapy in Turner syndrome that began more than a decade ago show that GH accelerates the linear growth rate. Several studies indicate that final height is also improved, although the magnitude of the increase has been debated. The age at which feminization is induced could be an important factor in determining the patient's ultimate growth response. To test this, 60 patients from a large (n = 117), previously unreported, clinical trial of GH treatment were randomly assigned to begin conjugated estrogens at either 12 or 15 yr of age. The 60 patients were all less than 11 yr of age at entry (mean, 9.5 yr) and received 0.375 mg/kg x week of GH for nearly 6 yr on a daily or three times weekly regimen. Height gain was calculated by comparing the study patients' final or near final heights to their pretreatment projected heights as well as to those of a separate set of age-matched, historical control patients. Patients in whom estrogen treatment was delayed until age 15 yr gained an average of 8.4 +/- 4.3 cm over their projected height, whereas those starting estrogen at 12 yr gained only 5.1 +/- 3.6 cm, on the average (P < 0.01). Analysis of the interval data showed that growth was stimulated for approximately 2 yr after estrogen initiation, but then declined in association with bone age advancement. Patients who were older than 11 yr at entry (n = 57) all initiated estrogen 1 yr after beginning GH and showed a mean gain in adult height of 4.7 cm, similar to those given estrogen at age 12 yr. Multivariate analysis revealed that the number of years of GH therapy before estrogen treatment was a strong factor in predicting height gained, indicating that the timing of estrogen introduction is an important determinant of final height in this cohort of GH-treated patients with Turner syndrome matched for baseline age and other characteristics.
Asunto(s)
Envejecimiento/fisiología , Terapia de Reemplazo de Estrógeno , Hormona del Crecimiento/uso terapéutico , Síndrome de Turner/tratamiento farmacológico , Adolescente , Estatura/efectos de los fármacos , Desarrollo Óseo/efectos de los fármacos , Niño , Método Doble Ciego , Femenino , Feminización/tratamiento farmacológico , Humanos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Short-term administration of growth hormone to children with idiopathic short stature results in increases in growth rate and standard-deviation scores for height. However, the effect of long-term growth hormone therapy on adult height in these children is unknown. METHODS: We studied 121 children with idiopathic short stature, all of whom had an initial height below the third percentile, low growth rates, and maximal stimulated serum concentrations of growth hormone of at least 10 microg per liter. The children were treated with growth hormone (0.3 mg per kilogram of body weight per week) for 2 to 10 years. Eighty of these children have reached adult height, with a bone age of at least 16 years in the boys and at least 14 years in the girls, and pubertal stage 4 or 5. The difference between the predicted adult height before treatment and achieved adult height was compared with the corresponding difference in three untreated normal or short-statured control groups. RESULTS: In the 80 children who have reached adult height, growth hormone treatment increased the mean standard-deviation score for height (number of standard deviations from the mean height for chronologic age) from -2.7 to -1.4. The mean (+/-SD) difference between predicted adult height before treatment and achieved adult height was +5.0+/-5.1 cm for boys and +5.9+/-5.2 cm for girls. The difference between predicted and achieved adult height among treated boys was 9.2 cm greater than the corresponding difference among untreated boys with initial standard-deviation scores of less than -2, and the difference among treated girls was 5.7 cm greater than the difference among untreated girls. CONCLUSION: Long-term administration of growth hormone to children with idiopathic short stature can increase adult height to a level above the predicted adult height and above the adult height of untreated historical control children.
Asunto(s)
Estatura/efectos de los fármacos , Crecimiento/efectos de los fármacos , Hormona de Crecimiento Humana/uso terapéutico , Adulto , Niño , Femenino , Humanos , Modelos Lineales , Estudios Longitudinales , MasculinoRESUMEN
It is now clear that parenteral growth hormone (GH) therapy stimulates growth and increases the adult stature of girls with Turner syndrome. In addition, oestrogens are given to almost all girls with this syndrome because of primary hypogonadism. Oestrogens influence both growth and maturation of the epiphyseal growth plates. Therefore, the form and timing of oestrogen therapy may have an important impact on the outcome of other growth-promoting therapies. To examine the impact of the timing of oestrogen initiation on growth, a randomized trial was conducted in patients with Turner syndrome who were receiving GH. Some patients received oestrogen at 12 years of age, while in others this treatment was not started until 15 years of age. Those girls that received oestrogen later were significantly taller as adults. The single most important factor in determining height gain appeared to be the number of years of GH therapy prior to the initiation of oestrogen treatment.
Asunto(s)
Estatura , Congéneres del Estradiol/uso terapéutico , Síndrome de Turner/tratamiento farmacológico , Factores de Edad , Estatura/efectos de los fármacos , Huesos/efectos de los fármacos , Congéneres del Estradiol/farmacología , Femenino , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Resultado del Tratamiento , Síndrome de Turner/fisiopatologíaRESUMEN
In a multicenter study the metabolic effects of 5 yr of GH therapy in children with idiopathic short stature were evaluated. Patients received 0.3 mg/kg.week recombinant human GH. Of the 121 patients who entered the study, data for 62 were analyzed at the final 5 yr point. Routine laboratory determinations were available for all 62 subjects at the 5 yr point. Special laboratory determinations, such as postprandial glucose and insulin, were available for only a subset of patients. Mean insulin-like growth factor I levels rose to 283 +/- 101 micrograms/L, within the normal range using age-appropriate reference standards. T4, cholesterol, triglycerides, blood chemistries, and blood pressure showed no significant changes during the 5-yr period. Mean baseline and 2-h postprandial glucose levels remained unchanged. Both fasting and postprandial insulin levels rose substantively from low normal levels to the normal range (median, 4.9-43 mU/L). Mean hemoglobin A1c levels remained within the normal range throughout the study. In summary, careful monitoring has not revealed any currently discernible metabolic side-effects of clinical significance after GH therapy in this 5-yr study of children with idiopathic short stature.
Asunto(s)
Estatura , Hormona de Crecimiento Humana/uso terapéutico , Adolescente , Glucemia/metabolismo , Niño , Colesterol/sangre , Ayuno , Femenino , Alimentos , Hemoglobina Glucada/metabolismo , Hormona de Crecimiento Humana/administración & dosificación , Humanos , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Tiroxina/sangre , Triglicéridos/sangreRESUMEN
Growth failure is common during long term treatment with glucocorticoids (GC) due to blunting of GH release, insulin-like growth factor I (IGF-I) bioactivity, and collagen synthesis. These effects could theoretically be reversed with GH therapy. The National Cooperative Growth Study database (n = 22,005) was searched for children meeting the following criteria: 1) pharmacological treatment with GC and GH for more than 12 months, 2) known type and dose of GC, and 3) height measurements for more than 12 months. A total of 83 patients were identified. Monitoring of glucose, insulin, IGF-I, IGF-binding protein-3, type 1 procollagen, osteocalcin, and glycosylated hemoglobin levels was performed in a subset of patients. Stimulated endogenous GH levels were less than 10 microg/L in 51% of patients and less than 7 microg/L in 37% of patients. The mean GC dose, expressed as prednisone equivalents, was 0.5 +/- 0.6 mg/kg day. Baseline evaluation revealed extreme short stature (mean height SD score = -3.7 +/- 1.2), delayed skeletal maturation (mean delay, 3.1 yr), and slowed growth rates (mean, 3.0 +/- 2.5 cm/yr). After 12 months of GH therapy (mean dose, 0.29 mg/kg x weeks), mean growth rate increased to 6.3 +/- 2.6 cm/yr, and height SD score improved by 0.21 +/- 0.4 (P < 0.01). During the second year of GH therapy (n = 44), the mean growth rate was 6.3 +/- 2.0 cm/yr. Prednisone equivalent dose and growth response to GH therapy were negatively correlated (r = -0.264; P < 0.05). Plasma concentrations of IGF-I, IGF-binding protein-3, procollagen, osteocalcin, and glycosylated hemoglobin increased with GH therapy, whereas glucose and insulin levels did not change. The following conclusions were reached. The growth-suppressing effects of GC are counterbalanced by GH therapy; the mean response is a doubling of baseline growth rate. Responsiveness to GH is negatively correlated with GC dose. Glycosylated hemoglobin levels increased slightly, but glucose and insulin levels were not altered by GH therapy.
Asunto(s)
Glucocorticoides/efectos adversos , Trastornos del Crecimiento/inducido químicamente , Trastornos del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Adolescente , Glucemia/metabolismo , Estatura , Niño , Estudios de Cohortes , Femenino , Glucocorticoides/administración & dosificación , Hemoglobina Glucada/metabolismo , Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/efectos adversos , Humanos , Insulina/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Osteocalcina/sangre , Procolágeno/sangre , Estudios RetrospectivosRESUMEN
OBJECTIVE: To evaluate growth rate and adult height with recombinant growth hormone (GH) treatment in girls with Turner syndrome (TS) and predictors of their growth response. METHODS: Data on girls with TS who were treated with GH in the National Cooperative Growth Study (NCGS) were evaluated. As of January 1997, there were 2798 girls with TS in the NCGS database, 2652 of whom had not previously received GH. Follow-up data on growth were available for 2475 subjects, and data on adult height were available for 622. RESULTS: The average age of girls with TS at enrollment in the NCGS was 10.1 +/- 3.6 years. These patients had severely short stature compared with that of unaffected American girls (height, 118.5 +/- 16.5 cm; height standard deviation score [SDS], -3.1 +/- 0.9), but their heights were typical of those of American girls with TS (TS-specific height SDS, 0.01 +/- 0.9). Treatment with GH for an average duration of 3.2 +/- 2.0 years resulted in an increase in height SDS of 0.8 +/- 0.7 compared with unaffected girls and of 1.2 +/- 0.8 compared with TS standards. Growth rates increased from 4.0 +/- 2.3 cm/year before treatment to 7.5 +/- 2.0 cm/year after 1 year of treatment. Duration of treatment with GH was the strongest predictor of change in height SDS. After 6 to 7 years of treatment with GH, there was a cumulative change of 2.0 in mean height SDS. The 622 girls who reached adult height were older when they began taking GH. Their mean height gain over pre-GH projected height was 6.4 +/- 4.9 cm after 3.7 +/- 1.9 years of treatment. Their adult height was 148.3 +/- 5.6 cm. CONCLUSIONS: Although the response to treatment with GH varied, it was associated with highly significant gains in growth and adult height in girls with TS. Duration of treatment with GH was the most important variable predicting adult height.
Asunto(s)
Trastornos del Crecimiento/terapia , Hormona del Crecimiento/uso terapéutico , Síndrome de Turner/complicaciones , Estatura , Niño , Femenino , Crecimiento , Trastornos del Crecimiento/complicaciones , HumanosRESUMEN
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.
Asunto(s)
Anabolizantes/uso terapéutico , Estatura , Hormona del Crecimiento/uso terapéutico , Oxandrolona/uso terapéutico , Síndrome de Turner/tratamiento farmacológico , Niño , Preescolar , Quimioterapia Combinada , Femenino , Humanos , Estudios Prospectivos , Resultado del Tratamiento , Síndrome de Turner/fisiopatologíaRESUMEN
Over a 9-year period (1985-1994) approximately 20,000 children received recombinant human growth hormone (rhGH) while enrolled in the National Cooperative Growth Study (NCGS), an observational, longitudinal study designed to monitor the long term efficacy and safety of rhGH administered to children in North America. Forty-four percent of the patients had idiopathic growth hormone deficiency (IGHD), 13.8% organic GHD (OGHD), 25% idiopathic short stature (ISS), 9.9% Turner's syndrome (TS), and 7.3% miscellaneous disorders. Eighty-five percent of the patients enrolled were Caucasian, and approximately two-thirds of the non-Turner patients were male. For the subset of patients treated for at least 4 years and who were prepubertal throughout this period (IGHD N=308, OGHD N=93, ISS N=169, TS N=82), mean growth rates increased in all patient categories and remained at or above pretreatment growth rates through 4 consecutive years of therapy with rhGH. Growth rates during administration of rhGH were greater in children in whom the pretreatment maximum stimulated GH concentration was < or =3 microg/l. Patients treated with 6 or 7 doses of rhGH each week grew more rapidly than did those receiving thrice weekly dosages, although the ratios of the increment in bone age to the increment in height age after two years of therapy were similar in the two treatment regimens. For patients treated with rhGH for 7 consecutive years, the mean height standard deviation scores increased by 2.5 in IGHD (N=169), 2.0 in OGHD (N=50), 1.9 in ISS (N=69), and 1.3 in TS (N=19), but remained below target heights in all categories. It is concluded that administration of rhGH increases growth rates in patients with IGHD, OGHD, ISS, and TS, and that this stimulatory effect can persist for at least 4 years.
Asunto(s)
Hormona de Crecimiento Humana/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Adolescente , Estatura/efectos de los fármacos , Niño , Esquema de Medicación , Femenino , Trastornos del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/sangre , Hormona de Crecimiento Humana/deficiencia , Humanos , Inyecciones , Estudios Longitudinales , Masculino , Concentración Osmolar , Proteínas Recombinantes/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Síndrome de Turner/tratamiento farmacológicoRESUMEN
OBJECTIVE: To assess the clinical utility of growth-hormone-binding protein (GHBP), along with growth hormone (GH), insulin-like growth factor I (IGF-I), and insulin-like growth factor-binding protein 3 (IGFBP-3), levels in the evaluation of short stature. STUDY DESIGN: Prospective substudy of the National Cooperative Growth Study, a multicenter observational study. RESULTS: A total of 6447 assessable subjects undergoing workup for short stature were enrolled at 197 sites. At baseline the cause of short stature was undefined in 77% of subjects. Mean GHBP levels were lowest in subjects with renal disease and highest in those with Turner syndrome. No cases of complete GH insensitivity syndrome (Laron syndrome) were identified. Subjects with low GHBP levels were among those tested for GH receptor mutations. IGF-I standard deviation scores (SDS) and IGFBP-3 SDS were positively correlated; both increased during GH therapy. There was a weak positive correlation between log peak GH levels and both IGF-I SDS and IGFBP-3 SDS and a weak negative correlation between log peak GH levels and GHBP SDS. Mean changes in GHBP SDS in subjects treated with GH and untreated subjects were not significant. Change in height SDS in subjects treated with GH was negatively correlated with age and IGF-I level but not correlated with baseline GHBP SDS. CONCLUSION: GHBP levels are GH independent and not predictive of responses to GH therapy, although low GHBP levels may indicate GH receptor abnormalities and partial GH insensitivity.
Asunto(s)
Proteínas Portadoras/sangre , Trastornos del Crecimiento/sangre , Hormona de Crecimiento Humana/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Factores de Edad , Estatura/efectos de los fármacos , Canadá , Niño , Estudios de Evaluación como Asunto , Femenino , Estudios de Seguimiento , Predicción , Crecimiento/efectos de los fármacos , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/genética , Hormona de Crecimiento Humana/genética , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Enfermedades Renales/sangre , Masculino , Mutación/genética , Estudios Prospectivos , Receptores de Somatotropina/genética , Síndrome , Síndrome de Turner/sangre , Estados UnidosRESUMEN
Carbohydrate metabolism was evaluated by fasting and postprandial glucose, insulin, and hemoglobin (Hb)Alc levels in children with chronic renal insufficiency and various other growth disorders treated with growth hormone. Mean fasting and postprandial glucose remained unchanged throughout the 5-year study period in all four study groups. Median fasting insulin levels rose from low-normal levels into the normal range after 5 years of growth hormone. Average fasting insulin level after 5 years was 10 mU/l. Median postprandial insulin values also rose, yet remained within the normal range at the 5-year mark. Mean Hb Alc levels remained within low to middle end of the normal range in the patients with growth hormone deficiency, Turner syndrome, and idiopathic short stature. Mean Hb Alc levels at the 5 years were slightly elevated to 6.3% for the patients with chronic renal insufficiency.
Asunto(s)
Metabolismo de los Hidratos de Carbono , Trastornos del Crecimiento/metabolismo , Hormona del Crecimiento/efectos adversos , Hormona del Crecimiento/deficiencia , Fallo Renal Crónico/metabolismo , Síndrome de Turner/metabolismo , Glucemia/metabolismo , Niño , Colesterol/sangre , Hemoglobina Glucada/metabolismo , Trastornos del Crecimiento/tratamiento farmacológico , Hormona del Crecimiento/uso terapéutico , Humanos , Insulina/sangre , Periodo Posprandial/fisiología , Potasio/sangre , Sodio/sangre , Tiroxina/sangre , Triglicéridos/sangre , Síndrome de Turner/tratamiento farmacológicoRESUMEN
For the National Cooperative Growth Study II substudy, data on spontaneous growth hormone (GH) secretion were collected from 5106 children with short stature. Of these, 2123 with complete 12-hour samples were subsequently enrolled in the NCGS. Compared with NCGS enrollees who were not in the NCGS II substudy, these children were significantly older (11.3 +/- 3.3 years vs 9.9 +/- 4.2 years), had a higher maximum reported GH level (13.3 +/- 10.5 micrograms/L vs 9.2 +/- 8.7 micrograms/L), and were more likely to be male (71% vs 62%) and pubertal (27.3% vs 21.9%) (p<0.001) for all). Height deficit, bone age delay, and pretreatment growth rates were similar. Children who were classified as having GH deficiency on the basis of their response to standard pharmacologic tests had lower spontaneous GH secretion than those who were classified as having idiopathic short stature, but considerable overlap was seen between the two groups on all indexes of spontaneous GH secretion. This finding suggests that the investigators were using serial sampling studies in examining children with short stature who were not growing well but had "normal" GH responses to standard pharmacologic testing.
Asunto(s)
Trastornos del Crecimiento/diagnóstico , Hormona del Crecimiento/sangre , Adolescente , Niño , Bases de Datos Factuales/estadística & datos numéricos , Servicios de Información sobre Medicamentos/estadística & datos numéricos , Femenino , Crecimiento/efectos de los fármacos , Crecimiento/fisiología , Trastornos del Crecimiento/sangre , Trastornos del Crecimiento/etiología , Hormona del Crecimiento/deficiencia , Humanos , MasculinoRESUMEN
The National Cooperative Growth Study includes growth data on more the 24,000 children in the United States and Canada who have been treated with growth hormone (GH). To determine whether dysregulation of GH release causes growth failure in children, we initiated the National Cooperative Growth Study substudy II to evaluate the diagnostic utility of serially sampled GH levels and to determine whether those patterns were responsible for the low growth rates in certain subsets of short children and whether children in any of the diagnostic categories would respond to GH therapy. A total of 3744 subjects whose mean height standardized for their chronological age was -2.8 SD and whose pretreatment growth rate was 4.2 cm/yr had complete 12-hour data sets-- serial samples obtained in a 12-hour overnight period. Pulsatile characteristics of GH release were assessed with the cluster algorithm. There was a virtually complete overlap of the GH pulsatile characteristics between control subjects and short children, but the insulin-like growth factor I (IGF-I) levels were markedly lower in the short children, suggesting impairment in the GH-IGF-I axis. THe growth response to administered GH showed only very weak correlations with the various cluster-derived parameters. Our results indicate that one must look beyond the release of GH to find an explanation for the short statures and low IGF-I levels in the subsets of children with idiopathic short stature.
Asunto(s)
Trastornos del Crecimiento/diagnóstico , Hormona del Crecimiento/sangre , Ciclos de Actividad/fisiología , Estatura/efectos de los fármacos , Bases de Datos Factuales/estadística & datos numéricos , Servicios de Información sobre Medicamentos/estadística & datos numéricos , Crecimiento/efectos de los fármacos , Crecimiento/fisiología , Trastornos del Crecimiento/sangre , Trastornos del Crecimiento/tratamiento farmacológico , Hormona del Crecimiento/uso terapéutico , Hormona Liberadora de Hormona del Crecimiento/fisiología , Humanos , Factor I del Crecimiento Similar a la Insulina/fisiología , Masculino , Estudios RetrospectivosRESUMEN
Long-term (5 years) treatment of 20 growth-retarded pre-pubertal children with chronic renal insufficiency (CRI) led to a significant (P < 0.00005) improvement in standardized height from -2.6 at baseline to -0.7 at five years. Eight patients were paused after reaching target height (50th centile midparental height) and 4 (50%) required re-initiation of recombinant human growth hormone (rhGH) because of a substantial decrease in standardized height. Growth potential was not adversely impacted with a delta height age (HA) minus delta bone age (BA) at five years of +0.5 (N = 8). The mean calculated CCr decreased from 32.2 +/- 15.2 ml/min/1.73 m2 at baseline to 24.6 +/- 14.7 ml/min/1.73 m2 at five years (P = 0.04), which would be consistent with the natural history of CRI in children. Despite the absence of clinical consequences, the increase in the mean fasting and two-hour post-prandial plasma insulin levels during treatment compared to baseline requires further investigation. The only clinically significant adverse event potentially related to rhGH was the development of avascular necrosis of the femoral head during the fourth year of treatment in one patient. Long-term rhGH treatment in children with CRI improves the potential of children with CRI achieving target adult height.