RESUMO
Activin and inhibin are peptide hormones produced in the gonads which may act as autocrine and/or paracrine regulators of testicular function. Sertoli cells produce inhibin, and it has recently been shown that Leydig cells can produce activin in vitro. To further explore the local actions of activin and inhibin in the testis, Sertoli and germ cells were isolated from immature rats and cocultured in vitro. In these cultures we demonstrate that activin A and activin B, but not inhibin A, stimulated spermatogonial proliferation in vitro. Activin increased [3H]thymidine incorporation 2- to 4-fold in cocultures after 48-72 h of treatment. Using autoradiography, the label was localized in the clusters of spermatogonia adhering to the Sertoli cell monolayer. Additionally, activin stimulated a reaggregation of the cultures into tubule-like structures. Fluorescence-activated cytometry was used to analyze the cell population based on size, DNA content, and lipid content. Sertoli cells were identified using Nile Red staining of intracellular lipid droplets; spermatogonia are Nile Red-negative. Activin treatment caused a marked increase in the fraction of Nile Red-negative cells in the cocultures. Activin also caused an increase in the percentage of these cells having 4C DNA. Lastly, specific binding of activin A to 2C, but not 4C, germ cells was demonstrated. These data demonstrate that activin acts as a regulator of spermatogonial proliferation in the male.
Assuntos
Inibinas/farmacologia , Células de Sertoli/fisiologia , Espermatogônias/citologia , Testículo/fisiologia , Ativinas , Animais , Comunicação Celular , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Replicação do DNA/efeitos dos fármacos , Citometria de Fluxo , Masculino , Microscopia Eletrônica , Ratos , Ratos Endogâmicos , Proteínas Recombinantes/farmacologia , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/ultraestrutura , Maturidade Sexual , Espermatogônias/efeitos dos fármacos , Espermatogônias/ultraestrutura , Testículo/efeitos dos fármacos , Testículo/ultraestrutura , Timidina/metabolismoRESUMO
Flow cytometry was used to separate and identify Sertoli and germ cell populations in primary rat testicular cultures derived from animals of different ages on the basis of cell size and DNA and lipid content. Multiparameter fluorescent evaluation of each cell preparation resulted in the assignment of specific staining patterns to Sertoli cells (diploid, high lipid content), spermatogonia (diploid, low lipid content), spermatocytes (large, tetraploid, high lipid content), and round spermatids (haploid, low lipid content). Each field was separately analyzed for inhibin and activin binding. Fluorescein isothiocyanate-conjugated activin bound with greatest intensity to spermatogonia, with little binding to leptotene or zygotene spermatocytes. Fluorescein isothiocyanate-conjugated inhibin bound to all stages of germ cells tested. Cross-competition data indicate that at least two and probably three distinct receptors exist for these peptides.
Assuntos
Inibinas/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores de Peptídeos , Células de Sertoli/metabolismo , Maturidade Sexual , Espermatozoides/metabolismo , Testículo/metabolismo , Receptores de Ativinas , Ativinas , Envelhecimento , Animais , Comunicação Celular , Separação Celular , Células Cultivadas , Citometria de Fluxo , Masculino , Ratos , Ratos Endogâmicos , Proteínas Recombinantes/metabolismo , Espermatócitos/metabolismo , Espermatogônias/metabolismo , Testículo/citologia , Testículo/crescimento & desenvolvimentoRESUMO
The relative contributions of GH, insulin-like growth factor-I (IGF-I), estradiol, and testosterone to the pubertal growth spurt are incompletely understood. We studied 8 patients (5 girls and 3 boys) with true precocious puberty and GH deficiency due to CNS lesions to assess the role of sex steroids in pubertal growth independent of an increase in circulating GH. Included is 1 patient with an unusual hypothalamic lesion due to head trauma. A control group of 17 GH-sufficient patients with true precocious puberty (13 girls and 4 boys) was matched for chronological age. The GH-deficient girls grew at a mean velocity of 9.2 cm/yr (range, 7.2-14.4), and the boy's mean height velocity was 7.9 cm/yr (6.1-9.9). Mean bone age was advanced in the GH-deficient group (girls, +2.7 SD; boys, +2.6 SD), but not as much as the GH-sufficient controls (girls, +5.4 SD; boys, +4.3 SD). The mean concentration of plasma IGF-I was lower in the GH-deficient group than in the control group, but was greater than the mean concentration in age-matched prepubertal GH-deficient patients. Four GH-deficient patients were treated with a potent agonist of LRF. This caused suppression of gonadal sex steroid concentrations and a fall in mean height velocity from 9.1 to 4.3 cm/yr after 1 yr of therapy; however, circulating GH and IGF-I values were not uniformly altered. We conclude that a substantial pubertal growth spurt can occur in patients with true precocious puberty and GH deficiency that is dependent on gonadal sex steroids yet unaccompanied by normal pubertal levels of circulating GH or IGF-I. Reversal of this growth acceleration is possible with sex steroid suppression. The results, in light of previous in vivo and in vitro studies, suggest that the normal pubertal growth spurt is mediated in part by direct effects of sex steroids at the growth plate.
Assuntos
Hormônio do Crescimento/deficiência , Crescimento/fisiologia , Puberdade Precoce/sangue , Determinação da Idade pelo Esqueleto , Estatura , Doenças do Sistema Nervoso Central/fisiopatologia , Criança , Pré-Escolar , Estradiol/sangue , Estradiol/fisiologia , Feminino , Hormônio do Crescimento/sangue , Hormônio do Crescimento/fisiologia , Humanos , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/fisiologia , Masculino , Testosterona/sangue , Testosterona/fisiologiaRESUMO
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.
Assuntos
Envelhecimento/fisiologia , Terapia de Reposição de Estrogênios , Hormônio do Crescimento/uso terapêutico , Síndrome de Turner/tratamento farmacológico , Adolescente , Estatura/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Criança , Método Duplo-Cego , Feminino , Feminização/tratamento farmacológico , Humanos , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
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.
Assuntos
Estatura/efeitos dos fármacos , Hormônio do Crescimento/uso terapêutico , Hormônio do Crescimento Humano/deficiência , Puberdade/efeitos dos fármacos , Adolescente , Índice de Massa Corporal , Densidade Óssea , Desenvolvimento Ósseo , Metabolismo dos Carboidratos , Criança , Feminino , Crescimento/efeitos dos fármacos , Hormônio do Crescimento/administração & dosagem , Hormônio do Crescimento/efeitos adversos , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , MasculinoRESUMO
One possible explanation for the growth failure in children with idiopathic short stature (ISS) is reduced peripheral responsiveness to GH. In Laron syndrome, growth retardation is caused by GH resistance due to GH receptor (GH-R) defects, which are associated in most cases with absent or low serum concentrations of the GH-R-related GH-binding protein (GHBP). We tested the hypothesis that some children with ISS have reduced serum concentrations of GHBP and that this may reflect decreased sensitivity to GH. A ligand-mediated immunofunctional assay was used to measure biochemically active GHBP in serum from 1549 children, including 773 controls, 573 with ISS, 107 with GH deficiency (GHD), and 96 with Turner syndrome (TS). Ages ranged from 1-17 yr. Serum GHBP concentrations in children with GHD, ISS, and TS were converted to SD scores and compared to controls by analysis of variance. In male and female ISS subjects, approximately 90% had GHBP concentrations below the age- and sex-adjusted mean for controls, and 20% had GHBP concentrations below the normal range. The mean serum GHBP SD score was lower in both males and females with GHD (-0.6) or ISS (-1.2) than in controls (both P < 0.005). The mean for ISS males was significantly lower than that for GHD males (P < 0.0001). The mean GHBP SD score for girls with TS (-0.3) did not differ significantly from that of the control females. The decreased levels of serum GHBP in some children with idiopathic short stature suggest that these children could have a defect at the level of the GH-R.
Assuntos
Proteínas de Transporte/sangue , Transtornos do Crescimento/sangue , Hormônio do Crescimento/sangue , Adolescente , Biomarcadores/sangue , Estatura , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento/deficiência , Humanos , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Valores de Referência , Fatores Sexuais , Síndrome de Turner/sangueRESUMO
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.
Assuntos
Glucocorticoides/efeitos adversos , Transtornos do Crescimento/induzido quimicamente , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Glicemia/metabolismo , Estatura , Criança , Estudos de Coortes , Feminino , Glucocorticoides/administração & dosagem , Hemoglobinas Glicadas/metabolismo , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Osteocalcina/sangue , Pró-Colágeno/sangue , Estudos RetrospectivosRESUMO
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.
Assuntos
Estatura , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Glicemia/metabolismo , Criança , Colesterol/sangue , Jejum , Feminino , Alimentos , Hemoglobinas Glicadas/metabolismo , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Tiroxina/sangue , Triglicerídeos/sangueRESUMO
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.
Assuntos
Hormônio do Crescimento/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Anticorpos/sangue , Criança , Pré-Escolar , Feminino , Crescimento/efeitos dos fármacos , Hormônio do Crescimento/efeitos adversos , Hormônio do Crescimento/imunologia , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , MasculinoRESUMO
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.
Assuntos
Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/farmacocinética , Criança , Pré-Escolar , Preparações de Ação Retardada , Esquema de Medicação , Feminino , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/tratamento farmacológicoRESUMO
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.
Assuntos
Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/farmacocinética , Adulto , Idoso , Glicemia/análise , Proteínas de Transporte/sangue , Preparações de Ação Retardada , Jejum , Feminino , Glicoproteínas/sangue , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/farmacologia , Humanos , Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Cinética , Masculino , Pessoa de Meia-Idade , Caracteres SexuaisRESUMO
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.
Assuntos
Transtornos do Crescimento/terapia , Hormônio do Crescimento/uso terapêutico , Síndrome de Turner/complicações , Estatura , Criança , Feminino , Crescimento , Transtornos do Crescimento/complicações , HumanosRESUMO
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.
Assuntos
Densidade Óssea/efeitos dos fármacos , Hormônio do Crescimento/uso terapêutico , Adulto , Animais , Remodelação Óssea , Ensaios Clínicos como Assunto , Hormônio do Crescimento/deficiência , Hormônio do Crescimento/farmacologia , HumanosRESUMO
The purpose of this study was to present US reference data for chronological ages at which stages of sexual maturation were observed in white youths. Recent serial data from 78 males and 67 females were analyzed to obtain descriptive statistics for the ages at onset of these stages and the mean ages at which the stages are observed. These reference data should assist the identification of white US youths who are maturing at rapid or slow rates and the interpretation of growth data.
Assuntos
Maturidade Sexual/genética , Maturidade Sexual/fisiologia , População Branca/genética , Adolescente , Envelhecimento/fisiologia , Criança , Feminino , Crescimento/fisiologia , Humanos , Masculino , Puberdade/fisiologia , Fatores de Tempo , Estados UnidosRESUMO
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.
Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Adolescente , Estatura/efeitos dos fármacos , Criança , Esquema de Medicação , Feminino , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Humanos , Injeções , Estudos Longitudinais , Masculino , Concentração Osmolar , Proteínas Recombinantes/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Síndrome de Turner/tratamento farmacológicoRESUMO
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.
Assuntos
Estatura , Congêneres do Estradiol/uso terapêutico , Síndrome de Turner/tratamento farmacológico , Fatores Etários , Estatura/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Congêneres do Estradiol/farmacologia , Feminino , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Resultado do Tratamento , Síndrome de Turner/fisiopatologiaRESUMO
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.
Assuntos
Estatura/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/genética , Estatura/fisiologia , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino , Mutação , Fenótipo , Receptores de Fatores de Crescimento/genética , Síndrome de Turner/genética , Cromossomo X/genética , Cromossomo Y/genéticaRESUMO
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.
Assuntos
Transtornos do Crescimento/diagnóstico , Hormônio do Crescimento/sangue , Adolescente , Criança , Bases de Dados Factuais/estatística & dados numéricos , Serviços de Informação sobre Medicamentos/estatística & dados numéricos , Feminino , Crescimento/efeitos dos fármacos , Crescimento/fisiologia , Transtornos do Crescimento/sangue , Transtornos do Crescimento/etiologia , Hormônio do Crescimento/deficiência , Humanos , MasculinoRESUMO
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.