Metabolic effects of growth hormone in children.
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Bone and Bones↗
Biomedical subjects
M B Ranke
Publications and source records attributed to M B Ranke.
Resistance of nitrogen metabolism to growth hormone treatment in the early phase after injury of patients with multiple injuries.
OBJECTIVES AND DESIGN: Several studies have shown an anticatabolic effect of recombinant human growth hormone (rhGH) in surgical patients. We investigated, in a prospective, randomized, double blind, and placebo-controlled study, the effect of r-hGH on hormone and nitrogen metabolism in 14 patients with multiple injuries in the early phase of injury. MATERIALS AND METHODS: All patients were treated in the intensive care unit, had mechanical ventilation, and were highly catabolic, with a mean daily nitrogen loss of 13.2 +/- 1.8 g. r-hGH was given subcutaneously (once a day, at 8 PM) in a dosage of 0.2 IU/kg.d for seven days, starting on the second day after injury. RESULTS: Administration of r-hGH evoked a significant increase in plasma concentrations of GH, insulin-like growth factor-I (IGF-I), and insulin-like growth factor binding-protein-3 (IGFBP-3). No significant differences were found for either daily or cumulative nitrogen balances (-103.1 +/- 14 g for patients receiving r-hGH and -92.1 +/- 18.1 for those with placebo). r-hGH therapy did not affect skeletal muscle extracellular water, nor did it affect plasma or muscle concentrations of total free amino acids or glutamine. Plasma albumin, prealbumin, and retinol-binding protein concentrations were also unchanged by r-hGH therapy, as were the urinary excretion of potassium and urea. CONCLUSIONS: We conclude that elevated plasma levels of GH, insulin, and IGF-I are unable to effect a protein anabolic drive in patients with multiple injuries during the early postinjury phase and assume that this r-hGH resistance to nitrogen metabolism takes place at the level distal to IGF-I.
Adult↗
Growth hormone insensitivity syndromes.
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Child↗
Growth hormone therapy in children: when to stop?
There is currently no consensus on when to start or stop growth hormone (GH) treatment for short stature. Observed height velocity and/or remaining growth potential are the usual guidelines for the efficacy of continued treatment, and the decision to stop GH therapy will thus vary with the underlying disease and individual circumstances, within the limitations of the social and financial environment. The consequences of discontinuing treatment must also be considered. In GH deficiency a chronologically differential progression of developmental events is likely, and while normal height may be attained GH-dependent gonadal or bone structure/function may be retarded. The decision to stop GH treatment can only be made with reference to the expanding knowledge of its complex biological role rather than adhering to convention.
Child↗
Dose-dependent responses in insulin-like growth factors, insulin-like growth factor-binding protein-3 and parameters of bone metabolism to growth hormone therapy in young adults with growth hormone deficiency.
There is increasing awareness that growth hormone (GH) replacement therapy is also essential in adult patients with growth hormone deficiency (GHD). There are little data available on the dose requirements for replacement therapy in this age group. In childhood, the growth response to GH therapy can serve as an indicator for correct replacement dose. Because this indicator does not exist in adults, we analyzed growth factors and biochemical markers of bone metabolism by specific radioimmunoassays in a group (n = 12) of adult patients (age, 20.0-31.6 years) with GHD with childhood onset before and after a 4-week treatment period (daily, s.c.) with recombinant, human GH at different doses (0.125, 0.25 and 0.5 IU/kg body weight/week). Comparing the basal levels to those on low-dose GH (0.125 IU/kg/week) and on a high dose (0.5 IU/kg/week), the following results were obtained. Insulin-like growth factor-I (IGF-I) in serum: basal, 68.6 +/- 37 ng/ml; low dose, 176.9 +/- 65 ng/ml (p < or = 0.05); high dose, 380.6 +/- 200 ng/ml (p < or = 0.01). IGF-binding protein-3 in serum: basal, 2.13 +/- 0.58 mg/l; low dose, 3.23 +/- 0.84 mg/l (p < or = 0.01); high dose, 3.97 +/- 0.82 mg/l. Osteocalcin in serum: basal, 3.88 +/- 1.27 ng/ml; low dose, 7.01 +/- 2.20 ng/ml (p < or = 0.01); no further increase. Procollagen-I peptide in serum: basal, 113.6 +/- 36.7 microgram/l; low dose, 211.6 +/- 90.4 microgram/l (p < or = 0.01); no further increase.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Spontaneous adult height in idiopathic short stature.
Two hundred and thirty-six patients with idiopathic short stature (ISS) (184 m, 52 f) who presented at a mean age of 12.2 (range 2.8-17.5) years, a mean height of -2.16 standard deviation score (SDS), a mean target height (THT) of -0.27 SDS (m = f), were reinvestigated at a mean age of 20.5 (range 18-24) years. 182(142 m, 37 f) (67%) had reached normal adult height (AHT) while 54 (39 m, 15 f) (23%) had not. However, only 23 (17 m, 6 f) did not reach a height within their familial target. Patients were subdivided into 2 groups according to deviation from familial height target: 60(44 m, 16 f) were considered adequate for their families (group 1), while 176 (140 m, 39 f) were smaller (group 2). Children in group 1 were younger and bone age (BA) was less retarded. Patients in group 1 reached their THT, this was not the case in group 2. Young age, low THT and low predicted adult height (PAH) at presentation were the factors associated with poor stratural outcome, but AHT could not be predicted in individuals. In boys, PAH (Bayley-Pinneau) (0.0 SDS) exceeded AHT (-0.7 SDS), in girls, both were almost identical (-0.79, -0.77 SDS). Since most children with ISS reach an AHT within the normal range, attempts to improve AHT by means of growth-promoting therapies appear to be justified only in a minority of selected patients with ISS. Methods to improve the accuracy of individual height prognoses are needed.
Adolescent↗
Insulin-like growth factor I improves height in growth hormone insensitivity: two years' results.
Thirty-one patients with growth hormone insensitivity syndrome (GHIS) and 2 with GH gene deletion (age 11.2 (3.7-22.9) years; BA (GP) 8.2 years; height -6.5 +/- 1.6 SDS) were recruited for the multicenter study. At birth, length was more retarded (-1.38 SDS) than weight (-0.56 SDS). The rhIGF-I dose was 40-120 micrograms/kg BW twice daily s.c. In 26 patients, first year HV increased from 3.9 +/- 1.8 to 8.5 +/- 2.1 cm/year (delta (d) HT SDS 0.8 +/- 0.5). In 18 patients, second year HV was 6.4 +/- 2.2 cm/year (dHT SDS 0.4 +/- 0.5). There was normal progression of puberty. Mean progression of BA was 1.2 and 1.5 years/year during the first and second year. There was no dose effect of IGF-I on growth. Weight-for-height index (WHI) and skinfold thickness were significantly correlated at start, 12 and 24 months (r = 0.83, 0.87 and 0.79). Changes in WHI were positively correlated with dHT SDS during the first and second year (r = 0.54, 0.56). Serum IGF-I rose, IGF-II decreased, and IGFBP-3 remained constant. Adverse events were (number of occasions): headache (21) (early); hypoglycemia (13); papilloedema (1) (reversible); Bell's palsy (1) (reversible); lipohypertrophy (7) (late); tonsillectomy/adenoidectomy (3) (late). The results show that there is effective long-term treatment of GHIS with systemically administered IGF-I and support the view that IGFBPs play an important role in the action of IGF-I.
Adolescent↗
Growth hormone therapy in Turner syndrome. Analysis of long-term results.
The favorable long-term results of growth hormone (GH), alone or in combination with oxandrolone, reported by an American study [J Pediatr 1992; 121:49-55], have so far not been confirmed by other investigators. However, from the presently available data it can be deduced that with higher than substitutive doses of GH, height can be improved during childhood and will be normalized in many patients with Turner syndrome. The future task must be to optimize treatment with respect to the dose and timing of GH (and oxandrolone) in individuals in order to ensure optimal statural outcome at the lowest risk and material costs.
Anabolic Agents↗
Nested polymerase chain reaction study of 53 cases with Turner's syndrome: is cytogenetically undetected Y mosaicism common?
Turner's syndrome patients with Y mosaicism face a high risk of developing gonadoblastoma. Cytogenetic analysis can fail to detect rare cells bearing a normal or structurally abnormal Y chromosome (low level Y mosaicism). We screened 53 individuals with Turner's syndrome for presence of sex-determining region Y (SRY), the testis-specific protein, Y encoded, gene, and the Y centromeric DYZ3 repeat using nested polymerase chain reaction (PCR). Thirty girls (57%) had the 45,X karyotype, determined through standard analysis of blood lymphocytes. The remaining 23 girls (43%) were mosaics and/or had structural abnormalities in 1 X-chromosome. Genomic DNA from blood leukocytes was amplified using 2 rounds of PCR. This method was sensitive enough to detect 0.0001% male DNA on a female background. None of 53 Turner's syndrome cases was positive for Y-specific loci after the first round of PCR. After the second round, 2 of 53 Turner's syndrome cases were positive for SRY mapping to the distal short arm of chromosome Y. In 1 SRY-positive subject, the karyotype was 45,X, and in the other, it was 46,Xi(Xq). None of 53 Turner's syndrome individuals, including the 2 SRY-positive subjects, were positive for the testis-specific protein, Y encoded, gene on the proximal short arm of chromosome Y or the centromeric DYZ3 repeat. These data exclude low level Y mosaicism in almost all Turner's syndrome cases tested.
Base Sequence↗
Screening for growth hormone (GH) gene splice-site mutations in sporadic cases with severe isolated GH deficiency using ectopic transcript analysis.
We screened 10 children with sporadic severe isolated GH deficiency (IGHD) for GH-1 gene splice site mutations using ectopic transcript analysis. None had a history of birth trauma, congenital defects, thyroid disorders, or PRL deficiency. The mean age of these patients at diagnosis was 3.5 yr; the mean height at diagnosis was -4.0 SD score. GH-1 gene deletion was excluded in all cases. Ribonucleic acid (RNA) from lymphocytes was reverse transcribed and amplified by nested polymerase chain reaction, using two primer pairs with annealing sites within exons 2 and 5 of the GH-1 gene. The main polymerase chain reaction fragment obtained was 460 basepairs and proved to be the amplification of the GH-1 transcript. We also found three shorter fragments which were alternatively spliced GH-1 transcripts, including a variant devoid of the first 45 basepairs of exon 3, a second lacking the whole exon 3, and a third one, not previously described, lacking both exon 3 and exon 4. We found the same pattern of alternative splicing in RNA from GH-producing pituitary tumor tissue, which served as a positive control. In 1 of 10 patients, a pathologically shortened main fragment lacking exon 3 was detected. As proved by sequencing genomic DNA, this was the result of a heterozygous splice site mutation, with transversion from G to C of the first base of the donor splice site of intron III generating a new DdeI recognition site. The other allele had no mutation. DdeI digestion enabled us to rule out the defect in the parents' DNA. Thus, the mutation was de novo. As the patient with the mutation displayed the most severe and earliest growth retardation in the study group and had virtually no GH in serum, it must be assumed that the heterozygous genetic defect resulted in a dominant negative effect. The reason for this is still unclear. Recently, within a family that exhibited the autosomal dominant phenotype of IGHD (IGHD-II), a heterozygous point mutation was located 5 bases down-stream from that we describe here. A similar effect on splicing was observed. In conclusion, analysis of ectopic GH-1 transcripts enabled us to detect 1) a new alternatively spliced GH-1 messenger RNA variant lacking exons 3 and 4, and 2) 1 of 10 sporadic cases of severe idiopathic IGHD due to a heterozygous de novo splice site mutation in the GH-1 gene that changes G to C in the first base of intron III.(ABSTRACT TRUNCATED AT 400 WORDS)
Base Sequence↗
Interpretation of growth hormone provocative tests: comparison of cut-off values in four European laboratories.
To compare interpretations of growth hormone (GH) provocative tests in laboratories using six different GH immunoassays (one enzymeimmunometric assay (EIMA, assay 1), one immunoradiometric assay (IRMA, assay 5), one time-resolved fluorimmunometric assay (TRFIA, assay 3) and three radioimmunoassays (RIAs, assays 2, 4 and 6)), aliquots of peak samples from GH provocative tests were distributed between the four participating laboratories, quantified in the respective immunoassays and interpreted according to the cut-off values for provocative tests defined for each assay method. There was a high degree of relative correlation between the different assays, but absolute GH estimates differed. Assays 2, 4, 5 and 6 yielded almost identical GH levels. Assays 1 and 3 yielded serum GH levels approximately 39% and 70%, respectively, of those of assays 2, 4, 5 and 6. Although the absolute GH level measured in the various assay methods varied, there was good agreement between the interpretation of a given sample among the participating laboratories. This indicates that the differences in estimates of serum GH concentration by different immunoassay systems can be compensated for when cut-off values are defined for each method.
Europe↗
Brightness matching and colour discrimination in young diabetics without retinopathy.
This study used the methods of the Farnsworth-Munsell 100-hue test (FM-100), heterochromatic brightness matching (HBM) and wavelength discrimination to test the sensitivity and colour vision of 20 juvenile diabetics with no (16) or very mild (4) retinopathy. Their results were compared to an age-matched control group. The FM-100 results showed a significant increase in error scores throughout the spectrum in comparison to the controls. This deterioration in colour vision was confirmed in the results for the wavelength discrimination task, tested between 440 and 640 nm, where the just noticeable difference in colour was, in general, larger for the diabetic group than the control group. Only at 460 nm were the results of the diabetics similar to those of the controls. The diabetic group were also less sensitive than the control group in the HBM task between 480 and 600 nm. The results show that a deficit in sensitivity and colour vision occurs in diabetics before the onset of a clinically visible retinopathy.
Adolescent↗
The ratio between serum levels of insulin-like growth factor (IGF)-I and the IGF binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients.
OBJECTIVE: Several in-vitro studies have suggested that the biological actions of IGF-I can be modified by the presence of specific IGF binding proteins. In man, the 24-hour serum levels of IGF-I and IGFBP-3 remain constant, but short-term changes in the IGF-I/IGFBP-3 ratio have been described following GH administration. Serum levels of IGF-I and IGFBP-3 decrease with age in normal adults and are elevated in active acromegaly due to excessive GH secretion. However, the individual ratios between serum levels of IGF-I and IGFBP-3 in acromegalic and healthy adults have not been described previously. METHODS AND MATERIALS: We studied this ratio in 198 healthy adults and in 56 acromegalic patients, grouped according to their serum GH levels (group I GH < 2mIU/l II GH 2-10 mIU/l; III GH > 10 mIU/l). In all subjects a single blood sample was drawn for IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 and GH measurements by specific RIAs. In 38 of the patients a 24-hour urinary collection was performed for GH determination. RESULTS: In healthy adults serum levels of IGF-I and IGFBP-3 decreased with increasing age (r = -0.52 and r = -0.34, respectively, P < 0.0001). In addition, the molar IGF-I/IGFBP-3 ratio declined with increasing age (r = -0.44, P = 0.0001). In patients with acromegaly and high serum GH levels (group III), circulating IGF-I was increased 7.97 standard deviations (SDS) and IGFBP-3 was increased 4.20 SDS (P < 0.0001). Serum levels of IGF-II were normal in all three groups (588 +/- 240 micrograms/l) whereas IGFBP-1 and IGFBP-2 levels were low and IGFBP-2 levels decreased significantly with increasing serum GH levels (P < 0.0001). The molar IGF-I/IGFBP-3 ratio in the acromegalic patients was significantly higher than in the controls (P < 0.0001) and correlated significantly with urinary GH excretion (r = 0.67, P < 0.0001) as well as with serum GH levels (r = 0.73, P < 0.0001). CONCLUSION: We demonstrated a decreasing molar IGF-I/IGFBP-3 ratio with increasing age in healthy adults and an increased ratio between serum IGF-I and IGFBP-3 levels in acromegalic patients. As IGF-II is normal and IGFBP-1 and IGFBP-2 are inversely correlated to the serum GH levels in the acromegalic patients, we speculate that the molar ratio between IGF-I and IGFBP-3 reflects free (biologically active) IGF-I and is dependent on GH levels.
Acromegaly↗
Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls. Pharmacia Study Group on Insulin-like Growth Factor I Treatment in Growth Hormone Insensitivity Syndromes.
A survey to identify children and adolescents with primary growth hormone insensitivity syndrome (GHIS) yielded 38 patients who were positively identified using a scoring system that included five criteria: height, basal growth hormone (GH), GH binding protein, basal insulin-like growth factor I (IGF-I) and the increase of IGF-I after 4 days of GH administration (IGF generation test). Because of an overlap of the accepted and excluded groups with respect to points scored, an attempt was made to improve the scoring system. The new criteria were: height below -3 SDS, basal GH 4 mU/l or above, GH binding below 10%, basal IGF-I and basal IGF binding protein-3 (IGFBP-3) below the 0.1 centile for age, an increase of IGF-I in the IGF generation test less than 15 micrograms/l, and the increase of IGFBP-3 less than 0.4 mg/l. With this scoring system, a clear separation between the accepted and the excluded groups was obtained. IGFBP-3 was included to give the GH-dependent parameters of the IGF system more weight and because the accuracy of IGFBP-3 in the IGF generation tests was greater than the accuracy of IGF-I, when the group of patients with GHIS was compared with a group of patients with GH deficiency. Unexpectedly, the IGF generation test was unable to segregate both cohorts completely. In the GHIS-positive group, a significant correlation was found between basal IGF-I or IGFBP-3 levels corrected for age (SDS) and height SDS (r = 0.49, p < 0.002 and r = 0.61, p < 0.0001, respectively). There was also a significant correlation between the changes of IGF-I or IGFBP-3 in the IGF generation test and height SDS. That is, the patients with a slight response to GH were those with the least growth retardation, suggesting the existence of partial GH insensitivity.
Adolescent↗
Adverse events during treatment with recombinant insulin-like growth factor I in patients with growth hormone insensitivity.
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Child↗
Bell's palsy after onset of insulin-like growth factor I therapy in a patient with growth hormone receptor deficiency.
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Child↗
Growth hormone treatment of idiopathic short stature: analysis of the database from KIGS, the Kabi Pharmacia International Growth Study.
Within the Kabi Pharmacia International Growth Study (KIGS) database, there is information on 1017 (700 male/317 female) patients with idiopathic short stature (ISS). These patients were started on recombinant human growth hormone (GH) at a median age of 10.8 years, a bone age of -1.8 SDS, a height of -2.6 SDS and a predicted adult height (PAH) (Bailey-Pinneau method) of -2.5 SDS. The median dose of GH was 0.6 IU/kg body weight/week and the frequency of injections was six/week. According to the relationship with target height the patients were classified into 'familial short stature (FSS)' (height SDS > target height SDS -1.28) and into 'non-FSS' (height SDS < target height SDS -1.28). During the first year of GH treatment there was an overall increment in the median height velocity from 4.4 to 7.4 cm/year. Over 3 years of GH treatment, cross-sectional analysis demonstrated an overall increment in median PAH of 1.2 SDS. There was a positive correlation between gain in PAH and the GH dose (n = 202, r = 0.18, p < 0.01) during the first year. Longitudinal analysis in 84 patients showed an overall increment of PAH of 0.7 SDS over 2 years of treatment. When applying the KIGS first-year prediction model for patients with idiopathic GH deficiency on cohorts of prepubertal children with FSS and non-FSS, a lower responsiveness to GH in the non-FSS group was observed. It is concluded that higher than substitutive doses of GH are required for the long-term improvement of growth in ISS.
Adolescent↗
Growth in Turner's syndrome.
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Body Height↗