Opposite regulation of IGF-I and IGF-I receptor mRNA and concomitant changes of GH receptor and IGF-II/M6P receptor mRNA in human IM-9 lymphoblasts.

Human IM-9 lymphoblasts synthesize IGF-I and express IGF-I receptors, IGF-II/M6P receptors and GH receptors. We have studied the regulation of mRNA expression of IGF-I, IGF-I receptors, IGF-II/M6P receptors and GH receptors in IM-9 cells upon serum-withdrawal and re-addition of serum. IM-9 cells were cultured in RPMI-1640 medium with or without serum for various periods of time. RNA was prepared using guanidinium thiocyanate and CsCl. Antisense riboprobes for human IGF-I, IGF-I receptor, IGF-II/M6P receptor, GH receptor and for comparison for human beta-actin were synthesized and labeled with 32P. Protected fragments of 379 bases and of 420 and 350 bases with the IGF-I receptor and with the IGF-I probe respectively and protected fragments of 670 bases and of 51 and 121 bases with the GH receptor and with the beta-actin probe were detected. For the human IGF-II/M6P receptor probe protected fragments of 260 bases were visualized in RNA samples. The amount of mRNA present in each lane (10 microgram total RNA) was determined by computed densitometry. The amount of IGF-mRNA expressed by IM-9 cells decreased rapidly (within two hours) and dramatically (more than 120%) after the withdrawal of serum and increased significantly (220%) after the re-addition of serum. This increase of IGF-I mRNA preceded the increase in cell number that was seen after 48 h of medium change. Conversely, the expression of IGF-I receptor mRNA and beta-actin mRNA increased by more than 250% after the withdrawal of serum within 2 and 8 h respectively, while GH receptor mRNA fell within 2-4 h. The expression of IGF-II/M6P receptor mRNA continued to increase throughout the duration of the cell culture experiment. We conclude that IGF-I and IGF-I receptor mRNAs are regulated in an opposite direction in serum-deprived IM-9 lymphoblasts. In addition, GH receptor mRNA expression parallels IGF-I mRNA expression.

Specific growth hormone receptors on human peripheral mononuclear cells: reexpression, identification, and characterization.

Although specific GH receptors have been demonstrated in various tissues of a number of species, the presence of GH receptors on human peripheral mononuclear cells (PMC) is controversial. Binding of human GH (hGH) to its receptor as the hypothesized initial step of hormone action was consequently studied using mononuclear cells from peripheral venous blood of normal subjects. Specific binding of [125I]hGH was rapid, reversible, and time and temperature dependent. Specific GH binding to PMC was maximal after 8-24 h of preincubation. Binding of hormone was maximal at 37 C after incubation of cells for 2 h. Dissociation of GH was maximal at 37 C after the addition of 6 M NaCl. A linear relationship between specific GH binding and cell number was found. Saturation of GH binding to 10(6) PMC was obtained with 25 ng iodinated hormones. Half-maximal inhibition of GH binding occurred at 12-25 ng unlabeled hGH/tube. Hypothalamic and pituitary hormones as well as insulin did not interfere with specific hGH binding to PMC. Scatchard analysis of [125I]hGH binding to PMC revealed a receptor with a mean affinity constant of 1.5 +/- 0.2 (+/- SD) X 10(9)/M-1 (n = 72) and a maximal binding capacity of 7.1 +/- 2.0 X 10(-11) M/10(6) cells. The concentrations of calcium, sodium, and magnesium ions in the incubation medium strongly influenced GH binding, whereas pH or potassium concentration did not. As interassay variation of the binding assay was low (14% for total binding; 6% for specific hGH binding), this direct approach to study tissue receptors for hGH in a human in vitro test was reproducible and should encourage the investigation of receptor regulation as well as the study of binding in human disease.

GH therapy in juvenile chronic arthritis: results of a two-year controlled study on growth and bone.

Disturbance of growth frequently occurs in children suffering from juvenile chronic arthritis (JCA). Recognition of growth impairment is important because reduced final height is one of the permanent consequences. The aim of this study was to evaluate the efficacy and safety of human GH (hGH) in growth-retarded prepubertal children with JCA. Thirty-five children were tested for GH deficiency (GHD) and randomly assigned to a study and an untreated control group; five were GH deficient and were part of the GHD group. All received glucocorticoids. The study group was treated with 1 IU/kg BW.wk hGH; the GHD group was given 0.5 IU. During 2 yr of hGH treatment growth velocity and height SD score increased compared with baseline values. There was a marked increase in growth velocity in the treated groups, but also some increase in the control group. Plasma levels of IGF-I and IGF-binding protein-3 increased with GH treatment. These results suggest that hGH might be useful in the treatment of growth impairment in JCA. GH may counteract the adverse effects of glucocorticoid therapy, but its effect is dependent on the disease activity. Long-term controlled studies are needed to determine the risks and benefits of GH therapy in JCA.

Growth retardation in Turner syndrome: aneuploidy, rather than specific gene loss, may explain growth failure.

The etiology of short stature (SST) in Turner syndrome (TS) is still a subject of speculation. A variety of hypotheses have been put forward, from SST as a result of increased intrauterine tissue pressure after fetal lymphedema to haploinsufficiency of a specific growth gene(s). These hypotheses have various statistical-auxological implications on the growth distribution in TS. Empirical research has provided no clear evidence for any of these theories, but the well known correlation between patients' and midparental height (MPH) could be established. The influence of undetected mosaic status has often been cited as a major problem in the investigation of growth in TS. However, an assessment of mosaic status (simultaneous analysis of karyotype and phenotype) and its effect on growth with inclusion of MPH has been not yet carried out for a large sample. The aim of this study was to evaluate growth and its complex relationship to mosaic status and MPH in TS. In a mixed cross-sectional and longitudinal study we retrospectively analyzed the auxological and clinical data of 447 patients with a pure loss of X-chromosomal material (n = 381 with 45,X0; n = 66 mosaics). The 447 patients were selected from a series of 609 consecutive patients with TS. To assess the effect of mosaic status on growth, we computed a bifactorial analysis of variance (phenotype, karyotype), including MPH as a covariate. In line with the mosaic hypothesis, we found a correlation between individual loss of X-chromosomal material and phenotypical expressivity. In contrast, no correlation was found with respect to growth. With respect to MPH, we found growth retardation (GR) even in those patients with "normal" height above the third percentile (-2 or more SD score). The interindividual variance of GR in TS (comparable to growth variance in the normal population) seems to be unrelated to other TS-specific factors (e.g. mosaic status or single gene loss). Instead, both interindividual variance and the global growth shift distribution are best explained by the presence of an unspecific aneuploidic effect. Furthermore, consideration of patient height in relation to MPH should lead to a better understanding of the nature of GR in TS than the commonly used, strictly qualitative definition of SST.

Childhood onset of GH deficiency: reassessment of GH status and effects of substitution.

The final height of 77 patients with growth hormone (GH) insufficiency of childhood onset was analysed. Patients were treated between 1968 and 1996 for 1-15 years. The mean final height in patients with severe GH deficiency was 163.9 cm (males) or 151.1 cm (female patients). In patients with partial GH insufficiency, the mean final heights were 166.2 and 157.7 cm, respectively, and in patients with GH deficiency caused by intracerebral tumours, 175.9 or 160.2 cm, respectively. Late established diagnosis, lack of (pituitary) GH during the time prior to 1980 or low frequency of injections per week were related to the fact that final height was often below the target height range. In four of 51 retested patients with childhood onset GH deficiency, a normal response of the pituitary gland to pharmacological testing was found, whereas all other patients still suffered from GH insufficiency. An increased amount of fat and a decreased amount of lean body mass as well as low bone mineral density (12 out of 15 patients) could be demonstrated at re-evaluation.

Elevated nerve growth factor and neurotrophin-3 levels in cerebrospinal fluid of children with hydrocephalus.

BACKGROUND: Elevated intracranial pressure (ICP) resulting from impaired drainage of cerebrospinal fluid (CSF) causes hydrocephalus with damage to the central nervous system. Clinical symptoms of elevated intracranial pressure (ICP) in infants may be difficult to diagnose, leading to delayed treatment by shunt placement. Until now, no biochemical marker of elevated ICP has been available for clinical diagnosis and monitoring. In experimental animal models, nerve growth factor (NGF) and neurotrophin-3 (NT-3) have been shown to be produced by glial cells as an adaptive response to hypoxia. We investigated whether concentrations of NGF and NT-3 are increased in the CSF of children with hydrocephalus. METHODS: NGF was determined in CSF samples collected from 42 hydrocephalic children on 65 occasions (taps or shunt placement surgery). CSF samples obtained by lumbar puncture from 22 children with suspected, but unconfirmed bacterial infection served as controls. Analysis was performed using ELISA techniques. RESULTS: NGF concentrations in hydrocephalic children were over 50-fold increased compared to controls (median 225 vs 4 pg/mL, p < 0.0001). NT-3 was detectable (> 1 pg/mL) in 14/31 hydrocephalus samples at 2-51 pg/mL but in none of 11 control samples (p = 0.007). CONCLUSION: NGF and NT-3 concentrations are increased in children with hydrocephalus. This may represent an adaptive response of the brain to elevated ICP.

Recombinant human growth hormone in short children born small for gestational age. German Study Group.

The effects of recombinant human growth hormone (rhGH) treatment in 69 prepubertal, non-GH deficient children born small for gestational age (SGA) were evaluated over 2 years. At start of the study mean age was 5.1 years, mean bone age was 3.8 years and mean height SDS was -4.0. The children were randomly allocated to 3 groups receiving no treatment or daily subcutaneous injections of rhGH at a dose of 0.1 IU/kg body weight (group 0.1 IU) or 0.2 IU/kg body weight (group 0.2 IU). At start of the study mean height velocity SDS was -1.4 in the control group, -0.7 in group 0.1 IU and -1.4 in group 0.2 IU. After 2 years there was a significant increase in height velocity SDS in children treated with rhGH as compared to untreated children. Mean height velocity SDS after the first year of treatment was -1.2 in the control group, 2.8 in group 0.1 IU and 5.5 in group 0.2 IU. Corresponding values during the second year were -0.9, 1.6 and 2.9. A statistically significant difference was observed between the groups receiving 0.1 IU/kg/day and 0.2 IU/kg/day during the first year of treatment, whereas no difference between the treatment groups was found during the second year. Catch-up growth, i.e. a height velocity 1 SD above the mean, was achieved for 86% of group 0.1 IU and 95% of group 0.2 IU during the first year of treatment and was maintained for 65% and 79% of the patients in group 0.1 IU and 0.2 IU respectively in the second year. GH treatment was associated with a distinct acceleration of bone age. Tolerance of treatment was good. No clear trends were seen in any of the laboratory variables. In conclusion, this study shows that daily rhGH given at a dose of 0.1-0.2 IU/kg/day for 24 months is an effective and safe therapy to increase linear growth and induce catch-up growth in short SGA children.

One-year treatment with recombinant human growth hormone of children with meningomyelocele and growth hormone deficiency: a comparison of supine length and arm span.

Growth retardation and precocious puberty are frequently found in children with meningomyelocele (MMC). Lower limb contractions, spasticity and kyphoscoliosis may lead to disproportionate short stature. Most of these patients have structural brain defects or hydrocephalus which can cause growth hormone deficiency. In this study, 19 children aged between 3.5 and 12.8 years with MMC and growth hormone (GH) deficiency were treated with recombinant human GH for a period of 12 months. Supine length, arm span and growth velocity were compared before, and after 6 and 12 months of treatment with rhGH (daily dose 2.0 IU/m2 BSA s.c.). Mean supine length standard deviation score (SDS) increased by +0.8 SDS after 6 months and +1.2 SDS after 12 months of therapy. Mean arm span standard deviation score increased by +0.9 SDS and +1.3 SDS. Growth velocity increased in supine length from 3.3 cm/yr (-2.1 SDS) to 8.4 cm/yr (+2.4 SDS) and in arm span from 4.8 cm/yr (-1.3 SDS) to 8.6 cm/yr (+3.1 SDS) in the first 6 months and was 8.1 cm/yr (+2.4 SDS) and 8.3 cm/yr (+2.6 SDS) after 12 months of therapy. Linear correlation between SDS growth velocity supine length and SDS growth velocity arm span during one year of treatment was excellent (r = 0.65, p < 0.0025). We surmise that body proportions do not deteriorate when growth velocity is stimulated in MMC patients. Both supine length and arm span measurements are necessary to document growth in children with spinal dysraphism.

Growth hormone treatment of short children born small for gestational age: metanalysis of four independent, randomized, controlled, multicentre studies.

A minority of children born small for gestational age (SGA) fail to achieve sufficient catch-up growth during infancy and remain short throughout childhood, apparently without being growth hormone (GH) deficient. The effect of GH administration was evaluated over 2 years in short prepubertal children born SGA. The children (n = 244), who were taking part in four independent multicentre studies, had been randomly allocated to groups receiving either no treatment or GH treatment at a daily dose of 0.1, 0.2 or 0.3 IU/kg (0.033, 0.067 or 0.1 mg/kg) s.c. At birth, their mean length SD score (SDS) was -3.6 and their mean weight SDS -2.6; at the start of the study, mean age was 5.2 years, bone age 3.8 years, height SDS -3.3, height SDS adjusted for parental height -2.4, weight SDS -4.7 and body mass index (BMI) SDS -1.4. The untreated children had a low-normal growth velocity and poor weight gain. Although bone maturation progressed more slowly than chronological age, final height prognosis tended to decrease, according to height SDS for bone age, GH treatment induced a dose-dependent effect on growth, up to a near doubling of height velocity and weight gain; BMI SDS was not altered. Bone maturation was also accelerated differentially; however, final height prognosis increased in all GH treatment groups. The more pronounced growth responses were observed in younger children with a lower height and weight SDS. In conclusion, GH administration is a promising therapy for normalizing short stature and low weight after insufficient catch-up growth in children born SGA. Long-term strategies incorporating GH therapy now remain to be established.

Growth hormone treatment of short children born small for gestational age: reappraisal of the rate of bone maturation over 2 years and metanalysis of height gain over 4 years.

A minority of children born small for gestational age (SGA) fail to achieve sufficient catch-up growth during infancy and remain short throughout childhood, apparently without being growth hormone (GH) deficient. A previous metanalysis of four trials revealed that GH treatment over a period of 2 years induced a dose-dependent acceleration of linear growth and, to a lesser extent, of the rate of bone maturation in short, prepubertal children born SGA. The rate of bone maturation and the change in height SDS for bone age from the previous 2-year metanalysis have been re-analysed according to chronological age (two prepubertal age groups: group A, 3.0-5.9 years old; group B, 6.0-8.9 years old). The rate of bone maturation was slower in younger than in older prepubertal children; this difference was more marked in children receiving high-dose (0.2 or 0.3 IU/kg/day) GH treatment (p < or = 0.01). Accordingly, the change in height SDS for bone age was increased by high-dose GH treatment in both age groups (p < or = 0.01), and was more pronounced in younger than in older children (1.45 +/- 0.28 versus 0.63 +/- 0.20; p < or = 0.01). Height SDS data from 100 short, prepubertal children born SGA have been analysed over 4 years. The change in height SDS appeared to be related to the average dose of GH. A mean GH dose of 0.1 IU/kg/day over 4 years was administered either as 0.1 IU/kg/day for 4 years (continuous) or as 0.2 IU/kg/day for 2 years, followed by 2 years without GH treatment (discontinuous). After 4 years of treatment, the increase in height SDS for the continuous and discontinuous treatment schedules was similar, being 1.42 +/- 0.10 SDS and 1.58 +/- 0.17 SDS, respectively. In a second regimen, a mean GH dose of 0.2 IU/kg/day over 3 years was administered either as 0.2 IU/kg/day for 3 years (continuous) or as 0.3 IU/kg/day for 2 years, followed by 1 year without GH treatment (discontinuous). After 3 years, the increase in height SDS with the continuous and discontinuous treatment schedules was similar, being 2.01 +/- 0.18 SDS and 2.22 +/- 0.16 SDS, respectively. GH administration was well tolerated in all treatment groups. In conclusion, the rate of bone maturation in short, prepubertal children born SGA treated with GH appeared to depend not only on the dose of GH, but also on the age of the child. GH treatment resulted in a prolonged increase in height SDS, the magnitude of the rise being dependent on the average GH dose rather than on the continuous or discontinuous mode of GH administration.

[Measles. A viral illness with risk of permanent damage]. / Masern. Eine Viruserkrankung mit Risiko bleibender Schäden.

Measles is a highly contagious exanthematous disease. After an incubation period of almost two weeks, catarrhal prodromic, associated with initial attacks of fever appear. Typical manifestations are Koplik's spots. The exanthema appears together with the second rise in temperature. The illness confers lifelong immunity. In individual cases, an encephalitis resulting in permanent neurological deficits must be expected. Every effort should be made to prevent this condition from arising. To this end, immunization with a combination measles, mumps, rubella (MMR) vaccine is recommended.

[Nocturnal growth hormone secretion in children with constitutional and acquired developmental delay]. / Nächtliche Wachstumshormonsekretion bei Kindern mit konstitutioneller und erworbener Entwicklungsverzögerung.

We investigated the spontaneous secretion of GH during sleep (20.00 to 8.00) in 76 children with short statute. No difference could be found between a group of 12 children with familiar short stature or a group of 28 children with familial delay of growth and development: mean GH level 5.88:5.71 maxima 26.9:25.4 ng/ml, and integrated concentration of GH 2360:2617 ng x min/ml. 14 children with severe growth hormone deficiency proven by 2 stimulation tests, secreted significantly lower amounts of GH (mean 0.83 ng/ml, maximum 2.9 ng/ml, integrated concentration 371 ng x min/ml). 22 children with nonfamilial delay of growth and development presented values being lower than the first two groups, but higher than the group of GH deficiency patients (mean 3.07 ng/ml, maximum 13.8 ng/ml, integrated concentration 1429 ng x min/ml). Since in these children the anamnesis revealed events like breech delivery, shock or commotio cerebri as the history of patients with GH deficiency does, these events apparently cause the defective GH secretion in nonfamilial delay of growth and development.

[Therapy of endocrine diseases in childhood and adolescence. 1. Goiter in childhood]. / Die Therapie endokriner Erkrankungen im Kindes- und Jugendalter. 1. Teil: Struma im Kindesalter.

Euthyroid or hypothyroid goitre in childhood is due to hyperstimulation by TSH in iodine deficiency or inborn errors of thyroid hormone synthesis. Hyperthyroid goitre results from presence of LATS. Hashimoto's strumitis may be hypo- or hyperthyroid. Therapy consists of iodine, thyroxine in hypothyroid goitres or in thyrostatic suppression in hyperthyroid goitres. Whereas hypothyroidism requests lifelong therapy, hyperthyroidism requires therapy for 1 to 2 years if successful. Otherwise, operative procedures are necessary.

[Therapy of endocrine diseases in childhood and adolescence. 2. Connatal athyreosis. 3. Diabetes insipidus neurohormonalis]. / Die Therapie endokriner Erkrankungen im Kindes- und Jugendalter. 2. Teil: Konnatale Athyreose, 3. Teil: Diabetes insipidus neurohormonalis.

Congenital athyreosis may be due to different though mostly unknown factors. It should be diagnosed by TSH-screening. Immediate therapy consists of supplementation of thyroxin. The dose should be adjusted to the child's needs controlled by normal growth and bone age advance, normalization of TSH and thyroxin levels in serum. The goal must be to reach normal intelligence. Therapy should be continued during the entire life. Absence of adiuretin is the cause for diabetes insipidus neurohormonalis due to genetic disorders, tumor or infection of the hypothalamo-pituitary system. The disorder is best treated with synthetic desamino-8-vasopressin (minirin, alternatively with an oily suspension of pitressin). Diabetes insipidus renalis and psychogenic polydipsia should be ruled out before this therapy is started.

[Therapy of endocrine diseases in childhood and adolescence. 4: Hypophyseal dwarfism]. / Die Therapie endokriner Erkrankungen im Kindes- und Jugendalter. Teil 4: Hypophysärer Minderwuchs.

A deficiency in growth hormone depresses growth and leads to dwarfism. The cause of hypopituitarism may be the destruction of the hypothalamus by a tumor infection or trauma. Birth trauma is often the underlying cause. Genetic forms or cerebral defects have also been described. Growth hormone may be completely lacking or partially reduced. Neurohormonal dysfunction is of particular interest. Administration, either intramuscular or subcutaneously, of human growth hormone leads initially to "catch-up" growth and to subsequent normal growth. Early treatment should be instituted if normal adult height is to be achieved.

[Delay of constitutional development--studies on therapy with growth hormone]. / Die Konstitutionelle Entwicklungsverzögerung--Untersuchungen zur Therapie mit Wachstumshormon.

Human growth hormone was given to 6 boys with constitutional delay of growth and development. Three patients had normal growth hormone responses following exercise or insulin-induced hypoglycemia. Subnormal growth rate (less than 2 SD below normal for bone age) was found in 4 patients. The mean growth rate of the patients treated with 12 U hGH/m2 per week increased from 4.6 to 5.1 cm/year which is not significant. Only 2 boys responded with an increment of the growth rate of more than 1 cm/year. In an age-matched control group with the same growth variation the growth rate was 4.9 and 5.0 cm/year during the same time periods. It can not be recommended to treat patients with constitutional delay of growth and development with hGH except those with severely depressed growth rate and subnormal spontaneous growth hormone secretion during sleep.