Is the response to growth hormone in short children born small for gestational age dependent on genetic or maternal factors?

BACKGROUND/AIMS: We investigated whether genetic or maternal/environmental risk factors for being born small for gestational age (SGA), e.g. Silver-Russell syndrome, congenital heart defects, infections of mothers or smoking during pregnancy, explain the variation in the first-year growth response to GH therapy. METHODS: Secondary analysis was made of growth response in 135 short prepubertal German children (66% males) enrolled in a SGA phase III trial. Initial mean patient age was 6.8 +/- 2.6 years; mean patient height SDS -3.8 +/- 1.2, and GH treatment dose was 0.066 mg/kg body weight per day. RESULTS: Growth velocity increased by 4.5 +/- 2.0 cm/year and height SDS by 1.0 +/- 0.5 SDS. Although patient number was limited and variation was high, both growth response (cm/year) and change in height SDS did not appear to differ between subgroups which also did not differ in terms of Studentized residuals set up in the KIGS growth prediction model for SGA. Likewise, in a step-forward multivariate analysis, the variables Silver-Russell syndrome, congenital heart defects, infections of mothers and smoking were not identified as independent factors influencing growth velocity. CONCLUSION: The retrospectively analyzed genetic and maternal/environmental risk factors for SGA do not appear to explain the observed patient variance in response to GH. Larger prospective studies are needed, however, to substantiate these preliminary findings.

Adult height after GH therapy in 188 Ullrich-Turner syndrome patients: results of the German IGLU Follow-up Study 2001.

OBJECTIVES: We aimed to evaluate the factors influencing true adult height (HT) after long-term (from 1987 to 2000) GH treatment in Ullrich-Turner syndrome (UTS) based on modalities conceived in the 1980s. DESIGN: Out of 347 near-adult (>16 Years) patients from 96 German centres, whose longitudinal growth was documented within KIGS (Pharmacia International Growth Database), 188 (45, X=59%; bone age >15 Years) were available for further anthropometric measurements. RESULTS: At a median GH dose of 0.88 (10th/90th percentiles: 0.47/1.06) IU/kg per week, a gain of 6.0 (-1.3/+13) cm above the projected adult height was recorded. Variables were recorded at GH start, after 1 Year GH, puberty onset, and last visit on GH therapy. At these visits, the median ages were 11.7, 12.7, 14.2, 16.6 and 18.7 Years; and median heights, 0.4, 1.1, 1.7, 1.7 and 1.3 SDS (UTS) respectively. Height gain (DeltaHT) after GH discontinuation was 1.5 cm. Total DeltaHT correlated (P<0.001) negatively with bone age and HT SDS at GH start, but positively with DeltaHT after the first Year, DeltaHT at puberty onset, and GH duration. Final HT correlated (P<0.001) positively with HT at GH start, first-Year DeltaHT, and HT at puberty onset. Body mass index increased slightly (P<0.05), with values at start and adult follow-up correlating highly (R=0.70, P<0.001). No major side effects of GH occurred. CONCLUSIONS: GH dosages conceived in the 1980s are safe but too low for most UTS patients. HT gain and height are determined by age and HT at GH start. Height gain during the first Year on GH is indicative of overall height gain. After spontaneous or induced puberty, little gain in height occurs.

Favorable final height outcome in girls with Ullrich-Turner syndrome treated with low-dose growth hormone together with oxandrolone despite starting treatment after 10 years of age.

The objective of this study was to find out whether moderate doses of growth hormone (GH) in combination with oxandrolone (Ox) and late initiation of puberty could improve adult height even in relatively old patients with Ullrich-Turner syndrome (UTS). Ninety-one patients with UTS were randomly assigned to receive either GH alone (Saizen, Ares-Serono, Geneva) 18 IU/m2/week (0.2 mg/kg/week) by daily s.c. injections (group GH) or a combination of GH and Ox 0.1 mg/kg/day p.o. (group GH + Ox). Prior to treatment mean age was 10.2 years (GH) and 10.5 years (GH + Ox), mean projected adult height (PAH) was 146.4 cm (GH) and 146.7 cm (GH + Ox). During year 2 the GH dose was increased in the GH group to 24 and later to 28 IU/m2/week (0.27 mg and later 0.31 mg/kg/week). In group GH + Ox, the Ox dose was reduced to 0.05 mg/kg/day after the first 12 months of therapy, and during the last treatment years the GH dose was raised to 24-28 IU/m2/week (0.27-0.31 mg/kg/week) due to declining growth promotion. Some of the patients of group GH were later given Ox in addition to GH because of waning growth velocity, whereas some of the patients of group GH + Ox were taken off Ox due to virilizing side-effects of the high Ox dose, thus making up a third group of patients: group GH + transient Ox. Puberty was induced at a mean age of 14.9 years. In group GH + Ox, cumulative growth during 5 years of therapy was twice the growth anticipated from standards of untreated patients with UTS. Forty-seven patients are now near or at final height: in group GH (n = 7), mean final height was 151.7 cm (PAH 148.1 cm, gain 3.6 cm); in group GH + Ox (n = 15), 155.1 cm (PAH 147.2 cm, gain 7.9 cm); and in group GH + transient Ox (n = 25), 152.8 cm (PAH 146.4 cm, gain 6.4 cm). These results should be regarded as an underestimate of true final height since some the patients are still growing. Moderate doses of GH plus Ox and late induction of puberty definitely improved final height even in patients with UTS treated relatively late.

An approach to model monitoring and surveillance data of wildlife diseases-exemplified by Classical Swine Fever in wild boar.

The analysis of epidemiological field data from monitoring and surveillance systems (MOSSs) in wild animals is of great importance in order to evaluate the performance of such systems. By parameter estimation from MOSS data, conclusions about disease dynamics in the observed population can be drawn. To strengthen the analysis, the implementation of a maximum likelihood estimation is the main aim of our work. The new approach presented here is based on an underlying simple SIR (susceptible-infected-recovered) model for a disease scenario in a wildlife population. The three corresponding classes are assumed to govern the intensities (number of animals in the classes) of non-homogeneous Poisson processes. A sampling rate was defined which describes the process of data collection (for MOSSs). Further, the performance of the diagnostics was implemented in the model by a diagnostic matrix containing misclassification rates. Both descriptions of these MOSS parts were included in the Poisson process approach. For simulation studies, the combined model demonstrates its ability to validly estimate epidemiological parameters, such as the basic reproduction rate R0. These parameters will help the evaluation of existing disease control systems. They will also enable comparison with other simulation models. The model has been tested with data from a Classical Swine Fever (CSF) outbreak in wild boars (Sus scrofa scrofa L.) from a region of Germany (1999-2002). The results show that the hunting strategy as a sole control tool is insufficient to decrease the threshold for susceptible animals to eradicate the disease, since the estimated R0 confirms an ongoing epidemic of CSF.

Impact of overweight on effectiveness of treatment with human growth hormone in growth hormone deficient children: analysis of German KIGS data.

BACKGROUND: We hypothesized that overweight children with growth hormone deficiency (GHD) demonstrate a lower response to growth hormone (GH) as a result of a misclassification since obesity is associated with lower GH peaks in stimulation tests. METHODS: Anthropometric data, response, and responsiveness to GH in the first year of treatment were compared in 1.712 prepubertal children with GHD from the German KIGS database according to BMI (underweight=group A, normal weight=group B, overweight=group C) (median age: group A, B, C: 7.3, 7.28, and 8.4 years). RESULTS: Maximum GH levels to tests (median: group A, B, C: 5.8, 5.8, and 4.0 µg/ml) were significantly lower in group C. IGF-I SDS levels were not different between the groups. Growth velocity in the first year of GH treatment was significantly lower in the underweight cohort (median: group A, B, C: 8.2, 8.8, and 9.0 cm/yr), while the gain in height was not different between groups. The difference between observed and predicted growth velocity expressed as Studentized residuals was not significantly different between groups. Separating the 164 overweight children into obese children (BMI>97th centile; n=71) and moderate overweight children (BMI>90th to 97th centile, n=93) demonstrated no significant difference in any parameter. CONCLUSIONS: Overweight prepubertal children with idiopathic GHD demonstrated similar levels of responsiveness to GH treatment compared to normal weight children. Furthermore, the IGF-I levels were low in overweight children. Therefore, a misclassification of GHD in overweight prepubertal children within the KIGS database seems unlikely. The first year growth prediction models can be applied to overweight and obese GHD children.

Leukemia in growth-hormone-treated patients: an update, 1992.

Since 1988 the number of growth hormone (GH)-treated patients has markedly increased worldwide. To date, leukemia has been observed in 31 patients during or following GH therapy and related malignancies in 2 further patients. Leukemia occurred in 10 patients in Japan, 10 in the USA, and 10 in Europe, and in 1 patient in Canada. In 29 patients GH therapy had been started in 1975 or later. The onset of leukemia was 1984 or later in 28 patients with a mean time between the start of GH therapy and leukemia onset of 5.0 (0.2-18.8) years. Patients had received both pituitary and recombinant GH in moderate doses. In 15 patients definite additional leukemia risk was evident: Fanconi anemia in 2, myelodysplastic syndrome in 1, Bloom's syndrome in 1, radiation for brain tumor (+chemotherapy) in 9, chemotherapy in 2. The leukemic patients without a strong additional risk do not represent a definitely higher leukemia incidence worldwide, except for Japan where the occurrence is higher than expected.

Replacement therapy in hypothalamus-pituitary insufficiency: management in the adolescent.

GH, formerly administered 2-3 times a week intramuscularly, is nowadays injected daily subcutaneously at a dosage of 14 IU/m2/day. In some patients, a 1.5- to 2.0-fold higher GH dosage is necessary for normal pubertal growth spurt. Though delayed initiation of puberty in additional gonadotropin deficiency may be favourable for final height, puberty should be induced in boys at bone age 12-13 years with low doses of testosterone enanthate, and in girls at bone age 12 years with low doses of ethinyl estradiol. Patients with additional ACTH deficiency should receive only a low-dose glucocorticoid replacement (but a steroid cover for physical stress situations). During GH therapy, thyroid function has to be evaluated regularly; often thyroxine replacement will be necessary.

Thyroid function in prematures with respiratory distress syndrome (RDS).

Reports on thyroid function in newborns with respiratory distress syndrome (RDS) are controversial, the significance of obtained results is not clear. Therefore we conducted a longitudinal study of thyroid function in 35 infants with RDS (gestational age 24-36 weeks, birth weights 650-2770 g). 43 well prematures, matched for gestational age, served as controls. No significant differences were observed in cord blood TSH, T3, T4, TBG values and T4:TBG ratios between infants with and without RDS. Prematures with RDS showed lower levels of T3, T4, TBG and T4:TBG at 24 hours of age and increases of TSH values at 72 hours. Subsequently these prematures exhibited a spontaneous rise in thyroid hormone levels. Even non-surviving RDS-infants had initial T3, T4, T4:TBG and TSH values within the normal range. Thyroid hormone concentrations correlated significantly with the severity of pulmonary disease. Depressed thyroid hormone levels were found to be the result and not the cause of RDS. T4 or T3 therapy is not warranted in this condition.

Recombinant human growth hormone and oxandrolone in treatment of short stature in girls with Turner syndrome.

91 girls with Turner syndrome (TS) with a mean chronological age (CA) and bone age (BA) of 10.3 +/- 2.3 and 8.9 +/- 1.9 years, respectively, were randomly assigned to subcutaneous treatment with recombinant human growth hormone (rhGH) alone (n = 47), 2.6 IU/m2 body surface area daily or combination treatment (n = 44) with the same dose of rhGH and oxandrolone 0.1 mg/kg body weight orally, for the first 12 months of this study. During the 1st year of therapy, there was a striking increase in height velocity (HV) in both groups, from 4.0 +/- 0.8 to 6.3 +/- 1.3 cm/year [HV standard (standards of untreated Turner patients) deviation score (SDS) for CA from 0.0 +/- 0.7 to 2.9 +/- 1.3] in the rhGH group and from 4.2 +/- 1.2 to 8.5 +2- 1.7 cm/year (HV SDS-CA from +0.3 +/- 1.0 to 5.6 +/- 1.6) in the combination group. The difference between the groups was statistically significant (p < 0.01). During the 2nd year of treatment, the rhGH dose was increased to 3.4 IU/m2 daily for the rhGH-alone group, whereas in the combination treatment group the oxandrolone dose was reduced to 0.05 mg/kg daily. HV was maintained at significantly higher levels than those prior to treatment, at 5.3 +/- 1.1 cm/year (HV SDS-CA: +2.1 +/- 1.3) and 6.2 +/- 1.5 cm/year (HV SDS-CA: +3.6 +/- 1.4) in the rhGH-alone and the combination group, respectively (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone therapy and leukaemia.

Following an initial report from Japan in 1987, 15 growth hormone (GH)-deficient patients developed leukaemia during or following GH treatment. Nearly all available pituitary and biosynthetic growth hormones have been used. In 14 of these 15 patients GH treatment was initiated in 1975 or later with doses between 4.5 and 18IU/m2 per week. The therapy period was between 0.17 and 8.0 years. Leukaemia occurred 0.2-11 years after the start of GH treatment. GH affects normally and abnormally growing blood cells in vitro and in animal experiments, but the clinical data in humans do not indicate GH induction of tumour growth. Seven out of the 14 patients under discussion had an additional increased leukaemia risk. Two other patients had been treated only for a very short time. Though no clear evidence of a strikingly augmented leukaemia incidence in GH-treated patients is found worldwide, the available data call for increased attention.

Psychoendocrinological studies in dwarfed children and adolescents.

Thirty-two dwarfed children and adolescents were studied clinically, by laboratory assessment, by a battery of psychological tests and a structured interview. Growth hormone deficiency was present in 16 cases, but in the remaining 16 cases there was no endocrine disease. Dwarfed children differed from nornal controls in perception, and a specific personality pattern emerged in the dwarfed children. The effects of age, sex, and socioeconomic status on personality traits were similar for dwarfs as for controls. Intelligence and personality variable were similar in dwarfs with and without endocrine disease. However, symptoms of the psychoendocrine syndrome, namely appetite and thirst disturbances, hypersensitivities, and impulse reduction, were more frequently seen among hypopituitary dwarfs. Social and coping behaviour was impaired in the majority of dwarfs. It is concluded that psychological disturbance occuring inchildren of small stature is a response to being small and is not attributable to any endocrine effect.

Effects of growth hormone on protein metabolism. Acute changes in plasma amino acids in growth retarded patients with and without growth hormone deficiency.

39 patients with growth retardation were investigated: 21 (group H) were suffering from GH deficiency and 18 (group N) had no endocrine disease except for two adequately treated patients with mild hypothyroidism. Analysis of 15 plasma amino acid concentrations was carried out before and 1 and 2 hours after intravenous HGH injection at a dosage of 2 mg per m2. Except for one amino acid no significant difference between mean pre-treatment amino acid values was observed in the two groups of patients. In group H there was a highly significant decrease in plasma concentration of 14 amino acids already 1 hour after HGH injection and of all 15 amino acids after 2 hours. This response of plasma amino acids to HGH was less pronounced in group N. For 5 amino acids a moderate correlation was found in group H between acute metabolic response to HGH and growth response to long-term HGH treatment. Our results following HGH injection may reflect increased plasma amino acid transfer into cells due to HGH.

Negative impact of growth-hormone deficiency on psychological functioning in dwarfed children and adolescents.

This study compares the psychological findings in three groups of dwarfed children and adolescents, namely those suffering from isolated growth-hormone deficiency, from multiple pituitary hormone deficiencies, and without endocrine disease. The study is based on psychometric data from one multifactorial intelligence test and several personality questionnaires. It was found that growth hormone deficiency had no impact on the psychological variables.

Action of growth hormone on erythropoiesis: changes in red blood cell enzyme activities in growth-retarded patients with and without growth hormone deficiency.

Fifteen red cell enzyme activities of growth-retarded patients with and without growth hormone (GH) deficiency were investigated before and after GH administration. The 15 enzymes were Hexokinase, phosphoglucomutase, glucose phosphate, isomerase, phosphofructokinase, fructose diphosphate aldolase, glyceraldehyde-3-phosphae dehydrogenase, triosephosphate isomerase, 2,3-diphosphoglycerate mutase, 3-phosphoglycerate kinase, 3-phosphoglycerate mutase, enolase, pyruvate kinase, glycose-6-phosphate dehydrogenase, 6-phosphogluconic dehydrogenase, glutathione reducase. Sixty-six subjects were studied: 30 normal control subjects (group N) and 36 patients (aged 5-23 years) with short stature. Complete endocrine evaluation showed 21 (group I) to have GH deficiency (10 patients with isolated GH deficiency) and 15 (group II) to have normal hypothalamic and pituitary function except for two patients with a moderate hypothyroidism. Both had been receiving thyroid hormone treatment for a long time before our studies. All 36 patients were treated with 2 mg human growth hormone intramuscularly for 7 days. Before GH treatment no significant difference was observed between hematologic data in group I (GH deficiency) and group II (no GH deficiency). After GH therapy there was a significant increase in reticulocyte count in both groups of patients with short stature. The mean pretreatment value in group I was 1.294% +/- 0.084 (SEM); the mean post-treatment value was 2.081% +/- 0.287 (SEM)< P less than 0.005. The mean pretreatment value in group II was 1.0% 0.184 (SEM); the mean post-treatment value was 1.407% +/- 0.193 (SEM), P less than 0.01. In group II (no GH deficiency) mean pretreatment erythrocyte enzyme activities were not significantly different from those activities observed in normal control subjects (group N). However, in patients who lacked GH, the pretreatment activities of five red cell enzymes (glucose phosphate isomerase, triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, 2,3-diphosphoglycerate mutase, 3-phosphoglycerate kinase) were significantly decreased before GH administration compared with the values in normal control subjects...

Precocious pseudopuberty associated with multiple ovarian follicular cysts and low plasma oestradiol concentrations.

A 6 year 11 month old girl had pseudoprecocious puberty caused by multiple ovarian follicular cysts. In contrast to previously reported patients, oestrogen levels in blood and urine were not elevated though gonadotropins were suppressed. Despite the lack of measurable oestrogen elevation the child developed distinct oestrogenic effects. After removal of large bilateral ovarian cysts endocrine aberrations normalized and precocity regressed.

Effect of cyproterone acetate (CA) on growth and endocrine function in precocious puberty.

16 girls with precocious puberty have been studied. Following low dosage cyproterone acetate (CA) therapy (mean daily dosage 65 mg/m2BSA) a beneficial effect on growth and skeletal maturation was observed. During high dosage therapy (150 mg/m2 per day) endocrinological studies were performed in 10 of these patients. There was no significant difference in HGH levels (insulin- and arginine-test), T3 and TSH values (TRH-test) between patients and controls, T4 concentration was significantly increased. Basal prolactin levels and prolactin response to TRH was definitely elevated. Oral glucose load and arginine infusion resulted in a significantly enhanced insulin release. There was a significant reduction in basal LH levels and an increase in FSH response to LH-RH. Basal and diurnal plasma cortisol values were markedly reduced and the cortisol release due to corticotrophin injection, lysinevasopressin (LVP) injection and insulin-hypoglycemia as well. A definite increase in basal ACTH levels was observed, during LVP- and insulin-hypoglycemia test ACTH concentrations were within or significantly above normal range. In our patients a primary adrenocortical insufficiency due to CA treatment was evident.

[More recent aspects of treatment for hypothyroidism and goitre in children and adolescents (author's transl)]. / Neuere Gesichtspunkte zur Behandlung der Hypothyreose und "blanden" Struma bei Kindern und Jugendlichen

According to more recent knowledge L-thyroxine alone is recommended for thyroid hormone replacement therapy, no longer the combination of L-thyroxine and triiodothyronin, since L-thyroxine is converted to triiodothyronine in the periphery of the body. Additional application of triiodothyronine causes unphysiological elevations of blood levels of triiodothyronine. When changing from the combined thyroid hormone therapy to treatment with L-thyroxine alone it is enough in most cases to replace the previous amount of L-thyroxine only; previous recommendations for the dosage of thyroid hormone were rather high. Average requirements of adults for L-thyroxine are around 170 mug per day. Children need about 90--100 mug per m2 body surface per day. -- When hypothyroidism is suspected in newborns or infants no protracted diagnostic procedures are justified with respect to brain development and its requirement of thyroid hormone during this period of life. Replacement therapy should be started within 1--2 days. The exact diagnosis can be established later, for instance during the third day of life when a temporary interuption of treatment for diagnostic purposes has no longer such negative effect on normal brain development. As long as physiological doses of L-thyroxine are used no side effects are to be expected for patients who later turn out to be euthyroid. -- Following exclusion of hyperthyroidism goitres in children and adolescents equally need thyroid hormone replacement therapy to reduce the size or prevent further enlargement or even the development of nodules within the gland. The dosage for this is about half to three quarters of the full replacement dose. The nature of thyroid nodules should be investigated, even surgically, since malignancies can develop in children and juveniles as well as in adults.

Long-term follow-up of children with craniopharyngioma.

Management of craniopharyngiomas is still controversial. 28 children with this tumor were studied. GH deficiency was present in 22 patients following surgery, 10 of these GH-lacking patients had normal or accelerated growth (usually associated with rapid weight gain) postoperatively. Somatomedin levels were normal in three of six normally growing patients. After craniotomy their basal and TRH-stimulated prolactin levels were in the normal range, but their insulin secretion was markedly increased. Postoperatively there was a significant correlation between peak insulin levels following arginine infusion and growth velocity in all patients. Complete tumor removal could be performed in 28% of our patients. Altogether 36% of all patients had at least one tumor recurrence. Recent literature with the addition of our series showed tumor recurrence in 22% of patients with "total" tumor excision and in 72% of patients with partial tumor removal. Radiotherapy seems to be capable of destroying craniopharyngioma tissue. The recurrence rate was only 26% in patients with subtotal excision plus radiotherapy. Unless radical tumor removal can be attempted with safety, subtotal tumor removal plus radiotherapy appears to be the treatment of choice for craniopharyngioma.