Insulin secretion in children with growth retardation

The effect of tolbutamide administration on insulin secretion was studied in 69 children with growth retardation. Diminished insulin secretion was found in all the patients, compared to the control group. This insulin deficit was most evident in patients with isolated, total GH deficiency and least evident in children with idiopathic short stature. Intermediate values were found in dwarfism due to isolated, partial GH deficiency.These results favour the hypothesis that hypoinsulinism contributes to the somatotropin deficiency in causing growth retardation.Abbreviations PD pituitary dwarfism - FSS familial short stature - GR growth retardation - GH growth hormone - ISS idiopathic short stature - tbt tolbutamide - GHtd isolated, total GH deficiency - GHpd isolated, partial GH deficiency     

Interactions between the thyroid hormones and the hormones of the growth hormone axis

The normal secretion and action of the thyroid hormones and the hormones of the GH/IGF-I (growth hormone/ insulin-like growth factor I) axis are interdependent. Their interactions often differ in man from animal studies in rodents and sheep. Thus neonates with congenital hypothyroidism are of normal length in humans but IUGR (intrauterine growth retardation) in sheep. Postnatally normal GH/IGF-I secretion and action depends on an euthyroid state. Present knowledge on the interactions between the two axes is reviewed in states of hypo- and hyperthyroidism, states of GH/IGF-I deprivation and hypersecretion, as well as the relationship between IGF-I and thyroid cancer. Emphasis is given to data in children and aspects of linear growth and skeletal maturation.     

Caloric restriction for 24 hours increases mean night growth hormone.

In obesity, serum growth hormone (GH) is usually low, confounding GH assessment of short obese children. We evaluated whether 24-h caloric restriction would permit better discrimination between normal GH secretion and GH deficiency (GHD) by elevating night GH levels. DESIGN AND PATIENTS: Serum was obtained every 20 minutes 2000-0800 h before and 2200-0400 h after 24 hours of caloric restriction (8% of usual calories) in 24 normal height children [14 normal (weight for height 10-90th percentile); 10 obese (weight for height > 95th percentile)] and in 31 short children (height shorter than -2.0 SD below mean for age). All samples from both nights per child were assayed for GH simultaneously to eliminate interassay variability. RESULTS: Mean GH increased significantly in all groups after caloric restriction (P < 0.01). Obese children had lower baseline mean GH and GH amplitude compared to normal (P < 0.01); GH increased into normal range after restriction. Basal GH studies in short children were not significantly below normal. Surprisingly, some with low stimulated GH increased their night GH into the normal range after caloric restriction. CONCLUSIONS: Caloric restriction for 24 h enhances night GH similarly in short and in normal children, and thus does not increase the diagnostic utility of night GH studies in non-obese short children. Caloric restriction reverses suppressed GH secretory state of obese children, perhaps by decreasing diet-dependent somatostatin inhibition of GH secretion.     

Investigation of Growth Hormone Secretion in Patients with Intrauterine Growth Retardation

Rochiccioli, P., Tauher, M., Moisan, V. and Pienkowski C. (Department of Paediatrics, CHU Rangneil, Toulonse Cedex, France). Investigations of growth hormone secretion in patients with intrauterine growth retardation. Acta Paediatr Scand [Suppl] 349: 42, 1989.
Growth hormone (GH) deficiencies have rarely been reported in intrauterine growth retardation (IUGR). This study has investigated GH secretion using GH provocation tests, 24-hour GH secretory profiles, and insulin-like growth factor I (IGF-I) measurements in 24 children with intrauterine growth retardation. The criteria for diagnosis were a birth length and weight below the 10th percentile for gestational age. The average age at investigation was 5.5 years, and the average growth retardation was -3.3 SD. Twenty children had shown catch-up growth between the ages of 6 months and 3 years, followed by varying decreases in growth velocity. Studies of GH secretion demonstrated GH deficiency in 16 patients, with neurosecretory dysfunction in six. Treatment with pituitary GH in nine children increased mean growth velocity from 3.5 cm/year to 7 cm/year. GH therapy should thus be effective in improving the height prognosis of children with intrauterine growth retardation.     

Short-term gluten challenge in children with coeliac disease does not impair spontaneous growth hormone secretion

BACKGROUND: Growth retardation in children with coeliac disease has been attributed to impaired growth hormone (GH) secretion observed in stimulation tests. OBJECTIVE: This study aimed at investigating the possible change in spontaneous GH secretion during a standardised gluten challenge. PATIENTS: Twelve children with previous enteropathy suggesting coeliac disease and a normal pre-challenge biopsy on a gluten-free diet were included; eight of them completed all parts of the study, including repeated 24-h GH sampling. METHODS: At the start and the end of a 5-6 weeks standardised gluten challenge, blood was drawn at a constant rate for 24 h and collected for GH analysis at 20-min intervals. The graph of plotted GH values was analysed by means of a computer program (PULSAR). RESULTS: No significant changes were seen in the measures of maximum GH peak, baseline GH values, area under the curve over the baseline (AUCb), the number of GH peaks or mean GH concentration. GH secretion rate (GHt) increased slightly. None of the characteristics of the 24-h profile was significantly correlated to the change of IGF-I. CONCLUSION: No impaired GH secretion was found. Thus, we speculate that decreased growth rate in celiac disease may not be primarily caused by changes in GH secretion. Instead it may be caused by changed peripheral sensitivity to GH.     

Growth and endocrine disorders secondary to cranial irradiation

External cranial radiation for the treatment of malignant diseases has become a frequent cause of growth hormone deficiency (GHD). The timing of occurrence and the frequency of GHD were related to the hypothalamic-pituitary radiation dose. Frequency varied from 50% in leukemia (2400 cGy) to 75% in face and neck tumors or medulloblastoma (2500-4500 cGy) and up to 100% in optic glioma (greater than 4500 cGy). The significantly more severe growth deficit in patients with GHD given higher radiation doses suggests different levels of residual GH secretion according to radiation dosage. The minimum harmful radiation dose is probably close to 1800-2000 cGy. Our data show that stimulation tests remain a useful means of defining GHD and predicting growth. A fair agreement between GH secretion and growth was found in most cases, regardless of the radiation dose. The only exception was a group of leukemic children (2400 cGy) who achieved normal prepubertal growth despite a low GH response. The 24-h spontaneous plasma GH profiles and IGF-I measurements may add information if growth is retarded despite a normal GH response. We showed that growth retardation occurring after some schedules of total body irradiation was not due to GH deficiency but rather to radiation-induced skeletal lesions. Early or true precocious puberty, generally associated with GHD, was another cause of height loss. As the role of GH deficiency in the final height reduction was demonstrated in all groups of patients after cranial radiation, we suggest that hGH therapy should be considered in any child with proven GH deficiency and significant growth retardation after such radiation.     

Growth hormone status in six children with fetal alcohol syndrome

Objective: Prenatal alcohol exposure may cause fetal alcohol syndrome (FAS), which is associated with pre- and postnatal growth retardation. Materials and methods: Spontaneous 24-h growth hormone (GH) secretion was measured in six prepubertal short children with FAS (two boys and four girls) aged 4-14 years. The response to a GH stimulation test, and levels of insulin-like growth factor-I (IGF-1) and IGF-binding protein-3 (IGFBP-3) were also measured. Comparisons were made between the children with FAS and healthy children of both normal and short stature, as well as children born small for gestational age (SGA). Results: There were no differences in the mean area under the curve above the baseline or the maximum level of GH during a 24-h period (GH_max) between the children with FAS and the reference groups. However, the estimated rate of spontaneous 24-h GH secretion in children with FAS was similar to that of children born SGA, but lower than in children of normal stature ( p = 0.02). The plasma concentrations of IGF-1 and IGFBP-3 were in the lower parts of the normal range. Conclusion: We conclude that GH secretion in short children with FAS is similar to that in short children born SGA; that is, in the lower range of normal children.     

Difficult hGH treatment in a patient with type III glycogen storage disease

The case of a boy affected by type III glycogen storage disease and total GH deficiency is reported. Substitutive treatment with hGH caused an extreme elevation of blood lipids. His lipid profile returned near to basal values 1 month after treatment was discontinued. The association of growth hormone and amylo-1-6-glucosidase deficiencies is unusual and difficult to treat; however growth hormone deficiency should be considered in patients with hepatic glycogenoses and severe growth retardation.Abbreviation GH growth hormone     

Growth response to growth hormone therapy following cranial irradiation

The growth response to growth hormone (GH) therapy has been studied in 12 children who received irradiation to the cranium alone either for brain gliomas, distant from the hypothalamic-pituitary axis, or as prophylaxis against CNS leukaemia. Seven children have completed GH treatment (mean duration 4 years) and five are presently on GH (mean duration 1.2 years). This response has been compared to that seen in 14 children with isolated idiopathic GH deficiency (IGHD), following GH therapy. Before treatment, the cranially irradiated patients (C-PRGHD) had higher standard deviation scores (SDS) for standing height, sitting height and leg length, and less bone age (BA) retardation, but started treatment at a similar age, and with a similar pre-treatment growth velocity and GH peak to standard provocative tests, compared to IGHD patients. GH produced a significant and similar increase in growth velocity (cm/year and SDS for BA) over the first 2 years' treatment in both groups. However C-PRGHD patients entered puberty and thus completed growth earlier than the IGHD group. As a result, cranially-irradiated children showed no change in height SDS with GH therapy, compared to catch-up growth in IGHD. Nevertheless, GH has enabled C-PRGHD patients to maintain their centile position and to achieve a more acceptable final height.Abbreviations GH growth hormone - IGHD idiopathic growth hormone deficiency - C-PRGHD post cranial-irradiation growth hormone deficiency - SDS standard deviation score - BA bone age - ALL acute lymphatic leukaemia - TSH thyroid stimulating hormone - CA chronological age - HA height age     

Glucocorticosteroids and growth hormone secretion under physiological conditions and in states of steroid excess

Cortisol and growth hormone (GH) secretion (spontaneous variations at night and the release induced by insulin hypoglycaemia) were investigated in 69 children and adolescents. Statistical analysis of approximately 600 pairs of cortisol and GH values in this study demonstrated that physiological fluctuations of cortisol do not alter GH secretion.A review of the literature shows that GH secretion is consistently depressed in Cushing's disease of central origin and in Cushing's syndrome due to adrenal carcinoma. When acutely administered, doses higher than 100 mg of cortisol (or equivalent amounts of other steroids) per adult are necessary to block GH secretion and the hormones have to be given several hours previously. In long-term steroid treatment, suppression of GH is observed in only 1 out of 3 patients. The effect apparently does not persist beyond elimination of the last dose, i.e. generally not longer than 12 to 24 h. These data can be taken as a rationale for intermittent or alternating dosage schedules, and for the use of short acting derivatives if long-term, high-dose steroid treatment is necessary in children.It remains to be established whether growth deficiency in exogenous hypercortisolism is due to suppression of GH secretion, decreased production of somatomedins, direct antagonism of the action of somatomedins on growing cartilage, or a combination of these mechanisms.Supported by Deutsche Forschungsgemeinschaft (Mu 254/5)In part presented at the Joint meeting, ESPR, ESPE, WGMM, Rotterdam, 1976Dedicated to Professor H. Bickel on the occasion of his 60th birthday     

Neurosecretory Dysfunction of Growth Hormone Secretion in Thalassemia Major

ABSTRACT. The growth retardation of children with thalassemia major is multifactorial. Along the endocrine axis of growth hormone (GH), serum somatomedin has been shown to be deficient and GH response to GH-relasing hormone impaired, while GH response to provocative stimuli is normal. We studied the spontaneous secretion of GH in seven patients with thalassemia major and growth retardation. Three of the patients were hypothyroid, and the other four were euthyroid. Spontaneous secretion of GH in all seven patients was subnormal: the number of pulses, the mean pulse amplitude, and the integrated concentration of GH were all lower than in 14 age- and sex-matched (10 pubertal and 4 prepubertal) control subjects. GH response to provocative stimuli was normal in the euthyroid patients. This pattern of response corresponds with the definition of neurosecretory dysfunction of GH secretion. It is concluded that the growth retardation of patients with thalassemia major is partly due to neurosecretory dysfunction of GH secretion.     

Neurosecretory dysfunction of growth hormone secretion in thalassemia major

The growth retardation of children with thalassemia major is multifactorial. Along the endocrine axis of growth hormone (GH), serum somatomedin has been shown to be deficient and GH response to GH-releasing hormone impaired, while GH response to provocative stimuli is normal. We studied the spontaneous secretion of GH in seven patients with thalassemia major and growth retardation. Three of the patients were hypothyroid, and the other four were euthyroid. Spontaneous secretion of GH in all seven patients was subnormal: the number of pulses, the mean pulse amplitude, and the integrated concentration of GH were all lower than in 14 age- and sex-matched (10 pubertal and 4 prepubertal) control subjects. GH response to provocative stimuli was normal in the euthyroid patients. This pattern of response corresponds with the definition of neurosecretory dysfunction of GH secretion. It is concluded that the growth retardation of patients with thalassemia major is partly due to neurosecretory dysfunction of GH secretion.     

Twenty-four-hour profile of growth hormone in cyclic nocturnal total parenteral nutrition

OBJECTIVE: To detect the effect of the loss of alimentation rhythmicity on a circadian rhythm of human growth hormone (HGH) secretion, a 24-hour profile of HGH was studied in a growing child on cyclic nocturnal total parenteral nutrition (TPN). Twenty-four-hour profiles of substrates and metabolic hormones were also studied to evaluate the efficiency of cyclic nocturnal TPN on childhood growth. STUDY DESIGN: Periodic blood samples from a child with megacystis-microcolon-intestinal-hypoperistalsis syndrome were obtained on five occasions, at ages 6, 7, 8, 9, and 11, when she was on cyclic nocturnal TPN. RESULTS: Peak HGH secretion appeared with the onset of deep sleep despite the concomitant hyperglycemia and hyperinsulinemia induced by TPN at night. Smaller peaks of HGH were also observed during the noninfusion period during the day. Twenty-four-hour profiles of substrates and metabolic hormones indicated a switch from glucose use during the infusion phase to an oxidation of lipids during the noninfusion period. CONCLUSION: The fact that the patient's growth curve remains within normal limits suggests that cyclic nocturnal TPN would be an efficient method of nutritional support. During cyclic nocturnal TPN, regular rhythm of HGH secretion occurs, and normal childhood growth is achieved.     

Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably

We have compared the growth and the body composition in children with Prader-Willi syndrome (PWS) with and without growth hormone treatment (recombinant GH 0.1 IU/kg/day) after a 1-y period. Twenty-nine prepubertal children with PWS, with mean body mass index (BMI) SDS of 2.2, and 10 (control) healthy obese children with mean BMI SDS of 5.6, underwent 24-h frequent blood sampling. Both PWS and control obese children had low and similar GH levels (0.7 /ng/l ± 0.4 SD). Serum IGF-I levels, however, were significantly lower in children with PWS (-1.5 SDS ± 0.8 SD vs -0.2 SDS ±0.8 SD). The 29 PWS children were randomized into 2 groups of 15 and 14 subjects for GH treatment and no treatment, respectively. Height velocity increased from -1.9 SDS to + 6.0 SDS in the treated group ( p < 0:001) and decreased from -0.1 SDS to -1.4 SDS in the control PWS group during the study year. BMI decreased significantly for the treated group (+3.0 SDS to + 2.0 SDS). Relative fat mass decreased significantly, while fat-free mass increased ( p < 0:001) for the treated group. No significant changes were noticed in body composition in the control PWS group. In conclusion, the low spontaneous 24-h GH secretion, regardless of body weight, and the exceptional response to growth hormone treatment together with the finding of low IGF-I levels suggest that growth hormone deficiency is a common feature of PWS, as a result of hypothalamic dysfunction. Treatment with growth hormone is beneficial for the majority of PWS children.     

Growth hormone secretion in children and adolescents with familial tall stature

Sixty-five patients (22 boys and 43 girls) presenting with familial tall stature were investigated with regard to growth hormone (GH) secretion, both physiological and after stimulation with thyrotropin releasing hormone (TRH) and growth hormone relasing hormone (GHRH). Plasma insulin-like growth factor-I (IGF-I) was also measured. Two groups of patients were distinguished according to their physiological secretion of GH: a high secretory group (n=49) with a mean 24 h integrated concentration of GH (IC-GH) of 5.4±2.3 g/l per minute and a large number of peaks (5.1±1.6 in 24 h), and a low secretory group (n=16) with a mean 24 h IC-GH of 2.1±0.5 g/l per minute and few peaks (3.3±1.3 in 24h). Plasma IGF-I levels and GH peak values after the TRH test were significantly higher in the high secretory group. These results indicate that familial tall stature is the consequence either of hypersecretion of GH or of hypersensivity to this hormone (IGF-I levels being normal in spite of low GH levels).     

Empty sella in short children with and without hypothalamic-pituitary abnormalities

A study was conducted on growth hormone (GH) response to oral clonidine (0.15 mg/m²), GH and cortisol responses to i.m. glucagon (0.1 mg/kg), and glucose response to an oral load of glucose (1.75 g/kg). Measurements were made on the circulating concentrations of free thyroxine (FT4), thyroid stimulating hormone (TSH) and different growth parameters and CT sellar images in 25 GH deficient children (Peak GH response to clonidine and glucagon<7 ug/ml), 15 growth retarded children (Ht<5th percentile for age and gender) with sickle cell disease (SCD) and GH deficiency, 30 randomly selected children with normal variant short stature (NVSS) (HtSDS 2SD below the mean for age and gender with normal GH response to stimulation (>10 ug/ml) and 20 age-matched normal children were evaluated. Out of the 25 children with GH deficiency, five had multiple pituitary hormonal deficiency (GH<TSH and/or ACTH. deficiencies), and 20 had isolated GH deficiency. Empty sella, either complete or partial, was detected in 9 out the 20 children with isolated GH deficiency (45%), 4 out of the 5 children with multiple pituitary deficiency (80%), all the children with SCD and GH deficiency (100%), 3 out of the 30 children with NVSS (10%) and in none of the normal children. The insulin-like growth factor-1 (IGF-I) concentrations were significantly lower in the two groups of children with GH deficiency compared to those with NVSS. The height standard deviation scores (HTSDS) were significantly lower and the annual growth velocity was slower in children with idiopathic GH deficiency and empty sella compared to those with NVSS and those with empty sella associated with SCD. The bone age delay (yr) did not differ among the 3 groups of children with short stature. All children with isolated GH deficiency associated with empty sella had normal body mass indices (BMI), while all the children with SCD and empty sella had BMI below the 5th percentile for the corresponding age and gender. None of the children had glucose intolerance. In conclusion, children with growth retardation and abnormal hypothalamic pituitary functions have high incidence of empty sella. However, empty sella is detected in considerable number (10%) of short children with normal hypothalamic pituitary function.     

Growth hormone secretion following administration of growth hormone releasing hormone in constitutional short stature and idiopathic growth hormone deficiency

A stimulation test using 1 microgram growth-hormone-releasing factor (GRF 1-29 X NH2)/kg bodyweight was performed in children with familial short stature and in children with constitutional delay of growth and development. The GH secretion induced by this means was not different in these groups, but there was a difference in the response between normal children and children with idiopathic growth hormone deficiency (GHD). GH secretion after GRF administration was significantly lower in the GHD group than in the other groups. However, 6 of 24 patients with GHD responded to the test with a normal increase in GH (greater than 10 ng/ml), and 11 with an intermediate response (2-10 ng/ml). Thus, the test does not differentiate individual patients with defective growth hormone secretion from normal short children.     

Age-Related Changes in Urinary Growth Hormone Level and Its Clinical Application

In order to establish the normal range of urinary growth hormone (GH) level for age and sex, which is important in the clinical application of urinary GH to diagnosis, we measured GH in the first morning urine specimens of 270 normal subjects aged 3 to 20 years. Urinary GH levels in patients wit documented GH deficiency were compared with those of the normal controls. In normal subjects, urinary GH levels showed a statistically significant change with age. They were relatively high in infancy and mid-puberty, reaching a peak at 11 to 12 years in girls and at 13 to 14 years in boys. Urinary GH levels in patients with complete GH deficiency were apparently lower (<-2.0SD) than those of the normal hildren, while the levels in patients withpartial GH deficiency overlapped with the normal range. When assessing GH secretion by using urinary GH measurement, consideration of age and sex is required, since the level changes isgnificantly wit these factors.     

Growth hormone deficiency, brain development, and intelligence.

Twenty-nine patients with growth hormone (GH) deficiency were selected according to the following criteria: no evidence of reversible GH deficiency, onset of growth retardation in early childhood, and no evidence of pituitary tumors or other direct pituitary trauma. Fourteen patients had evidence of multiple hormone deficiencies, 14 had isolated GH deficiency, and one patient questionable isolated GH deficiency. Psychometric testing showed a normal IQ distribution. The GH deficiency was not associated with deficiencies in specific mental abilities. Likewise, GH treatment in later childhood and adolescence did not seem to influence intelligence. Patients with multiple hormone deficiencies had somewhat lower IQs than patients with isolated GH deficiency when socioeconomic status was controlled. We conclude that GH deficiency itself does not seem to affect human brain development and intelligence.