Growth hormone treatment strategy for short children born small for gestational age

Several studies performed in the last 15 years have shown that growth hormone (GH) induces a profound catch-up in height in short children born small for gestational age (SGA). We know from more recent studies that final height can be normalized through GH treatment. In Europe, GH is now a recognized indication, enabling treatment of short children born SGA. Treatment is given to the most severe growth-retarded children after the age of 4 years. A dose of 0.035 mg/kg per day is recommended. However, in our opinion a higher dose would be more efficient in very short children, especially if they are treated later in childhood.     

Reduced pituitary volume in children with short stature: clinical and radiological correlates

A retrospective evaluation of 80 cases of growth retardation evaluated at the H?pital Sainte-Justine of Montreal has revealed that 20 of them (25%; 15 boys and 5 girls) had a reduction of pituitary volume as revealed by high-resolution CT scanning of the pituitary gland. Of these patients, 8 had complete growth hormone (GH) deficiency, as evaluated by arginine infusion and L-Dopa-propranolol testing and nocturnal blood sampling, and 3 had GH neurosecretory dysfunction. Five patients had combined or multiple hormonal deficiencies. A statistically significant correlation was found between nocturnal plasma GH values and pituitary volumes. From this study it can be concluded that reduced pituitary volume is a frequent finding in growth-retarded children with hypopituitarism.     

ECG wave form, short term heart rate variability and plasma catecholamine concentrations in intrauterine growth-retarded guinea-pig fetuses

Electrocardiogram waveform, short term heart rate variability and catecholamine concentrations were studied with maternally-induced anesthesia in eleven growth-retarded guinea-pig fetuses and their normal-sized littermates at 63 days of gestation. Intrauterine growth retardation was induced by unilateral uterine artery ligation performed between day 32 and 35. In the growth-retarded group fetal weight was reduced by 45%. Blood gases, acid-base status and oxygen content were similar in the two groups. The growth-retarded guinea-pig fetuses were hypoglycemic and demonstrated a rise in hemoglobin concentration. The T/QRS ratio (T wave amplitude/QRS amplitude) was similar in both groups. The short-term heart rate variability was significantly reduced in the growth-retarded group. Plasma catecholamine concentrations were increased in growth-retarded fetuses but differed only significantly for noradrenaline compared to controls. We suggest that similar T/QRS ratio in both groups of fetuses indicates that aerobic myocardial metabolism is maintained among growth-retarded fetuses. The mechanism behind the reduced variability is unclear.     

Studies on the growth of the fetal guinea pig. Changes in plasma hormone concentration during normal and abnormal growth

The endocrine changes associated with fetal growth retardation caused by unilateral uterine artery ligation of guinea pigs at day 30 of pregnancy were studied. Plasma hormone levels in fetuses that, about 20 or 30 days later, were 35-50% of normal size were measured by radioimmunoassay. The small fetuses were severely hypoglycaemic and hypoinsulinaemic; both showing close correlation and relationship to the degree of growth retardation. Plasma thyroid and cortisol and concentrations were much lower than normal and that glucagon and androstenedione were much higher. Plasma growth hormone level appeared to be unaffected by growth retardation. The developmental changes in glucagon and thyroid hormone concentrations were consistent with a delay in the timing of prenatal events in growth-retarded fetuses. However the late cortisol rise, although somewhat blunted, still occurred at 58-60 in the small fetal guinea pigs.     

Growth hormone and tumour recurrence.

OBJECTIVE--To determine whether using growth hormone to treat radiation induced growth hormone deficiency causes tumour recurrence. DESIGN--Comparison of tumour recurrence rates in children treated with growth hormone for radiation induced deficiency and an untreated population. Computed tomograms from children with brain tumours were reviewed when starting growth hormone and subsequently. SETTING--North West region. PATIENTS--207 children treated for brain tumour, 47 of whom received growth hormone and 161 children with acute lymphoblastic leukaemia 15 of whom received growth hormone. MAIN OUTCOME MEASURES--Tumour recurrence and changes in appearances on computed tomography. RESULTS--Among children with brain tumour, five (11%) who received growth hormone had recurrences compared with 42 (26%) who did not receive growth hormone. Also adjusting for other variables that might affect tumour recurrence the estimated relative risk of recurrence was 0.82 (95% confidence interval 0.28 to 2.37). The only child with acute lymphoblastic leukaemia who relapsed while taking growth hormone had relapsed previously before starting treatment. Two of the five children with brain tumours who relapsed had abnormal appearances on computed tomography when growth hormone was started. 14 other children who remained relapse free and had follow up computed tomography showed no deterioration in radiological appearance during treatment. CONCLUSIONS--In this population growth hormone did not increase the risk of tumour recurrence but continued surveillance is essential. Abnormal results on computed tomography are not a contraindication to treatment with growth hormone.     

Intermittent recombinant growth hormone treatment in short children born small for gestational age: four-year results of a randomized trial of two different treatment regimens

BACKGROUND: Treatment of short children born small for gestational age SGA with recombinant human growth hormone r-hGH increases growth velocity during childhood. As in other indications, the growth velocity in these patients is more marked during the first year of treatment and then decreases. This study was undertaken to evaluate the efficacy of different r-hGH treatment schedules (67 microg/kg/day in a discontinuous or continuous regimen) during the second year of r-hGH treatment by comparing height velocity changes and total gain of height over a 4-year period. METHODS: 58 growth-retarded SGA children aged 2-5 years were randomized to a TOTO regimen (4 years alternating treatment (T) and observation (O), n = 30) or a TTOO regimen (2 years' treatment, followed by 2 years' observation, n = 28). Height velocity HV and total height gain were assessed during the 4-year study. RESULTS: In both groups, HV and HV standard deviation score HV-SDSCA increased during treatment and decreased during observation periods. Interruption of treatment in the TOTO group did not result in a better gain in height standard deviation score H-SDSCA when compared with the TTOO group. After 4 years of study, the gain in H-SDSCA was 1.4 + or - 01 in the TOTO group and 1.6 + or - 0.2 in the TTOO group leading to a mean height of -2.0 + or - 1.0 SDS and -2.0 + or - 0.8 SDS, respectively. The rate of bone maturation was similar in the two groups. CONCLUSIONS: In short SGA children, TOTO and TTOO regimens produced significant improvements in growth during r-hGH treatment. However, treatment interruption after 1 year did not influence the overall gain in height SDS when compared with 2 years' continuous treatment.     

Variation in early neonatal mortality for different types of fetal growth retardation

Birth and first-48-hr death records were analyzed for 10,024 liveborn infants in Mexico City and 12,786 liveborn infants in Santa Cruz, Bolivia. The objective of the analysis was to characterize the early postnatal mortality rates for different types of fetal growth retardation and prematurity. Infants who were delivered prior to 37 weeks of gestation had 23-100 times the mortality risk of infants born at full term and normal weight. Light-for-gestational-age infants (birth weight less than 2,900 g) were further divided into proportionately growth-retarded with normal Rohrer's index (weight/height) and disproportionately growth-retarded with low Rohrer's index. The proportionately growth-retarded infant had nearly twice the mortality of the full-term, appropriate-weight infants, whereas the disproportionately growth-retarded infants had 2.9-5.7 times the mortality rate of the full-term, appropriate-weight infants. There were some differences between samples in mortality rates and prevalence of the different classes of small infants, but the pattern of mortality within samples was consistent between samples.     

血清生长激素水平与儿童单纯性肥胖伴身高略矮的关系

目的:探讨血清生长激素(growth hormone,GH)水平与儿童单纯性肥胖伴身高略矮的关系。方法:选择2013年1月~2013年11月27例在我院儿童保健科门诊就诊的被诊断为单纯性肥胖症的儿童,且其身高均小于同龄儿童平均身高5 cm以上,采用放射免疫法检测其血清生长激素水平,分析其生长激素水平的变化及其意义。结果:27例患儿化验结果显示生长激素完全缺乏者22例,部分缺乏5例。结论:生长激素缺乏可能是肥胖伴身高略矮儿童患肥胖症的重要原因,测定血清生长激素水平有助于了解肥胖伴身高略矮儿童体内生长激素水平从而应用于肥胖症的病因治疗。     

Absence of catch-down growth in Russell-Silver syndrome after short-term growth hormone treatment

We describe 3 children with Russell-Silver syndrome without growth hormone insufficiency who were treated with growth hormone for 2, 3. 7 and 6 years, showing a rapid growth acceleration. After cessation of growth hormone treatment, they grew at a normal rate without 'catch-down' growth. It may be possible that short intra-uterine growth retardation (IUGR) children with dysmorphic features respond to growth hormone therapy differently from non-dysmorphic IUGR short children. Short-term growth hormone treatment for children with Russell-Silver syndrome may avoid side effects and diminish costs.     

Interrelationship of Growth and Plasma Amino Acid Concentration in the Chick Fed Casein Diets as Influenced by Dietary Protein and Amino Acid Levels

Chicks fed a 20% casein-sucrose diet showed severe growth depression, but dietary supplementation with 0.7% arginine-HCl, 0.35% glycine and 0.35% dl-methionine improved the growth rate to almost that of chicks fed a practical diet. Chicks fed high protein diets containing 64% casein showed normal growth, irrespective of the supplementation with such amino acids. Plasma arginine concentration of growth-retarded chicks was significantly lower than that of normal chicks. Plasma threonine/arginine ratio was negatively correlated with the growth rate of the chicks, the ratio of normal chicks being 3 ~ 4 whereas that of growth-retarded chicks was about 24. No lysine-arginine antagonism occurred-under high casein feeding.     

Dominant dwarfism in transgenic rats by targeting human growth hormone (GH) expression to hypothalamic GH-releasing factor neurons.

Expression of human growth hormone (hGH) was targeted to growth hormone-releasing (GRF) neurons in the hypothalamus of transgenic rats. This induced dominant dwarfism by local feedback inhibition of GRF. One line, bearing a single copy of a GRF-hGH transgene, has been characterized in detail, and has been termed Tgr (for Transgenic growth-retarded). hGH was detected by immunocytochemistry in the brain, restricted to the median eminence of the hypothalamus. Low levels were also detected in the anterior pituitary gland by radioimmunoassay. Transgene expression in these sites was confirmed by RT-PCR. Tgr rats had reduced hypothalamic GRF and mRNA, in contrast to the increased GRF expression which accompanies GH deficiency in other dwarf rats. Endogenous GH mRNA, GH content, pituitary size and somatotroph cell number were also reduced significantly in Tgr rats. Pituitary adrenocorticotrophic hormone (ACTH) and thyroid-stimulating hormone (TSH) levels were normal, but prolactin content, mRNA levels and lactotroph cell numbers were also slightly reduced, probably due to feedback inhibition of prolactin by the lactogenic properties of the hGH transgene. This is the first dominant dwarf rat strain to be reported and will provide a valuable model for evaluating the effects of transgene expression on endogenous GH secretion, as well as the use of GH secretagogues for the treatment of dwarfism.     

Effects of human growth hormone on immune functions: in vitro studies on cells of normal and growth hormone-deficient children

We have studied the in vitro effects of human growth hormone on cell surface markers and mitogenic responses of peripheral blood lymphocytes (PBL) of normal and growth hormone-deficient children before, during and after treatment with growth hormone. Growth hormone resulted in a decrease in B cell expression but it did not affect expression of T cell subsets. Growth hormone depressed the proliferation of PBL of normal and untreated growth hormone-deficient children. The proliferative responses to phytohemagglutinin (PHA) versus PHA with growth hormone were not statistically different, though the responses of most normal and on treatment children were diminished by the addition of growth hormone. PBL derived from growth hormone-deficient children during treatment with human growth hormone exhibited significantly greater spontaneous proliferation then the PBL of normal children. Growth hormone further significantly enhanced their proliferation. PHA and PHA with growth hormone resulted in significantly greater proliferation of these patients' PBL when compared to those of normal children. We demonstrated that human growth hormone had substantial in vitro effects on immune functions. These effects, some of which depend on the treatment status of the children, may need to be considered in the clinical use of human growth hormone.     

Growth hormone in blood sampled continuously during pentobarbitone-induced sleep in children.

Growth hormone has been estimated in blood sampled continuously in periods each lasting 30 min during the first 3-4 h of pentobarbitone-induced sleep in 69 children. With only two half-hour samples, almost the same information was obtained as with the estimation of growth hormone in all samples. In this way 95% of normally growing children showed growth hormone levels of 5 muU/ml of more. Children with growth retardation of unknown cause and overweight children showed on the average lower growth hormone levels, not rarely even below 5 muU/ml. Pituitary dwarfs all had maximum growth hormone levels of 3 muU/ml or less. Growth hormone levels during sleep may be normal in children who show negative results on provocation, while subnormal growth hormone levels during sleep have been encountered in some children with retarded growth who had a normal response upon provocation.     

Dietary supplementation with glutamine improves gastrointestinal barrier function and promotes compensatory growth of growth-retarded yaks

The growth retardation of yaks commonly exists on the Tibetan Plateau, and the gastrointestinal barrier function of growth-retarded yaks is disrupted. Glutamine (Gln) is an effective feed additive to improve the gastrointestinal barrier function of animals. This research evaluated the effects of Gln on growth performance, serum permeability parameters, gastrointestinal morphology and barrier function of growth-retarded yaks. Thirty-two male growth-retarded yaks (74.0 ± 6.16 kg of BW and 480 ± 5.50 days of age) were randomly allocated to 4 groups: the negative control (GRY, fed basal ration), Gln1 (fed basal ration and 60 g/d Gln per yak), Gln2 (120 g/d) and Gln3 (180 g/d). Another 8 male growth normal yaks (112 ± 6.11 kg of BW and 480 ± 5.00 days of age) with same breed were used as a positive control (GNY, fed basal ration). The results showed that GRY had lower growth performance and higher (P < 0.05) diamine oxidase, D-lactic acid and lipopolysaccharide concentrations in serum as compared to GNY. Glutamine improved the average daily gain (ADG) of growth-retarded yaks, and the Gln2 group displayed highest ADG. Glutamine supplementation reduced markers of gut permeability in growth-retarded yaks. The GRY and Gln2 groups were selected to study the gastrointestinal barrier function. Growth-retarded yaks fed Gln2 showed higher (P < 0.05) height and surface area of ruminal papillae as compared to GRY. A similar trend of height and surface area in jejunal villus was found between GRY and Gln2 groups. The Gln2 increased (P < 0.05) the concentrations of secretory immunoglobulin A in jejunum and ileum of growth-retarded yaks. The rumen and jejunum of Gln2 yaks exhibited lower (P < 0.05) interleukin-1β and higher (P < 0.05) interleukin-10 mRNA expressions. Growth-retarded yaks fed Gln2 increased (P < 0.05) the expressions of claudin-1, occludin and zonula occludens-1 in the rumen and jejunum. In conclusion, dietary supplementation with Gln could improve the gastrointestinal barrier function and promote the compensatory growth of growth-retarded yaks.     

Growth hormone receptors in lymphocytes of growth hormone-deficient children

Human growth hormone was injected intravenously into 18 growth hormone-deficient children and growth hormone binding sites in lymphocytes were investigated. Fresh circulating lymphocytes had a low initial value for the binding of growth hormone to solubilized receptors (3.45 +/- 1.46%) but after growth hormone injection, the binding rapidly increased to 14.8 +/- 4.2% at 2 1/2 h and 8.7 +/- 1.8% at 5 h. The sharp increase in binding is due to increase in the number of binding sites. Two control children who received chorionic gonadotropin had no change in lymphocyte growth hormone receptors. The methodological differences between the present study and previous attempts to identify human growth receptors in lymphocytes were (1) lymphocytes were separated and disrupted with Triton X-100 as quickly as possible (to avoid error from receptor leaking out of the cell) and (2) the receptors were assayed at 2 1/2 h after growth hormone administration (previous studies were 12-24 h later). One possible explanation for the data is that growth hormone receptor from liver is taken up by lymphocytes and rapidly released again, thus, contributing to the hormonal receptor economy in humans.     

Zip1, Zip2, and Zip8 mRNA Expressions Were Associated with Growth Hormone Level During the Growth Hormone Provocation Test in Children with Short Stature

Short stature of children is affected by multiple factors. One of them is growth hormone (GH) deficiency. Growth hormone therapy can increase the final height of children with growth hormone deficiency. Zinc is found to induce dimerization and to enhance the bioactivity of human GH. Two gene families have been identified involved in zinc homeostasis. Previous studies in our laboratory have shown that Zip1, Zip2, Zip6, and ZnT1 mRNA were associated with zinc level in established human breast cancer in nude mice model; Zip8 was significantly lower in zinc-deficient Wistar rats in kidney. In this study, five zinc transporters: Zip1, Zip2, Zip6, Zip8, and ZnT1 were chosen. We aimed to investigate the mRNA expression of zinc transporters and to explore the relationship between zinc transporters and growth hormone in short stature children. Growth hormone provocation test is used to confirm the diagnosis of growth hormone deficiency. Six short children for the test were enrolled. At the same time, 15 sex- and age-matched normal children were enrolled as control. The expression levels of zinc transporters in peripheral blood mononuclear cells were determined by quantitative real-time PCR. Zip1 and Zip2 mRNA expression positively correlated with growth hormone level (r?=?0.5133, P?=?0.0371; r?=?0.6719, P?=?0.0032); Zip8 mRNA expression negatively correlated with growth hormone level (r?=??0.5264, P?=?0.0285) during the test in short stature children. The average expression level of Zip2 was significantly higher and Zip6, Zip8 mRNA levels were significantly lower in short stature children than in health controls at 0 min (P?<?0.05, P?<?0.05).     

Circadian rhythm of circulating glucose,insulin and growth hormone in spontaneously hypertensive rats

Circulating levels of growth hormone (GH), insulin, and glucose were measured at hourly intervals during a 24 h period to establish the diurnal rhythm of these hormones in spontaneously hypertensive rats (SHR). There was no statistically significant correlation between circulating GH levels and pituitary GH content. Serum GH appeared to be higher at night in female SHR and higher during day-light hrs in male SHR. GH levels fluctuated considerably, whereas insulin levels showed much less diurnal variation. Although there was no statistically significant correlation between blood glucose and insulin levels, glucose levels rose and fell considerably during the 24 hr period with a definite decline in blood glucose during the nocturnal hyperactivity observed in SHR. These findings are of interest in that SHR have giant-sized islets of Langerhans, develop hyperglycemia spontaneously, and are growth-retarded compared to most normotensive strains of rat.     

Suppression of growth hormone by oral glucose in the evaluation of tall stature

Excess secretion of growth hormone is a rare diagnosis in children or adolescents with tall stature. An oral glucose tolerance test (OGT) with determination of growth hormone is generally recommended to exclude this disorder. In order to test the validity of this approach in pediatric subjects, OGT tests were performed in 126 tall subjects (age: 12.4 +/- 1.8 years; height: 3.1 +/- 0.8 SDS). Nonsuppression was present in 39 subjects, however, anthropometric analysis and follow-up excluded the diagnosis of eosinophilic pituitary adenoma in all patients. The lowest GH concentration was reached 90 min after ingestion of oral glucose, GH rose above baseline at 180 min. Plasma concentrations of glucose and insulin did not differ between suppressors and nonsuppressors. In conclusion, absent suppression of growth hormone by oral glucose is common in tall children and adolescents. The test is therefore not recommended as a general screening for excess growth hormone. Prolonging the test beyond 120 min does not increase the diagnostic value.