Growth hormone treatment in children with short stature due to IUGR

Most of the children with intrauterine growth retardation show fair catch-up growth by two years of age, while approximately 10% of them fails the catch-up and remains short as adult. Growth hormone has been applied to those who stay short (height<-2SD of mean) in relatively high dose, and favorable results come out in terms of not only height but also psychosocial positiveness. The long-term out come, however, should be carefully monitored, especially the effect of early pubertal onset for height and pubertal height gain on the final height, and metabolic effect of long-term pharmacological dose of GH exposure from early childhood, such as glucose intolerance.     

Recombinant human growth hormone therapy does not increase microalbuminuria in children with short stature

OBJECTIVE Concerns have been raised about possible adverse effects of growth hormone on renal function. We measured microalbuminuria as a sensitive index of early glomerular damage in children being treated with recombinant human growth hormone. DESIGN AND PATIENTS Microalbuminuria was measured in a group of 17 children with short stature being treated with recombinant human growth hormone and in a group of 13 patients with idiopathic short stature not receiving therapy. MEASUREMENTS Microalbuminuria was measured by a commercially available ELISA and urinary creatinines were determined using a Beckman creatinine analyser. RESULTS The level of microalbuminuria was 0 484 ± 0 275 g albumin/mol creatinine (mean ± SD) in the patients receiving growth hormone and 0 681 ±0 574 g albumin/mol creatinine in the untreated controls. There was no statistically significant difference between these values. CONCLUSIONS Treatment with recombinant human growth hormone does not cause an increase in microalbuminuria in children with normal renal function. This supports the safety of this medication in growth hormone deficient children with normal renal function.     

Impaired glucose tolerance and mild hyperglycemia in sucrose-fed rats does not impair insulin secretion

We fed normal rats a high sucrose diet in order to test the hypothesis that mild hyperglycemia can induce defects in pancreatic beta-cell function and impair glucosestimulated insulin release. Rats provided with free access to a sucrose solution (35%) voluntarily consumed 50% more carbohydrate than control per day. After 7 days of sucrose feeding, glucose tolerance was significantly impaired; the area under the glucose tolerance test curve (GTT) was 683±61 mmol/120 min compared with 472±56 mmol/120 min in controls (P<0.05). Impaired glucose tolerance was still present after a further 12 days (area under the GTT: 749±99 mmol/120 min). Sucrosefed rats were significantly (P<0.05) hyperglycemic by 1.5 mmol/l over controls. When insulin secretion was assessed in vivo and in vitro in control and sucrose-fed rats, no significant differences were apparent in plasma samples collected over a 1-h period or in statically incubated or perifused isolated pancreatic islets. In addition, the rates of glucose utilisation and oxidation were normal in islets from sucrose-fed rats. These data do not support the hypothesis that minimal hyperglycemia is sufficient to impair glucose-stimulated insulin release.     

生长激素治疗特发性矮小症的研究进展

特发性矮小症(ISS)是一种病因未明的矮小症,目前较常用的治疗药物是生长激素(GH),本文就GH治疗ISS的适应证、有效性、安全性及目前的争议进行综述.     

Growth hormone treatment in children with idiopathic short stature: correlation of growth response with peripheral thyroid hormone action

Objective Idiopathic short stature (ISS) describes short children with normal GH secretion. Although GH treatment increases their heights, growth response to the therapy differs among patients. Thyroid hormones (TH) are essential for longitudinal growth acting mainly through TH receptors (TR) α and β. We have previously reported that GH treatment reduced peripheral TH action in Turner Syndrome by TR down‐regulation. The aims of the study were to assess the effect of GH treatment to ISS on peripheral TH action and the correlation between thyroid status and growth response to the therapy. Subjects, design and measurements Eighteen normal (control) and twenty‐five ISS children were enrolled and evaluated before and after 12 months of life time (control) or 12 months of GH therapy (ISS). Fasting blood was used for serum biochemical evaluations, peripheral blood mononuclear cells for TR mRNA determination by QRT‐PCR and growth parameters by standard methods. Results GH treatment modified neither TR mRNA levels nor serum markers of TH action in ISS evaluated as a whole group. However, the individual change in TRβ mRNA levels correlated to the change in sex hormone–binding globulin (SHBG) levels after GH therapy. The growth response to GH correlated positively with the change in TRα mRNA level and negatively with that in TRβ mRNA, TSH and SHBG levels. The change in each TR mRNA isoform after GH treatment correlated negatively with its own basal level. Conclusions GH therapy induced individual changes in TR expression in ISS that correlated with their growth response. The basal TR mRNA level could predetermine the change in TR expression and therefore the sensitivity to GH treatment.     

C-reactive protein does not impair insulin suppression of glucose release in primary hepatocytes

Recent studies have suggested that CRP may interfere with insulin signaling in skeletal muscle and endothelial cells. The aim of this study was to determine whether highly purified CRP increased the rate of glucose appearance in primary hepatocytes in the absence or presence of insulin. Primary rat hepatocytes were provided glucose-free media containing 10 mM lactate, 1 mM pyruvate, 0, 1 or 10 nM insulin, and 0 or 10 μg/ml of purified CRP for 6h. Purified CRP did not increase glucose release in the absence of insulin and did not reduce the ability of insulin to suppress glucose release.     

Growth hormone secretory pattern and response to treatment in children with short stature followed to adult height

OBJECTIVE: To compare the relative utility of GH stimulation tests and assays of spontaneous GH secretion as predictors of change in height standard deviation score at the end of GH treatment in children with short stature. PATIENTS AND METHODS: We retrospectively studied 116 children (67 boys and 49 girls) with subnormal growth rates and short stature, defined as a height of more than 2SD below the mean for age and sex. The patients were classified according to their pattern of findings on baseline pharmacological GH stimulation tests and a 12-h assay of nocturnal spontaneous GH secretion. Twenty-eight patients (24%) had normal hormone levels by both methods (group I); 14 (12%) had normal levels by stimulation tests but subnormal levels by the physiological assay (group II); 48 (41%) had subnormal levels on pharmacological stimulation, with normal physiologic levels (group III); and 26 (22%) had subnormal levels by both methods (group IV). All children in groups II and IV, and 27 in group III, designated IIIb, were treated with recombinant GH at 0.7 U (0.23 mg/kg) of body weight per week. GH secretory patterns were related to final height SD scores and other growth parameters, after the patients had attained their adult stature 6.7 +/- 2.2 years (SD) after GH evaluation. RESULTS: The five groups were similar with respect to mean baseline height SD scores for chronological as well as bone age. Whether assessed as absolute or parentally adjusted (relative) values, mean gains in height SD scores were significantly greater in treated patients with physiological hormone deficiency (groups II and IV) than in those with normal hormone levels (group I, untreated controls). Relative height gains were 1.03 +/- 1.45 cm (6.6 +/- 9.28 cm) and 1.85 +/- 1.21 cm (SDS; 11.8 +/- 7.74 cm) in groups II and IV respectively, compared with only 0.11 +/- 0.42 cm (0.7 +/- 2.68 cm) in group I (P < 0.01 and P < 0.001). GH treatment failed to improve either the absolute or parentally adjusted final height of patients with GH deficiency by stimulation tests but normal levels by physiological assay. CONCLUSION: Long-term administration of GH to short children with normal spontaneous GH secretion is not associated with an appreciable increase in adult height.     

Short children with familial short stature show enhancement of somatotroph secretion but normal IGF-I levels

The aim of the present study was to evaluate the GH status in children with familial, idiopathic short stature (FSS). To this goal we evaluated the GH response to GHRH (1 microg/kg iv) + arginine (ARG) (0.5 g/kg iv) test which is one of the most potent and reproducible provocative tests of somatotroph secretion, in 67 children with FSS [50 boys and 17 girls, age 10.8+/-0.4 yr, pubertal stages I-III, height between -3.6 and -1.6 standard deviation score (SDS), target height <10 degrees centile, normality of both spontaneous and stimulated GH secretion as well as of IGF-I levels]. The results in FSS were compared with those in groups of children of normal height (NHC) (42 NHC, 35 boys and 7 girls, age 12.0+/-0.5 yr, pubertal stages I-III, height between -1.3 and 1.4 SDS, height velocity standard deviation score (HVSDS)>25 degrees centile, GH peak >20 microg/l after GHRH+ARG test, mean GH concentration [mGHc]>3 microg/l) and children with organic GH deficiency (GHD) (38 GHD, 29 boys and 9 girls, age 11.2+/-3.7 yr, pubertal stages I-III, height between -5.7 and -1.3 SDS, GH peak <20 microg/l after GHRH +ARG test, mGHc <3 mg/l). Basal IGF-I levels and mGHc were also evaluated in each group over 8 nocturnal hours. IGF-I levels in FSS (209.2+/-15.6 microg/l) were similar to those in NHC (237.2+/-17.2 microg/l) and both were higher (p<0.0001) than those in GHD (72.0+/-4.0 microg/l). The GH response to GHRH +ARG test in FSS (peak: 66.4+/-5.6 microg/l) was very marked and higher (p<0.01) than that in NHC (53.3+/-4.5 microg/l) which, in turn, was higher (p<0.01) than in GHD (8.2+/-0.8 microg/l). Similarly, the mGHc in FSS was higher than in NHC (6.7+/-0.5 microg/l vs 5.1+/-0.7 microg/l, p<0.05) which, in turn, was higher than in GHD (1.5+/-0.2 microg/l, p<0.0001). In conclusion, our present study demonstrates that short children with FSS show enhancement of both basal and stimulated GH secretion but normal IGF-I levels. These findings suggest that increased somatotroph function would be devoted to maintain normal IGF-I levels thus reflecting a slight impairment of peripheral GH sensitivity in FSS.     

Use of growth hormone in children with short stature and normal growth hormone secretion a growing problem.

The ethical, economic, psychologic, social, and growth attainment outcome issues related to the use of GH therapy in normal children with short stature are discussed. Although some short children accelerate their growth velocity with GH treatment, the limited available data do not suggest a significant benefit in final height attainment. An international survey of 99 normal short children treated with GH for at least 3 years reported a net improvement in mean height gain of <1 cm/year. Only in one-third was the result considered very good or good; 40% stated that there was no benefit. Thus, it seems unlikely that GH will dramatically increase final height in short children. On this basis, the use of GH for the treatment of the normal child with short stature outside of carefully controlled clinical trials cannot be recommended at present.     

生长激素在矮身材儿童中的临床应用

人生长激素(hGH)是脑神经垂体嗜酸性细胞分泌的一种蛋白质激素,它是体内最重要的促进生长的激素.儿童身高的增长主要是通过长骨骨干与骨骺之间的软骨板中的细胞分裂增殖实现的,生长激素(GH)正是对这种软骨细胞的分裂增殖具有显著的促进作用.     

Cholinergic enhancement of pyridostigmine potentiates spontaneous diurnal but not nocturnal growth hormone secretion in short children

It has been shown that enhanced cholinergic tone induced by pyridostigmine (PD) increases both basal and GHRH-stimulated GH levels in both adults and children. In this study the effects of PD (60 mg orally) on GH secretion were studied both in the morning (from 8.00 to 12.00) and in the night (from 23.00 to 3.00) in 7 short children previously shown as having a normal spontaneous nocturnal GH secretion. In the morning, PD induced a GH increase higher than saline (peak, mean +/- SEM: 17.4 +/- 3.4 vs. 5.5 +/- 3.0 ng/ml, p less than 0.02; area under curve (AUC): 360.8 +/- 71.4 vs. 109.4 +/- 44.7 ng/ml/h, p less than 0.01). In the night, no difference was observed between GH secretion after PD (peak: 16.7 +/- 2.4 ng/ml; AUC: 468.2 +/- 95.5 ng/ml/h) and saline (peak: 16.0 +/- 2.7 ng/ml; AUC: 409.1 +/- 97.7 ng/ml/h). Spontaneous GH secretion was higher during the night than in the morning (p less than 0.02) whereas nocturnal GH secretion overlapped with that in the morning after PD. The ability of PD to increase GH secretion during the morning but not GH hypersecretion occurring at night implies that the cholinergic tone in the central nervous system areas controlling GH secretion is already maximally stimulated at night. Since, reportedly, the cholinergic system negatively modulates somatostatin secretion, presence of a physiologically reduced somatostatinergic tone may be envisaged at night.     

Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose

Subjects with impaired fasting glucose (IFG) are at increased risk for type 2 diabetes. We recently demonstrated that IFG subjects have increased hepatic insulin resistance with normal insulin sensitivity in skeletal muscle. In this study, we quantitated the insulin secretion rate from deconvolution analysis of the plasma C-peptide concentration during an oral glucose tolerance test (OGTT) and compared the results in IFG subjects with those in subjects with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). One hundred and one NGT subjects, 64 subjects with isolated IGT, 24 subjects with isolated IFG, and 48 subjects with combined (IFG + IGT) glucose intolerance (CGI) received an OGTT. Plasma glucose, insulin, and C-peptide concentrations were measured before and every 15 min after glucose ingestion. Insulin secretion rate (ISR) was determined by deconvolution of plasma C-peptide concentration. Inverse of the Matsuda index of whole body insulin sensitivity was used as a measure of insulin resistance; 56 subjects also received a euglycemic hyperinsulinemic clamp. The insulin secretion/insulin resistance (disposition) index was calculated as the ratio between incremental area under the ISR curve (∆ISR[AUC]) to incremental area under the glucose curve (∆G[AUC]) factored by the severity of insulin resistance (measured by Matsuda index during OGTT or glucose disposal during insulin clamp). Compared to NGT, the insulin secretion/insulin resistance index during first 30 min of OGTT was reduced by 47, 49, and 74% in IFG, IGT, and CGI, respectively (all < 0.0001). The insulin secretion/insulin resistance index during the second hour (60–120 min) of the OGTT in subjects with IFG was similar to that in NGT (0.79 ± 0.6 vs. 0.72 ± 0.5, respectively, P = NS), but was profoundly reduced in subjects with IGT and CGI (0.31 ± 0.2 and 0.19 ± 0.11, respectively; P < 0.0001 vs. both NGT and IFG). Early-phase insulin secretion is impaired in both IFG and IGT, while the late-phase insulin secretion is impaired only in subjects with IGT.     

Combining protein and carbohydrate increases postprandial insulin levels but does not improve glucose response in patients with type 2 diabetes

ObjectiveA combined load of carbohydrate and protein stimulates insulin secretion. However, results on postprandial glucose responses in type 2 diabetic (T2D) subjects have been inconclusive. Therefore, we investigated the effects of co-ingestion of carbohydrate and protein on glucose and insulin responses in these subjects.MethodsAfter an overnight fast, 30 subjects consumed a drink containing 50 g of slowly-digested isomaltulose (ISO), combined either with a mixture of 21 g whey/soy (ISO + WS) or with 21 g casein (ISO + C) in a randomized order on separate days. In another experiment, the subjects consumed a control drink containing only 50 g ISO.ResultsNo significant differences in glucose responses were observed after ingestion of the drinks. Compared to ingestion of ISO alone, insulin response was ~ 190%–270% higher (P < .001), whereas insulin action was lower (P < .01) after ingestion of ISO + WS and ISO + C. Plasma insulin levels increased more significantly (P < .001) after ingestion of ISO + WS compared to ISO + C and were positively correlated with total amino acid levels (P < .001). Insulin action, however, showed a greater decrease following ingestion of ISO + WS than ISO + C (P < .01).ConclusionsCombining carbohydrate with protein can elevate postprandial insulin levels, but decreases insulin action, and therefore does not improve glucose response in T2D subjects. Our results further suggest that different types of proteins (i.e., fast-absorbing whey/soy vs. slow-absorbing casein) differently modulate insulin response and insulin action. A fast-absorbing protein mixture reduces insulin action to a greater extent than a slow-absorbing protein, and therefore may not be recommended for glycemic control in T2D patients.     

Leptin responses to insulin administration in children with short stature

Abstract The aim of the study was to investigate the effect of standard insulin tolerance test on plasma leptin levels in children with idiopathic short stature (ISS) and in children with growth hormone deficiency (GHD). Furthermore, plasma leptin levels were analyzed with regard to age, body mass index (BMI), and plasma levels of human growth hormone and of insulin-like growth factor-1 (IGF-1). Sixty-three patients with a height below the third percentile, an age of 10.24 +/- 0.40 years and a BMI standard deviation score (SDS) of -0.78 +/- 0.13 (weight SDS -0.07 +/- 0.12; height SDS -2.39 +/- 0.10) were investigated (mean +/- SD). Based on responses to insulin tolerance test, the patients were classified as ISS (n = 49) or GHD (n = 14). Plasma leptin levels were significantly lower in all patients 60 minutes ( P < .001) and 120 minutes ( P < .001) after insulin administration. This effect was independent of GHD, and no difference in leptin decrease was found when comparing patients with ISS to those with GHD. A correlation was found when comparing plasma leptin levels of all patients to BMI SDS (r = 0.43; P < .001) and plasma IGF-1 levels (r = 0.31; P < .01). Furthermore, positive correlation was found when BMI SDS was compared to IGF-1 (r = 0.25; P < .05). In summary, we found that insulin administration in children with short stature decreases plasma leptin levels, equally in those with and without GHD.