Growth hormone therapy for short children born small for gestational age

Approximately 10% of all children born small for gestational age (SGA) fail to achieve sufficient catch-up growth and remain with short stature throughout childhood and adult life. Abnormalities of the GH/IGF-1 axis are not always identified. Several studies have demonstrated that GH is an effective and well-tolerated therapy and most children will reach a normal adult height. In this review, it can be seen the encouraging results of GH treatment in growth-retarded children born SGA highlighting the benefits of early treatment.     

Long-Term Outcome of Growth Hormone Therapy in Children and Adolescents

Growth hormone (GH) has been available for more than 4 decades for the treatment of GH deficiency. Initially, GH was extracted from the pituitary glands of human cadavers, but its use was discontinued following the transmission of the Creutzfeldt-Jakob virus. After the development of recombinant GH (somatropin) in 1985, an 'unlimited' commercial source of GH has been available, allowing for the treatment of a large number of short GH-deficient and -sufficient children. Refinements in both the dosage and the frequency of administration of GH have allowed GH-deficient children to reach nearly normal final heights, although mostly they are still below their target heights. Decreased bone mineral densities and increased concentrations of fasting and postprandial lipids, coagulation factors, and several independent cardiovascular risk factors have been reported in GH-deficient children and adolescents and appear to improve with GH administration. The short-term administration of GH to mostly non-GH-deficient short children with Turner syndrome, chronic renal insufficiency (CRI), intrauterine growth retardation (IUGR), and idiopathic short stature (ISS) has resulted in increased growth velocities. In addition, the final height of patients with Turner syndrome and CRI appears to improve with the long-term administration of GH. Final height data are still lacking in adolescents with IUGR, but height standard deviation score and final height predictions appear to improve with therapy. Based on the incomplete and inconclusive available data, one must conclude that GH treatment of children with ISS cannot be advised. The use of GH at replacement doses in children with GH deficiency has resulted in rare and generally reversible adverse effects. The long-term administration of pharmacologic GH doses to short, mostly non-GH-deficient children must, however, still be viewed with caution, as long-term complications cannot as yet be fully evaluated. GH therapy must be individualized and should be limited only to children with severe short stature or a significantly decreased growth velocity, to children under considerable stress due to their short stature, and to patients in whom low GH or low insulin-like growth factor-1 secretion might be the rate-limiting factors for growth. The cost of the medication and the inconvenience of daily GH injections to otherwise mostly healthy short children must also be taken into account.     

Cushing disease as possible cause of persistent growth failure despite growth hormone therapy in a small for gestational age male

Growth hormone (GH) therapy in children with small for gestational age (SGA) has been shown to be of significant therapeutic benefit. We report the case of an 11-year-old Caucasian male who developed early adrenarche, hypertension and insulin resistance on GH therapy for SGA and profound short stature (ht −5 SD). This patient demonstrated a poor response to GH therapy and developed physical and biochemical findings of insulin resistance responsive to metformin therapy. He remained hypertensive, however, and continued to have elevated serum dehydroepiandrosterone sulfate levels. Urinary free cortisol excretion was subsequently found to be elevated. The diagnosis of Cushing’s disease was confirmed with inferior petrosal sinus sampling and pituitary MRI. The patient underwent partial adenohypophysectomy with resulting normalization of plasma cortisol levels and associated symptoms. Our patient’s diagnosis of Cushing’s disease was complicated by his past history of poor growth since birth and history of SGA. The signs of Cushing’s disease did not overtly appear until GH therapy was initiated to help treat severe short stature. It is possible that the metabolic effects of GH therapy unmasked the presence of underlying Cushing’s disease.     

Small for gestational age: short stature and beyond

Depending on the definitions used, up to 10% of all live-born neonates are small for gestational age (SGA). Although the vast majority of these children show catch-up growth by 2 yr of age, one in 10 does not. It is increasingly recognized that those who are born SGA are at risk of developing metabolic disease later in life. Reduced fetal growth has been shown to be associated with an increased risk of insulin resistance, obesity, cardiovascular disease, and type 2 diabetes mellitus. The majority of pathology is seen in adults who show spontaneous catch-up growth as children. There is evidence to suggest that some of the metabolic consequences of intrauterine growth retardation in children born SGA can be mitigated by ensuring early appropriate catch-up growth, while avoiding excessive weight gain. Implicitly, this argument questions current infant formula feeding practices. The risk is less clear for individuals who do not show catch-up growth and who are treated with GH for short stature. Recent data, however, suggest that long-term treatment with GH does not increase the risk of type 2 diabetes mellitus and the metabolic syndrome in young adults born SGA.     

Pycnodysostosis: clinical, radiologic, and endocrine evaluation and linear growth after growth hormone therapy

Pycnodysostosis is a rare hereditary bone abnormality with an autosomal recessive mode of inheritance. We report the clinical, radiologic, and endocrine status of 8 children with this rare disease. All patients had the characteristic phenotype of the disorder including short stature (8 of 8), increased bone density (7 of 8), separated cranial sutures (8 of 8), large fontanel with delayed closure (8 of 8), obtuse mandibular angle (8 of 8), delayed teeth eruption (8 of 8), enamel hypoplasia (7 of 8), dysplastic acromial ends of the clavicles (6 of 8), frontal bossing (6 of 8), ocular proptosis (8 of 8), and dysplastic nails (8 of 8). Developmental evaluation according to the revised Denever developmental screening showed normal motor, fine motor-adaptive language, and personal social abilities in all the children. All had normal hepatic and renal functions. Serum calcium and phosphorus concentrations were normal. Two children had low serum alkaline phosphatase concentration. Short stature is a characteristic feature of pycnodysostosis. Seven of the 8 children were born short (length standard deviation score [SDS] = -3 to -1.5). Deceleration of linear growth was significant during the first 3 years of life. All the children had height SDS below -3 at the end of their third year of life. Although short stature is a feature of this genetic disorder, defective growth hormone (GH) secretion in response to provocation with clonidine and glucagon was found in 4 of the 8 patients. These 4 patients had pituitary hypoplasia on the magnetic resonance imaging (MRI) of their brain. In addition, 3 of these 4 patients had demyelination of the cerebrum. Patients with pycnodysostosis (n = 8) had low circulating concentrations of insulin-like growth factor-1 (IGF-1) compared with normal age-matched short children with constitutional short stature (CSS). IGF-I increased significantly after injecting GH for 3 days in these patients. Physiologic replacement with GH (18 U/m(2)/week) divided in daily evening doses subcutaneously increased IGF-1 concentration and improved linear growth velocity and height standard deviation scores (HtSDS) in the 4 children with GH deficiency. These data ruled out GH resistance and proved the usefulness of GH therapy in the management of short stature in these patients. In summary, some patients with pycnodysostosis have partial GH deficiency and low IGF-1 concentration. GH therapy markedly increases IGF-I secretion and improves their linear growth. MRI study of the brain including the hypothalamic-pituitary area is recommended in these children because of the high incidence of pituitary hypoplasia and cerebral demyelination.     

Growth hormone (GH) provocative testing frequently does not reflect endogenous GH secretion

GH secretion was studied in 73 children with classical GH deficiency or GH neurosecretory dysfunction (GHND), intrinsic short stature, or normal stature. The GH-deficient group was defined by a peak GH secretory response below 10 ng/ml to all provocative tests (arginine, L-dopa, insulin hypoglycemia, and clonidine). GHND was defined by a mean serum 24-h GH concentration below 3 ng/ml, with a normal response (greater than or equal to 10 ng/ml) to provocative testing. Twenty-one GH-deficient children, 21 children with GHND, and 18 short control children underwent provocative GH testing and a 24-h study with GH sampling every 20 min. A group of 13 normal stature control children also underwent 24-h GH sampling. The mean stimulated peak serum GH level [4.7 +/- 0.6 (+/- SEM) ng/ml] in the GH-deficient group was significantly below that in the GHND (19.5 +/- 1.7 ng/ml) and short control groups (24.0 +/- 3.5 ng/ml; P less than 0.01). The mean 24-h serum GH concentration was reduced in GH-deficient (1.5 +/- 0.2 ng/ml) and GHND (2.0 +/- 0.1 ng/ml) children compared to those in short (5.6 +/- 0.5 ng/ml) and normal stature (5.8 +/- 0.8 ng/ml) control children (P less than 0.01). Peak GH concentrations after provocative testing correlated poorly with 24-h mean concentrations in GH-deficient, GHND, and short control children (r = 0.38, 0.23, and 0.41, respectively; P = NS for all groups). Mean serum GH concentrations from blood sampling intervals of 12 h (day/night; 0800-2000/2000-0800 h, respectively) or even 6 h (day; 0900-1500 h) were statistically different in GHND or GH-deficient groups compared to those in control children; however, there was significantly more overlap for individual children using the 6- and 12-h daytime intervals than for the 24-h data. Plasma somatomedin-C/insulin-like growth factor I correlated with mean 24-h GH concentration endogenous secretion (r = 0.7; P less than 0.001). These data suggest that provocative GH testing frequently does not correlate with endogenous GH secretion.     

Growth and adult height in GH-treated children with nonacquired GH deficiency and idiopathic short stature: the influence of pituitary magnetic resonance imaging findings

We analyzed the final height of 146 short children with either nonacquired GH deficiency or idiopathic short stature. Our purpose was 1) to assess growth according to the pituitary magnetic resonance imaging findings in the 63 GH-treated children with GH deficiency and 2) to compare the growth of the GH-deficient patients with normal magnetic resonance imaging (n = 48) to that of 32 treated and 51 untreated children with idiopathic short stature (GH peak to provocative tests >10 microg/liter). The mean GH dose was 0.44 IU/kg.wk (0.15 mg/kg.wk), given for a mean duration of 4.6 yr. Among the GH-deficient children, 15 had hypothalamic-pituitary abnormalities (stalk agenesis), all with total GH deficiency (GH peak <5 microg/liter). They were significantly shorter and younger at the time of diagnosis than those with normal magnetic resonance imaging, had better catch-up growth (+2.7 +/- 0.9 vs. +1.3 +/- 0.8 SD score; P < 0.01), and reached greater final height (-1.1 +/- 1.0 vs. -1.7 +/- 1.0 SD score; P < 0.05). Among patients with normal magnetic resonance imaging, there was no difference in catch-up growth and final height between partial and total GH deficiencies. GH-deficient subjects with normal magnetic resonance imaging and treated and untreated patients with idiopathic short stature had comparable auxological characteristics, age at evaluation, and target height. Although they had different catch-up growth (+1.3 +/- 0.8, +0.9 +/- 0.6, and +0.7 +/- 0.9 SD score, respectively; P < 0.01, by ANOVA), these patients reached a similar final height (-1.7 +/- 1.0, -2.1 +/- 0.8, and -2.1 +/- 1.0 SD score, respectively; P = 0.13). Pituitary magnetic resonance imaging findings show the heterogeneity within the group of nonacquired GH deficiency and help to predict the response to GH treatment in these patients. The similarities in growth between the GH-deficient children with normal magnetic resonance imaging and those with idiopathic short stature suggest that the short stature in the former subjects is at least partly due to factors other than GH deficiency.     

GH responsiveness in a large multinational cohort of SGA children with short stature (NESTEGG) is related to the exon 3 GHR polymorphism

OBJECTIVE: The polymorphic deletion of exon 3 of the GH receptor (d3-GHR) has recently been linked to the magnitude of growth response to recombinant human GH (rhGH) therapy in short children with or without GH deficiency. We investigated this association in a large multinational cohort from the Network of European Studies of Genes in Growth (NESTEGG), comprising short children born small for gestational age (SGA). DESIGN: The study included short prepubertal SGA children treated with rhGH for 1 or 2 years. POPULATION: Two hundred and forty white Caucasian SGA children (138 male, 102 female) aged 6.6 +/- 2.3 years with a height at -3.0 +/- 0.7 SDS at start of rhGH treatment; 193 ethnically matched controls. METHODS: The GHR polymorphism (fl/fl, fl/d3 or d3/d3) was genotyped by polymerase chain reaction (PCR) multiplex assay. Growth velocity (G/V) in cm/year and changes in GV during the first and second year of rhGH treatment were evaluated. RESULTS: The change in GV was significantly greater in SGA children carrying one or two copies of the d3-GHR allele (P = 0.038 for the first year and P = 0.041 for the second year of GH treatment), but the change in height was not significantly different. Birthweight was significantly lower in SGA children with the d3/d3 genotype than in SGA children with the fl/fl genotype (P = 0.034) and in those with the fl/d3 genotype (P = 0.016). CONCLUSION: Our data, based on a large cohort, showed that the exon 3 GHR polymorphism is associated with responsiveness to rhGH treatment in SGA children with short stature.     

Early, discontinuous, high dose growth hormone treatment to normalize height and weight of short children born small for gestational age: results over 6 years.

Most children born small for gestational age (SGA) normalize their size through spontaneous catch-up growth within the first 2 yr after birth. Some SGA children fail to do so and maintain an abnormally short stature throughout childhood. We have previously reported that high dose GH treatment (66 or 100 microg/kg x day s.c. over 2 yr; age at start, 2-8 yr; n = 38) induces pronounced catch-up growth in short children born SGA, thereby normalizing their height and weight in childhood. Here, we report on the further prepubertal growth course of these children over the first 4 yr after withdrawal of early, high dose GH treatment. Of the 38 treated children, none developed precocious puberty, and 22 remained prepubertal. Mean age of the latter at start of GH was 4.4 yr, height was -3.7 SD score, and height after adjustment for midparental height was -2.9 SD score. Height increased by an average of 2.5 SD during the 2 yr of GH treatment and decreased by 0.4 and 0.3 SD, respectively, during the first and second year after GH withdrawal. Subsequently, when stature was not extremely short at the start (mean adjusted height SD score, -2.7; n = 13), no further GH treatment was given, and the adjusted height was stabilized around -1.0 SD score; when stature was very short at the start (mean adjusted height, -3.3 SD score; n = 9), a second course of GH treatment (66 microg/kg x day s.c.) was initiated either 2 yr (n = 5) or 3 yr (n = 4) after initial GH withdrawal. This second course was associated with renewed catch-up growth and also resulted in a mean adjusted height of -1.0 SD score. In each subgroup, the pattern of the weight course paralleled that of the height course; GH treatment was well tolerated. In conclusion, early, discontinuous, high dose GH treatment appears to be a safe and efficient option to normalize prepubertal height and weight in the majority of short SGA children. It remains to be examined whether the normalized stature will be maintained during pubertal development, either with or without further GH treatment.     

Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardation

Approximately 10% of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5% of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene.     

Effects of systemic growth hormone (GH) administration on regional adipose tissue in children with non-GH-deficient short stature.

Chronic administration of exogenous GH to GH-deficient children is associated with a selective depletion of the abdominal sc fat depot and a resultant relative increase in gluteal, relative to abdominal, adipocyte lipid content. In GH-deficient children, the degree of this change in relative lipid content per adipocyte appears to be correlated with decreases in sensitivity of abdominal subcutaneous fat to the antilipolytic action of insulin. We studied abdominal and gluteal sc adipose tissue from 10 children with short stature (height less than 5% ile, growth velocity less than 5 cm/yr, bone age delayed at least 2 yr), who were not GH deficient based upon provocative testing (non-GH-deficient short stature) 1) before beginning and 2) after 3 months of therapy with exogenous GH (Humatrope, 0.1 mg/kg sc 3 times/week). In abdominal and gluteal adipocytes, we measured lipid content, rates of reesterification of fatty acids released by ongoing lipolysis and rates of in vitro lipolysis and lipogenesis in response to insulin, adenosine, and various adrenoreceptor agonists. These biochemical measures were correlated with measures of statural growth and adipose tissue distribution in each subject. We found that GH therapy was associated with a significant reduction in abdominal adipocyte size (0.48 microgram +/- 0.08 lipid per cell prior to therapy vs. 0.43 microgram +/- 0.08 lipid per cell after therapy, P less than 0.05) and a significant increase in responsiveness of gluteal sc adipose tissue to the lipogenic actions of insulin. The significant correlations of changes in abdominal adipocyte volume with changes in regional adipose tissue insulin sensitivity that were noted in GH-deficient children were not noted in this subject population, perhaps due to effects of endogenous GH on pretreatment insulin responsiveness of adipose tissue. These data reaffirm that GH has site-specific effects on regional adipose tissue depots.     

The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children

CONTEXT: A protein polymorphism of the GH receptor (GHR) based on the genomic deletion of exon 3 (d3-GHR) has recently been linked to the magnitude of growth response to high-dose recombinant human GH (rhGH) therapy of short children without GH deficiency. OBJECTIVE: This study tests the novel association in two distinct groups of rhGH-treated patients, short girls with Turner syndrome and short children born small for gestational age (SGA). DESIGN: The retrospective study included all children who were treated with rhGH during the last 18 yr at our hospital. PATIENTS: Patients with Turner syndrome were defined by the specific karyotype (n = 53), short children born SGA were determined by birth length and/or weight less than -2.0 sd score and a height at start of rhGH therapy less than -2.0 sd score (n = 60). Exclusion criteria were puberty, an age less than 3.5 or more than 14 yr, and GH deficiency. MATERIALS AND METHODS: Growth prediction for the first year of therapy was calculated on the basis of rhGH dose, age, weight, height, and gender-adjusted midparental height according to the prediction models by Ranke et al. The GHR-exon 3 locus was genotyped using a PCR multiplex assay. GH, IGF-I, and IGF binding protein 3 (IGFBP-3) were measured by RIA. INTERVENTION: For growth promotion, a mean rhGH dose of 38 mug/kg.d (sd, +/-8) was administered in Turner syndrome patients and 56 mug/kg.d (sd, +/-11) in short children born SGA. RESULTS: No significant difference in height, spontaneous height velocity, IGF-I, and IGFBP-3 levels was found at the start of rhGH therapy in the three GHR genotype groups studied. At the first year of treatment, girls with Turner syndrome carrying one or two d3-GHR alleles showed a significantly higher increment in height velocity (P = 0.019) and exceeded their growth prediction significantly (P = 0.007), whereas their increments of IGF-I and IGFBP-3, weight, and height were not significantly different. Carriers of d3-GHR in the group of short children born SGA grew significantly faster than predicted (P = 0.023). However, in comparison to the carriers of full-length GHR, gain of height velocity was not significantly higher (P = 0.067). The mean gain of height associated with d3-GHR accounted for approximately 0.75 cm in SGA and 1.5 cm in Turner syndrome during the first year of rhGH therapy. CONCLUSIONS: Our data support the theory that there is increased responsiveness to high-dose rhGH in association with the d3-GHR genotype. The magnitude of this effect may depend on the primary origin of the short stature.     

Growth hormone treatment in children.

GH therapy increases final height in GH-deficient children. Short-term growth acceleration is also seen in children with many other causes of shortness. This review covers the diagnosis of GH-deficiency (GHD) and the details of GH treatment and its long-term results in GH-deficient patients and in those with other conditions, including "idiopathic short stature" and Turner syndrome. The efficacy of GH in enhancing adult stature in children with diagnoses other than GHD and Turner syndrome has not been established, and the only other indication for which it is approved by the U.S. Food and Drug Administration is chronic renal insufficiency. Broadening of the indications for GH use in childhood can only occur if supported by the results of carefully performed clinical trials. (Trends Endocrinol Metab 1997;8:92-97). (c) 1997, Elsevier Science Inc.     

Optimal use of growth hormone therapy for maximizing adult height in children born small for gestational age

Growth retardation is a well-known complication of being born small for gestational age (SGA). Approximately 10% of children born SGA do not experience postnatal catch-up growth and are at risk for short adult height. The use of growth hormone (GH) therapy in these short children appears to increase their adult height, but modalities of GH administration remain controversial. Numerous therapeutic strategies have been developed to optimize the efficacy of GH treatment. Data concerning the influence of age at start of GH treatment, duration of GH treatment, GH dosage and method of GH administration on height gain and adult height are reported in this chapter. Longitudinal studies addressing the safety of GH treatment in SGA children are reassuring, but long-term follow-up remains necessary. Recommendations on the management of SGA children during GH treatment are given.     

Body composition, blood pressure, and lipid metabolism before and during long-term growth hormone (GH) treatment in children with short stature born small for gestational age either with or without GH deficiency

To assess the effects of long-term continuous GH treatment on body composition, blood pressure (BP), and lipid metabolism in children with short stature born small for gestational age (SGA), body mass index (BMI), skinfold thickness measurements, systemic BP measurements, and levels of blood lipids were evaluated in 79 children with a baseline age of 3-11 yr with short stature (height SD-score, < -1.88) born SGA (birth length SD-score, < -1.88). Twenty-two of the 79 children were GH deficient (GHD). All children participated in a randomized, double-blind, dose-response multicenter GH trial. Four- and 6-yr data were compared between two GH dosage groups (3 vs. 6 IU/m2 body surface/day). Untreated children with short stature born SGA are lean (mean BMI SD-score, -1.3; mean SD-score skinfolds, -0.8), have a higher systolic BP (SD-score, 0.7) but normal diastolic BP (SD-score, -0.1), and normal lipids (total cholesterol, 4.7 mmol/L; low-density lipoprotein, 2.9 mmol/L; high-density lipoprotein, 1.3 mmol/L) compared with healthy peers. During long-term continuous GH treatment, the BMI normalized without overall changes in sc fat compared with age-matched references, whereas the BP SD-score and the atherogenic index decreased significantly. Although the mean 6-yr increase in height SD-score was significantly higher in the children receiving GH treatment with 6 IU/m2 x day (2.7) than in those receiving treatment with 3 IU/m2 day (2.2), no differences in the changes in BMI, skinfold measurements, BP, and lipids were found between the GH dosage groups. The pretreatment SD-scores for BMI, skinfold, and BP, as well as the lipid levels, were not significantly different between GHD and non-GHD children, but after 6 yr of GH treatment the skinfold SD-score and BP SD-score had decreased significantly more in the GHD than in the non-GHD children. Our data indicate that GH treatment has at least up to 6 yr positive instead of negative effects on body composition, BP, and lipid metabolism. In view of the reported higher risk of cardiovascular diseases in later life in children born SGA, further research into adulthood remains warranted.     

Benefit of postponing normal puberty for improving final height

Experiments of nature and clinical observations have provided indications that postponing puberty may increase final height in short children. In children with central precocious puberty, a GnRH analog (GnRHa) alone is efficacious in increasing final height, but in other conditions a combination of growth hormone (GH) and GnRHa is needed. In GH-deficient children with early onset of puberty and poor height prediction, the combination of GH and GnRHa increases final height by 1.0-1.3 s.d. In children with idiopathic short stature and persistent short stature after intrauterine growth retardation, the combination also appears to be beneficial. Potential side effects include weight gain, a negative effect on bone mineralization, and psychosocial consequences. More data on long-term safety have to be collected before the combination of GH and GnRHa in children with idiopathic short stature should be considered for clinical use outside clinical trials.     

MRI findings of the pituitary gland in short children born small for gestational age (SGA) in comparison with growth hormone-deficient (GHD) children and children with normal stature

BACKGROUND: Disturbances in the GH/IGF-I axis are reported in 25-60% of short children born small for gestational age (SGA). We hypothesized that these abnormalities might be related to abnormalities in the pituitary region. Therefore, the results of magnetic resonance imaging (MRI) of short SGA children were compared to MRI results of other groups of short children and to normal controls. PATIENTS AND METHODS: MRI was performed in four groups of short children: SGA children without GH deficiency (SGA group; n = 17), SGA children with isolated GH deficiency (SGA + IGHD group; n = 10), non-SGA children with isolated GH deficiency (IGHD group; n = 24) and non-SGA children with multiple pituitary hormone deficiencies (MPHD group; n = 15). MRI was also performed in children with normal stature (control group; n = 13). Pituitary height (PH) and thickness of the pituitary stalk (PS) were measured and their relationship with the maximum GH peak during a GH stimulation test, serum IGF-I and IGFBP-3 levels was evaluated. RESULTS: Short SGA children either with or without IGHD did not show major anatomical abnormalities in the hypothalamic-pituitary region in contrast to 58% of the non-SGA IGHD children and 87% of the MPHD children who had anatomical abnormalities. PH in SGA children without GHD was normal whereas it was significantly lower in SGA children with IGHD. The lowest PHs were measured in non-SGA children with MPHD. A moderate decrease in PH was associated with significantly lower maximum serum GH peaks and lower serum IGF-I and IGFBP-3 levels. CONCLUSION: Measuring PHs in children with less severe GHD, who underwent MRI as part of the diagnostic process, might support the diagnosis of GHD even in the absence of anatomical abnormalities. Our study demonstrates that there is no indication to perform MRI of the pituitary region in short children born SGA without GHD.     

Neutrophil count in small-for-gestational age children: contrasting effects of metformin and growth hormone therapy

A minority of children born small for gestational age (SGA) maintain a slow weight gain and a short stature (SS). At the other end of the spectrum are SGA children who show rapid postnatal weight gain and catch-up growth; these subjects may develop hyperinsulinemia, exaggerated adrenarche with precocious pubarche (PP), and an associated proinflammatory state with raised IL-6 and reduced adiponectin levels. Metformin therapy in SGA-PP girls attenuates the hyperinsulinemia, the adrenal androgen excess, and the proinflammatory state. In contrast, GH therapy in SGA-SS children promotes height gain but may induce hyperinsulinemia. Both groups are associated with increased risk markers for future cardiovascular disease. Therefore, we studied markers of inflammation in both SGA subpopulations at baseline and after their respectively corrective therapies. SGA-PP girls (n = 33; mean age, 8 yr; body mass index, 18.5 kg/m(2)) were randomized to remain untreated or to receive metformin (425 mg/d) for 6 months. SGA-SS children (n = 29; mean age, 7 yr; body mass index, 14.7 kg/m(2)) were randomly assigned to remain untreated or to receive GH (60 mug/kg/d). In SGA-PP girls, the mean neutrophil count (4.0 x 1000/mm(3)) was more than 2 sd above the mean reference level (2.8 x 1000/mm(3), P < 0.001); this remained stable over 6 months in untreated girls but dropped in metformin-treated girls by -1.1 x 1000/mm(3) (P = 0.002). In SGA-SS children, neutrophil counts were also higher at baseline (3.3 x 1000/mm(3), P < 0.01). This remained stable in untreated children but rose in GH-treated children by +1.1 x 1000/mm(3) (P = 0.004). GH-treated children also showed a rise in circulating IL-6 and dehydroepiandrosterone-sulfate levels and a fall in adiponectin levels. In conclusion, neutrophil counts were elevated in SGA children. In SGA girls with PP, the present results corroborate the antiinflammatory benefits of metformin therapy. In contrast, high-dose GH therapy in short SGA children may increase neutrophil counts and lead to a less favorable adipocytokine profile. Future studies with combined GH plus metformin treatment in short SGA children may clarify whether insulin resistance is a mechanism linking GH therapy to markers of inflammation.     

Growth outcomes in individuals with idiopathic short stature treated with growth hormone therapy

The few studies that have evaluated the long-term height outcomes following growth hormone (GH) treatment in children with idiopathic short stature (ISS) have shown a growth response to GH treatment similar to that in GH-deficient children. A literature search of all randomized and nonrandomized studies of GH treatment in children with ISS from prepubertal years to adult height or near-adult height published over the last 10 years identified six publications (none was a classic meta-analysis). Several studies showed a dose-dependent response in height outcome. Overall, the younger the patient and the greater the difference in current height vs. parental height at start of treatment, the more substantial the gain in height. Height improvement ranged from 0.5 to 1.3 standard deviation score (SDS). The magnitude of height gain was substantial, even after adjustment for growth changes in control subjects (0.5 to 1 SDS), and it was comparable to that seen in other non-GH-deficient syndromes. Only two studies reported data from matched control subjects. Interestingly, there was no difference in height gain between familial short stature and non-familial short stature after adjusting for spontaneous height gain to adult age in non-GH-treated control subjects. To summarize, patients with ISS can benefit from GH treatment with respect to growth outcome, with results maintained into adulthood.     

Circadian variation of plasma cortisol in prepubertal children with normal stature, short stature and growth hormone deficiency

OBJECTIVES: When studying the relationship between spontaneous secretion of growth hormone (GH) and cortisol in children, most studies show no correlation in mean levels of these two hormones, while others found positive or even strongly negative correlations. These contradictory results could be partly due to the inability to properly compare hormones that are characterized by circadian and ultradian variations in their secretory profiles. We aim here to study possible differences in rhythm characteristics of plasma cortisol with stature and to compare the circadian secretory patients of cortisol and GH. PATIENTS: We analysed data from 135 prepubertal children: (1) 14 GH-deficient children; (2) 36 children with short stature (2-3 SD below their peer group mean); (3) 57 children with very short stature (3-4 SD below their peer group mean); and (4) a reference group of 28 children with normal stature (+/- 2 SD). Subjects were living in a hospital setting on a diurnal waking (07.30-22.30 h), nocturnal resting routine during sampling, consuming the usual hospital diet at fixed times. MEASUREMENTS: Cortisol and GH concentrations were determined by radioimmunoassay in plasma obtained at about 2-3 h intervals during most of the day and at half-hour intervals between 22.00 and 02.00 h. Circadian rhythm characteristics obtained by least-squares estimation were compared between groups divided according to gender and stature with a parameter test. RESULTS: Show a statistically significant circadian rhythm in cortisol secretion for all groups studied (P < 0.001 in all cases). A comparison of circadian parameters indicated similar characteristics between subjects of short, very short and normal stature. Despite a borderline statistically significant difference in rhythm-adjusted mean and amplitude of GH between nondeficient and GH-deficient children, there was no difference in the circadian pattern of cortisol secretion between these two groups. No correlation was found in circadian mean, amplitude, average, standard deviation, standard error, minimum or maximum between GH and cortisol for any of the groups of children. CONCLUSIONS: Any possible relation between GH and cortisol remains unclear. Moreover, GH-deficient children are not necessarily characterized by either hyper- or hypocortisolaemia.