Final height data, body composition and glucose metabolism in growth hormone-treated short children born small for gestational age

Low birth weight has been associated with impaired insulin sensitivity, type 2 diabetes mellitus, hypertension and cardiovascular disease in later life. GH therapy is known to increase fasting and postprandial insulin levels. For this reason concern has been expressed regarding the possible detrimental effects of GH therapy in children born small for gestational age (SGA). To assess the effects of GH therapy on body composition, carbohydrate metabolism and final height in short SGA children, 165 prepubertal short children born SGA were enrolled in either a multicentre, double-blind, randomized, dose-response GH trial (n = 75) or in a GH controlled trial (n = 90). The inclusion criteria were: (1) birth length standard deviation score (SDS) below -2; (2) age 3-8 years; (3) height SDS below -2. The children's mean (SD) age was 7.3 (2.1) years (GH dose-response trial) and 6.0 (1.5) years (GH controlled trial), birth length SDS was -3.6 and height SDS was -3.0 (0.7). In the GH dose-response trial, children were randomly assigned to either 1 mg GH/m(2) per day (group A, n = 41) or 2 mg GH/m(2) per day (group B, n = 38) ( approximately 0.033 or 0.067 mg/kg per day, respectively). In the GH controlled trial, children were randomly assigned to 1 mg GH/m(2) per day (n = 60) or served as controls (n = 30). Subjects underwent standard oral glucose tolerance tests and measurement of body mass index, systolic and diastolic blood pressure and serum lipids at baseline and after 1 and 6 years of GH therapy and again 6 months after discontinuation of GH. Body composition was measured by dual energy x-ray absorptiometry at baseline and again after 3 years in the GH controlled trial. Mean (SD) final height SDS was not significantly different between the two GH dosage groups: -1.2 (0.7) in group A and -0.8 (0.7) in group B. At the start of GH therapy, 8% of children had impaired glucose tolerance (IGT). Systolic blood pressure was significantly higher in comparison with healthy peers. GH therapy induced considerably higher fasting and glucose-stimulated insulin levels after 1 and 6 years, regardless of GH dosage. After 6 years, 4% of children had IGT. Six months after discontinuation of GH, glucose levels remained normal, whereas fasting and glucose-stimulated insulin returned to levels comparable to those of healthy peers. None of the children developed diabetes. During 6 years of GH therapy both systolic and diastolic blood pressure decreased significantly and remained so after discontinuation of GH therapy. At baseline all children had reduced bone mineral content and lean body mass. Fat mass was not significantly lower than normal. Treatment with 1 mg GH/m(2) per day resulted in a significant increase in (and normalization of) bone mineral content and lean body mass in comparison with untreated short SGA controls. Fat mass decreased during the first year of GH but returned to values comparable to those at baseline in the following 2 years of GH therapy. We found that long-term, continuous GH therapy in short children born SGA leads to a normalization of height during childhood and to a normal final height in most children, regardless of GH dosage. Only very short or relatively older children may need a dosage of 2 mg GH/m(2) per day. Long-term GH therapy had no adverse effects on glucose levels and serum lipids and had a positive effect on blood pressure, even with GH dosages of up to 2 mg/m(2) per day. However, as has been reported in other patient groups, GH induced higher fasting and glucose-stimulated insulin levels, indicating insulin resistance. After discontinuation of GH serum insulin levels returned to normal age-reference levels. Short SGA children have a reduction in bone mineral content and lean body mass when compared with healthy controls, which significantly improved (normalized) with GH therapy at a dose of 1 mg/m(2) per day.     

Food intake of children with short stature born small for gestational age before and during a randomized GH trial

Parents of short children born SGA often report that their children have a serious lack of appetite and a low food intake. In this study we investigated food intake, by using a standardized 7-day food questionnaire, in 88 short SGA children before start of GH treatment. The intake was compared with the recommended daily intake (RDI) of age-matched children. We also compared the food intake of GH-treated children (n=62) with randomized controls (n=26) after 1 year of GH treatment. In addition, we evaluated the effect of food intake and GH treatment on body composition and serum levels of IGF-I, IGFBP-3 and leptin. Our study shows that caloric intake, fat and carbohydrate intake of short SGA children aged 5.9 (1.6) years was significantly lower compared to the RDI for age-matched children. One year of GH treatment resulted in a significant increase of caloric, fat, carbohydrate and protein intake compared to baseline. Compared to randomized controls, caloric, carbohydrate and protein intake increased significantly after 1 year of GH treatment. Short SGA children had significantly lower SDS scores for LBM, fat mass, skinfold (SF) and BMI compared to age-matched references. They also had significantly lower serum IGF-I, IGFBP-3 and leptin levels. GH treatment resulted in a significant increase of height, LBM, BMI, IGF-I and IGFBP-3 SDS and a significant decrease of SF SDS and leptin SDS. In conclusion, our study shows that short SGA children have indeed a lower food intake than age-matched controls. During GH treatment the food intake increased significantly compared to baseline in contrast to the randomized control group.     

Growth hormone treatment in short Japanese children born small for gestational age

Recent reports have shown that high-dose growth hormone (GH) treatment in short children born with small for gestational age (SGA) resulted in a pronounced acceleration of linear growth. We describe the results of multicenter trials of recombinant human GH (rhGH) treatment in short SGA children in Japan. Two clinical studies were performed and the results were combined. Study 1 comprised 104 SGA children and study 2 comprised 61 SGA children. The patients were divided into three groups: group 1 consisted of 20 patients (13 boys and 7 girls) who received rhGH 25 microg/kg per day six or seven times per week in the first year and 50 microg/kg per day in the second year and thereafter; group 2 consisted of 48 patients (28 boys, 20 girls) who received rhGH 45/50 microg/kg per day; group 3 consisted of 44 patients (28 boys, 16 girls) who received 90/100 microg/kg per day. The mean increments in height SDS were 0.46, 0.67 and 0.94 SD in boys and 0.49, 0.79 and 0.93 SD in girls in groups 1, 2 and 3, respectively. The mean increment in height SDS at 2 years in group 3 was significantly greater than that in group 1, but it was not significantly different from that in group 2 in boys and girls. Our data demonstrated that high-dose GH administration significantly improved height velocity and height SDS in short SGA children. Additional studies are necessary to optimize a long-term GH treatment regimen and combined luteinizing hormone releasing hormone analog treatment for final height. Careful observation is also necessary to assess the metabolic effects of high-dose GH, especially on carbohydrate metabolism.     

Effects of growth hormone treatment on cognitive function and head circumference in children born small for gestational age

Short stature is not the only problem faced by children born small for gestational age (SGA). Being born SGA has also been associated with lowered intelligence, poor academic performance, low social competence and behavioural problems. This paper summarizes the results of a randomized, double-blind, growth hormone (GH) dose-response study (1 or 2 mg/m2/day [ approximately 0.035 or 0.07 mg/kg/day]) on growth, intelligence quotient (IQ) and psychosocial functioning in 79 children born SGA at the start, and after 2 and 8 years of GH therapy, and addresses the associations with head circumference. Mean age at start of therapy was 7.4 years; mean duration of GH treatment was 8.0 years. In 2001, 91% of children born SGA had reached a normal height (> -2.0 standard deviation score [SDS]). Block-design s-score (Performal IQ) and Total IQ score increased (p < 0.001 for both indices) from scores significantly lower than those of Dutch peers at the start of therapy (p < 0.001) to scores that were comparable to those of Dutch peers in 2001. Vocabulary s-score (Verbal IQ) was normal at the start of therapy and remained so over time. Externalizing Problem Behaviour SDS and Total Problem Behaviour SDS improved during GH therapy (p < 0.01-0.05) to scores comparable to those of Dutch peers. Internalizing Problem Behaviour SDS was comparable to that of Dutch peers at the start of therapy and remained so, whereas Self-Perception improved from the start of GH therapy until 2001 (p < 0.001), when it reached normal scores. Head circumference SDS at the start of GH therapy and head growth during GH therapy were positively related to all IQ scores (p < 0.01), whereas neither were related to height SDS at the start of, or to its improvement during, GH therapy. A significant improvement in height and head circumference in children born SGA was seen after only 3 years of GH therapy, in contrast to randomized SGA controls. In conclusion, most children born SGA showed a normalization of height during GH therapy and, in parallel to this, a significant improvement in Performal IQ and Total IQ. In addition, problem behaviour and self-perception improved significantly. Interestingly, Performal, Verbal and Total IQ scores were positively related to head circumference, both at the start of, and during, GH therapy; head circumference increased in GH-treated children born SGA, but not in untreated SGA controls. These results are encouraging but also warrant confirmational studies and further investigations into the effects of GH on the central nervous system.     

Methylphenidate and the Response to Growth Hormone Treatment in Short Children Born Small for Gestational Age

Background

Growth hormone (GH) treatment has become a frequently applied growth promoting therapy in short children born small for gestational age (SGA). Children born SGA have a higher risk of developing attention deficit hyperactivity disorder (ADHD). Treatment of ADHD with methylphenidate (MP) has greatly increased in recent years, therefore more children are being treated with GH and MP simultaneously. Some studies have found an association between MP treatment and growth deceleration, but data are contradictory.

Objective

To explore the effects of MP treatment on growth in GH-treated short SGA children

Methods

Anthropometric measurements were performed in 78 GH-treated short SGA children (mean age 10.6 yr), 39 of whom were also treated with MP (SGA-GH/MP). The SGA-GH/MP group was compared to 39 SGA-GH treated subjects. They were matched for sex, age and height at start of GH, height SDS at start of MP treatment and target height SDS. Serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels were yearly determined. Growth, serum IGF-I and IGFBP-3 levels during the first three years of treatment were analyzed using repeated measures regression analysis.

Results

The SGA-GH/MP group had a lower height gain during the first 3 years than the SGA-GH subjects, only significant between 6 and 12 months of MP treatment. After 3 years of MP treatment, the height gain was 0.2 SDS (±0.1 SD) lower in the SGA-GH/MP group (P = 0.17). Adult height was not significantly different between the SGA-GH/MP and SGA-GH group (−1.9 SDS and −1.9 SDS respectively, P = 0.46). Moreover, during the first 3 years of MP treatment IGF-I and IGFBP-3 measurements were similar in both groups.

Conclusion

MP has some negative effect on growth during the first years in short SGA children treated with GH, but adult height is not affected.     

IGF-I and IGF binding protein-3 levels during initial GH dosage step-up are indicators of GH sensitivity in GH-deficient children and short children born small for gestational age

BACKGROUND: A stepwise increment of the GH dose is an approach aimed at avoiding adverse events. We investigated GH sensitivity by studying IGF-I and IGFBP-3 concentrations during the initial phase of GH treatment. METHODS: Our investigation was part of the regular follow-up of prepubertal children with GH deficiency (GHD) (n = 31) and small for gestational age (SGA) (n = 23). Dosage was increased in three steps: one-third at the start, two-thirds after 14 days, and the full dose after 28 days (full dose: GHD = 28 microg/kg body weight (BW)/day; SGA = 60 microg/kg BW/day). Blood samples were taken on days 0, 14 and 28, as well as in conjunction with anthropometrical examinations after 3, 6 and 12 months. IGF-I and IGFBP-3 were measured by means of published in-house RIAs and age-related references were used to calculate standard deviation scores (SDS). Height velocity (cm/year) and Delta HT SDS were taken as growth response parameters. RESULTS: Before GH treatment (GHD vs. SGA; median and p values): age (years) (6.6 vs. 6.0; n.s.), HT SDS (-2.6 vs. -3.2; p < 0.05); GH amount after stepping up (mug/kg BW/day) (28 vs. 60; p < 0.01); BW SDS (-0.5 vs. -2.9; p < 0.01); max. GH stimulated (microg/l) (5.6 vs. 10.8; p < 0.01); IGF-I SDS (-3.5 vs. -1.8; p < 0.01); IGFBP-3 SDS (-2.0 vs. 0.8; p < 0.01). After 1 year of GH therapy: HT velocity (cm/year) (9.8 vs. 9.6; n.s.), Delta HT SDS (0.9 vs. 0.9; n.s.); WT velocity (kg/year) (3.3 vs. 3.5; n.s.). Our results show that changes in growth similar to GHD could be induced in SGA by a dosage that was twice as high as the replacement dose given in GHD. GH dose and HT velocity did not correlate in both groups. IGF-I and IGFBP-3 increased as follows in GHD and SGA during stepping up of the dosage (ng/ml, GHD vs. SGA): at start, 54 vs. 89; at day 14, 78 vs. 132; at day 28, 90 vs. 167; at 3 months, 118 vs. 218. There was the same relationship between dose levels and absolute IGF-I concentrations in both groups. In terms of IGF-I SDS, the dose-response curve in SGA showed a shift to the right in comparison to GHD, thus indicating lower sensitivity to GH. The dynamics of IGF-I and IGFBP-3 differed, as IGFBP-3 peaked earlier (on day 28). In GHD, IGF-I SDS at 3 months was -0.7 vs. +0.9 in SGA. Near-identical levels were found for Delta IGF-I SDS and IGFBP-3 SDS above basal levels for each time-point investigated. First year HT velocity in GHD correlated negatively with basal IGF-I SDS (R(2) = 0.33; p <0.001) and basal IGFBP-3 (R(2) = 0.17; p <0.05) but did not correlate with the IGF-I increment during the 0- to 3-month period. Conversely, first year HT velocity correlated (+) in SGA with the IGF SDS increment during the 0- to 3-month period (R(2) = 0.26; p = <0.05). Height velocity in SGA, however, correlated neither with basal IGF-I and IGFBP-3 nor with the 0- to 3-month increments of IGFBP-3 SDS. CONCLUSIONS: IGFs increase during initial GH therapy, thus raising questions about short-term IGF generation tests. (I) In terms of IGF generation, substantially lower sensitivity to GH was observable in SGA. (II) Higher GH sensitivity during first year catch-up growth is associated with GHD, but in SGA it is attributable to increases in IGF. A wider range of GH dosages needs to be explored in order to gain further insight into the relationship between GH dose, IGF levels, and growth. Monitoring IGFs is a practical means for exploring GH sensitivity during dosage stepping up.     

Adult height in patients treated for isolated growth hormone deficiency: role of birth weight

To evaluate the effect of growth hormone (GH) administration on adult height (AH) in two groups of isolated GH-deficient (IGHD) children born either small (birth weight below -2 SD) or appropriate (birth weight above -2 SD) for gestational age (GA). Out of 35 prepubertal IGHD children, 14 small for GA (SGA, group A) and 21 appropriate for GA (AGA, group B) were examined. All patients received continuous GH treatment at a median dose of 0.028 mg/kg/day (range 0.023-0.032) in group A and 0.024 (range 0.023-0.028) in group B. GH treatment was administered for a period of 67.0 months (range 42.37-96.05) in group A and 54.31 months (range 47.14-69.31) in group B. All children were measured using a Harpenden stadiometer every 6 months until they reached AH (growth velocity <1 cm/year). The patients underwent a retesting a few months after stopping GH therapy. A significant difference was found between group A and B as expected for birth weight SD, -2.70 (range -2.87 to -2.29) and -0.73 (range -1.30 to 0.14) respectively (p < 0.000001) and interestingly also for body mass index SDS (BMI SDS) at retesting, 0.08 (range 0.30 to -1.51) and 0.61 (range 0.73 to -1.10) respectively (p < 0.04). We observed no significant differences between groups A and B in height (expressed as the SDS for chronological age, height SDS) at diagnosis (p = 0.75), height SDS at start of puberty (p = 0.51), height SDS at retesting (p = 0.50), target height SDS (TH SDS) (p = 0.47), AH SDS (p = 0.92), corrected height SDS (height SDS - TH SDS) (p = 0.60), BMI SDS at diagnosis (p = 0.25), GH dosage (p = 0.34) and therapy duration (p = 0.52). GH treatment with a standard dose in short IGHD children leads to a normalization of AH without any significant difference between SGA and AGA patients.     

Serum leptin in short children born small for gestational age: dose-dependent effect of growth hormone treatment

OBJECTIVE: To study the effects of different regimens of growth hormone (GH) treatment on serum leptin levels in 78 short prepubertal children born small for gestational age (SGA). METHODS: The children were originally included in two independent multicenter trials, one in Belgium and one in the Nordic countries. SGA children were randomized either to remain untreated or to be treated with GH at a daily dose of 0.1, 0.2 or 0.3 IU/kg for 2 years. Thereafter, treatment was continued for another 2 years in the Nordic children, whereas it was discontinued in the Belgian children. RESULTS: In the GH treatment groups, a significant dose-dependent decrease in leptin levels was found during the first year of therapy, with a mean decrease of 13, 23 and 32% in the groups receiving GH at 0.1, 0.2 and 0.3 IU/kg, respectively. When high-dose treatment was interrupted, serum leptin increased within 1 year to pretreatment levels. CONCLUSION: Serum leptin levels in short children born SGA are transiently reduced by GH treatment in a dose-dependent fashion. The most pronounced changes in serum leptin were documented within the first year after initiation and withdrawal of high-dose GH treatment.     

Plasma levels of insulin-like binding protein-2 in prepubertal short children and its diagnostic value in the evaluation of growth hormone deficiency

AIM: This study was designed to investigate whether determination of plasma insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) levels could be of benefit in the evaluation of childhood growth hormone (GH) deficiency (GHD). METHOD: A retrospective analysis was performed on 91 prepubertal children referred for investigation of short stature. Maximal GH levels in plasma after provocative stimuli were between 1.0 and 93.0 mU/l, 6 subjects exhibiting peak values of <5 mU/l. Initially a GH peak of 20 mU/l was used as a cutoff limit to define GHD and idiopathic short stature (ISS) patients. The results of GH provocative tests were compared to age- and gender-based standard deviation scores (SDS) of plasma IGFBP-2, IGF-I, IGFBP-3 and the molar ratios of the latter two to IGFBP-2. The respective normative range values for these parameters were determined in plasma samples from 353 healthy children (i.e. 171 girls, 182 boys). RESULTS: Circulating IGFBP-2 levels did not correlate with height SDS, height velocity SDS or the peak GH levels after provocative stimuli. A weak negative relationship was found between IGFBP-2 and IGF-I. Plasma levels of IGFBP-2 in GHD patients were higher than those of ISS children, who had normal levels. Although at the optimal cutoff point of -0.71 SDS 91.5% of the GHD patients were identified correctly, a substantial proportion (71.9%) of the ISS subjects also had IGFBP-2 levels above this limit. The use of various combinations of IGFBP-2, IGF-I, IGFBP-3 and the derived ratios only slightly improved the diagnostic efficiency as compared to the results of the individual tests. Neither IGFBP-2 nor the IGFBP-3/IGFBP-2 and IGF-I/IGFBP-2 ratios were found to be related to the short- (1 year) or long-term (3 years) growth response to GH therapy. CONCLUSION: It is concluded that none of the tests investigated, either alone or in various combinations, are reliable in either predicting the peak GH level after provocative stimuli in prepubertal short children or in predicting their growth response to GH.     

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.     

Bone age progression during the first year of growth hormone therapy in pre-pubertal children with idiopathic growth hormone deficiency, Turner syndrome or idiopathic short stature, and in short children born small for gestational age: analysis of data from KIGS (Pfizer International Growth Database)

BACKGROUND/AIMS: The beneficial effects of growth hormone (GH) therapy on statural growth in children are well established, but the effects on skeletal maturation are less clear. The progression of bone age (BA) was therefore studied during the first year of GH treatment in pre-pubertal children with idiopathic GH deficiency (GHD), Turner syndrome (TS) or idiopathic short stature (ISS), and in short pre-pubertal children born small for gestational age (SGA). METHODS: Cross-sectional data on 2,209 short children with idiopathic GHD, 694 with TS, 569 with ISS and 153 with SGA were analysed. Longitudinal data were also analysed from 308 children with idiopathic GHD, 99 with TS, 57 with ISS and 29 with SGA. All patients included in the study were enrolled in KIGS (Pfizer International Growth Database) and were being treated with recombinant human GH (Genotropin). BA was assessed using the Greulich and Pyle method at baseline and after 1 year of GH therapy. RESULTS: In all groups of patients the mean progression of BA was 1 year during the year of GH therapy, although there was considerable individual variation. Progression of BA was not correlated with chronological age, BA, height SD score (SDS) or body mass index SDS at the onset of GH therapy. There was also no consistent effect of the GH dose on BA progression. CONCLUSION: Progression of BA appears to be normal in patients receiving GH in these diagnostic groups, at least over the first year of treatment in pre-puberty.     

Growth hormone treatment of short children born small for gestational age: a US perspective

Research during the last decade shows clearly that growth hormone (GH) therapy causes a sustained increase in growth velocity when applied to short children born small for gestational age (SGA). This occurs even though GH deficiency per se is an unlikely explanation for their lack of catch-up growth. In the United States, children born weighing less than -2 SD for gestational age and who show no growth recovery (usually defined as stature persisting below -2 SD at age 2 years) are eligible for GH treatment using doses up to 0.48 mg/kg per week. The management of these children brings new challenges to the pediatric endocrinologist. Intrauterine growth retardation reflects a variety of etiologies, some of which merit special consideration and may respond variably to GH. The dose of GH used exceeds physiologic replacement and is higher than that commonly used to treat other non-GH-deficient conditions such as Turner syndrome. Thus, what constitutes optimal therapy in terms of dose, timing and patient selection remains an important question. While GH therapy provides a means by which one aspect of the SGA syndrome can be helped, there are other issues for SGA apart from height. Future efforts should include studies that better define how GH should be used in the short child born SGA and address more broadly the medical, social and psychological needs of these patients.     

Growth hormone activates renin-aldosterone system in children with idiopathic short stature and in a pseudohypoaldosteronism patient with a mutation in epithelial sodium channel alpha subunit

Growth hormone (GH) treatment causes salt and water retention, and this effect has been suggested to be mediated by activation of epithelial sodium channel (ENaC). Multi-system pseudohypoaldosteronism (PHA) is a salt wasting disease resulting from mutations in ENaC subunit genes. We examined effects of GH therapy for 12-21 months on the renin-angiotensin-aldosterone system (RAAS) in 12 children with idiopathic short stature (ISS) and a PHA patient with defective ENaC function and concomitant GH deficiency. On GH therapy (0.7 U/kg/week), plasma renin activity (PRA), serum aldosterone and insulin-like growth factor-I (IGF-I) levels were periodically determined every 1-3 months in all children. The PHA patient was studied for 6 yr during which time serum, urine, and sweat electrolytes and secretion rate were also examined before, on and off GH therapy. In the PHA patient, mean plasma aldosterone concentration, 7.7 nmol/l (278 ng/dl) before therapy (n=9) rose to 73 nmol/l (2650 ng/dl) 10 months after GH. PRA and IGF-I increased similarly, reaching a plateau between 8 and 12 months. Off GH, there was a decrease to pretreatment levels in 30 months. Aldosterone and PRA strongly correlated with IGF-I (r=0.66 and 0.67). GH therapy also improved the growth rate, and increased both sweat secretion rate and Na(+)/K(+) ratio. In children with ISS, aldosterone and IGF-I peaked 6-12 months after GH. Off GH their levels normalized in 3 months. These findings indicate that long-term GH activates the RAAS in both children with ISS and a PHA patient, and that this effect does not depend on a fully functional ENaC.     

Five-year follow-up of a 13-year-old boy with a pituitary adenoma causing gigantism--effect of octreotide therapy

BACKGROUND/AIM: In children, there is little experience with octreotide therapy for pituitary tumors, especially growth hormone (GH) producing adenomas. We report on a 13-year-old boy with gigantism due to a GH-producing pituitary adenoma caused by a Gsalpha mutation on the basis of McCune-Albright syndrome. METHODS: At the age of 6.5 years a GH- and prolactin-producing pituitary adenoma was diagnosed. The adenoma was surgically removed. Immediately thereafter, the small adenoma residuum was treated with octreotide (2 x 100 microg/day s.c.). RESULTS: During therapy with octreotide, the growth rate dropped to normal values; however, rose again after 2 years of treatment. The insulin-like growth factor I (IGF-I) levels remained above the 95th percentile, the GH level mostly >2 microg/l. After 5 years of octreotide therapy, GH (6.9 microg/l), IGF-I (620 microg/l), IGF-binding protein 3 (5.4 mg/l), and prolactin (17.0 ng/ml) levels were still elevated. The growth velocity was +2.4 SDS (standard deviation score), the pubertal status was mature, and the bone age was 14.3 years (prospective final height 208 cm). A magnetic resonance imaging scan showed an unchanged residual 4-mm rim of adenoma at the pituitary site. Side effects from octreotide therapy were not reported by the patient or his family. The therapy was changed to the long-acting release octreotide analog octreotide-LAR. After 1 year of treatment with octreotide-LAR, the GH level was 1.0 microg/l, and the prospective final height dropped by 10 cm. CONCLUSIONS: This case demonstrates that combined surgical and medical treatment can influence the prognosis of childhood gigantism; however, the prognosis of this rare condition remains uncertain.     

Subcutaneous treatment with growth hormone-releasing hormone for short stature

In the present study we report the effects of therapy with growth hormone-releasing factor (1-29)NH2 (GRF) on growth rate, plasma levels of insulin growth factor I (IGF-I) and growth hormone (GH) secretion in 11 children who were selected solely on the basis of their short stature and normal GH secretion on standard provocative tests. All children received GRF for 6 months (5 micrograms/kg body weight subcutaneously) each evening. The 24-hour GH secretory profile was studied before and after 6 months of treatment. Simultaneously, GH secretory responses to single intravenous bolus GRF (1.5 micrograms/kg body weight) were also studied before, during, and 6 months off therapy with GRF(1-29)NH2. Plasma levels of IGF-I were measured before, during (1, 2 and 6 months), and after 6 months off therapy with GRF. Statural growth was measured at 3-month intervals. The peak plasma GH level in response to GRF was 56.04 +/- (SD) 24.46 ng/ml before treatment, and similar results were found after therapy. The 24-hour GH secretory profile did not show differences before, during, and after treatment. Comparably, no differences were found in GH pulse frequency, pulse amplitude, pulse height, pulse increment, pulse area and total area before, and 6 months off therapy with GRF. The increments in serum IGF-I achieved were not significantly different at all intervals studied. All patients increased growth velocities (mean +/- SD, cm/year) in response to GRF therapy. Our results demonstrate that GRF administration was effective in accelerating growth velocity in 11 children without GH deficiency.     

Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat

Growth hormone (GH) therapy is often associated with adverse side effects, including impaired insulin sensitivity. GH treatment of children with idiopathic short stature does not lead to an optimized final adult height. It has been demonstrated that FFA reduction induced by pharmacological antilipolysis can stimulate GH secretion per se in both normal subjects and those with GH deficiency. However, to date, no investigation has been undertaken to establish efficacy of combination treatment with GH and FFA regulators on linear body growth. Using a model of maternal undernutrition in the rat to induce growth-restricted offspring, we investigated the hypothesis that combination treatment with GH and FFA regulators can enhance linear body growth above that of GH alone. At postnatal day 28, male offspring of normally nourished mothers (controls) and offspring born with low birth weight [small for gestational age (SGA)] were treated with saline, GH, or GH (5 mg.kg(-1).day(-1)) in combination with acipimox (GH + acipimox, 20 mg.kg(-1).day(-1)) or fenofibrate (GH + fenofibrate, 30 mg.kg(-1).day(-1)) for 40 days. GH plus acipimox treatment significantly enhanced linear body growth in the control and SGA animals above that of GH, as quantified by tibial and total body length. Treatment with GH significantly increased fasting plasma insulin, insulin-to-glucose ratio, and plasma volumes in control and SGA animals but was not significantly different between saline and GH-plus-acipimox-treated animals. GH-induced lipolysis was blocked by GH plus acipimox treatment in both control and SGA animals, concomitant with a significant reduction in fasting plasma FFA and insulin concentrations. This is the first study to show that GH plus acipimox combination therapy, via pharmacological blocking of lipolysis during GH exposure, can significantly enhance the efficacy of GH in linear growth promotion and ameliorate unwanted metabolic side effects.     

Growth in disorders of adrenal hyperfunction

Growth is disturbed by adrenal hypersecretion of androgens or cortisol. Androgen excess in virilizing adrenal tumours causes advanced growth and bone age. In 9 girls with virilizing tumours, mean heights at diagnosis and final heights were 1.23 +/- 0.42 and 1.3 +/- 0.37 SDS respectively. In poorly controlled CAH, excess androgens cause early epiphyseal fusion and adult short stature. Increased growth occurs only after 18 months of age, even in untreated CAH, i.e. hydrocortisone >10 mg/m(2)/day is not generally required and may suppress infantile growth, affecting childhood and adult height. Growth was studied in 19 patients, aged 6.4-17.8 years, with Cushing's disease (CD). At diagnosis, mean height SDS was -1.81 (1.2 to -4.17), 53% < -1.8 SDS, height velocity in 6 was 0.9-3.8 cm/year and mean BMI SDS 2.29 (0.7-5.06). From 1983 to 2001, CD was cured in 18 patients (61%) by transsphenoidal surgery (TSS) alone and 39% by TSS plus pituitary irradiation (RT). In 13 patients, growth hormone (GH) was assessed by ITT/glucagons at 1-108 months after cure. Four had severe GH deficiency (<9 mU/l), 7 subnormal (10-29 mU/l) and 2 normal (>30 mU/l) GH status. Subnormal GH was present in 7 subjects >2 years after TSS or RT cure. In 10 subjects, aged 12.9 +/- 3.4 years, growth after cure was studied for 9.1 +/- 5.0 years. Nine had no catch-up growth in the interval of 0.3-1.1 years after cure (mean HV 5.3 +/- 2.4 cm/year). All these had GH deficiency peak GH 0.5-20.9 mU/l, and received hGH 2.7 mg/m(2)/week, 3 with GnRHa. All 10 showed long-term catch-up growth with mean delta SDS at diagnosis (Ht SDS-target Ht SDS) -1.72 +/- 1.26 improving to -0.83 +/- 1.08 (p = 0.0005) at latest of final Ht. At diagnosis, virilization was present in 82% of 17 patients with CD. Mean SDS values of serum androstenedione, DHEA-S and testosterone were normal, i.e. 0.72 (-2.9 to 3.0), -0.8 (6.0 to 2.2), 0.7 (-7.9 to 9.5) respectively, whereas SHBG was reduced at -2.1 (-5.3 to 1.2), increasing free androgen levels. Bone age (BA) was delayed (mean 1.46 years) in 14/16 patients, suggesting cortisol excess contributed more then androgen effect to skeletal maturation. In conclusion, most paediatric patients with CD had subnormal linear growth with delayed BA. After cure by TSS or pituitary irradiation, GH deficiency was frequent and persisted for many years. Treatment with hGH induced significant long-term catch-up growth leading to reasonable final height.     

Dehydroepiandrosterone sulfate treatment for atrichia pubis

OBJECTIVE: To evaluate the efficacy of oral dehydroepiandrosterone sulfate (DHEAS) treatment for atrichia pubis in female adolescents. STUDY DESIGN: Two XY female adolescents with 17-hydroxylase deficiency and 2 XX females with panhypopituitarism presenting with atrichia pubis were treated with a daily dosage of DHEAS 10 mg/m2 body surface in addition to their regular substitution therapy. The dosage was increased according to clinical response. Pubic hair stages, growth and serum DHEAS were evaluated and in 1 case also serum IGFs and IGFBPs. RESULTS: A dosage of 10 mg/m2 for 1 year led to serum DHEAS levels at the lower limit of the normal range. 15 mg/m2 was needed to achieve pubic hair stage 4-5 and axillary hair in patients with 17-hydroxylase deficiency. In panhypopituitarism, pubic hair developed at a slower pace and reached stage 4 on a dosage of 25-30 mg/m2. Baseline serum IGF-I SDS was -0.67 and did not change on the initial dosage of DHEAS, in combination with submaximal estrogen substitution (10 microg ethinyl estradiol). On the combination of 15 mg/m2 DHEAS and full estrogen substitution, IGF-I SDS increased to an average of -0.15. IGFBP-3 SDS increased from 1.4 to a mean of 2.6 in the first year, and went back to 1.4 in the second year. IGFBP-6 SDS was low at baseline (-2.5) and rose to -1.9 and -1.7 IGF-II and IGFBP-1 showed an irregular pattern. CONCLUSIONS: Oral administration of DHEAS in a dosage of 15 mg/m2 o.d. is an efficacious treatment for atrichia pubis. For females with a panhypopituitarism a higher dosage appears needed. Given this and other biological actions of DHEAS, substitution therapy with DHEAS or DHEA to females with adrenal androgen deficiency appears rational.     

Quality of life in adolescents born small for gestational age: does growth hormone make a difference?

BACKGROUND/AIMS: To evaluate quality of life (QoL) in adolescents born SGA without spontaneous catch-up growth, treated with and without long-term growth hormone (GH) therapy. Additionally, to assess whether GH treatment has a positive effect on QoL, besides improving adult height and height SDS during childhood. METHODS: Two groups of adolescents born SGA without spontaneous catch-up growth participated in the QoL evaluation; a GH-treated group (n = 44, mean GH duration: 8.8 (1.7) years) and an untreated group (n = 28), both mean age 15.8 (2.1) years. QoL was measured by self-reports of the TACQOL-S, a disorder-specific questionnaire, and the CHQ, a generic questionnaire. RESULTS: The GH group scored significantly better health status and health-related QoL on several scales of the TACQOL-S. On all TACQOL-S scales the GH group scored better QoL than the untreated group, with effect sizes of moderate to large, not all differences reaching statistical significance. The generic CHQ did not reveal significant differences in QoL between the GH group and the untreated group. CONCLUSIONS: Firstly, adolescents born SGA, with a GH-induced improved height, had in many aspects a better QoL than untreated adolescents born SGA, according to the disorder-specific questionnaire. Secondly, we advise to use, in addition to a generic questionnaire, a disorder-specific questionnaire for measuring QoL in children treated for short stature, as the generic CHQ did not reveal such differences.     

Effect of different growth hormone dosages on the growth velocity in children born small for gestational age

To assess whether short-term growth hormone (GH) treatment can improve the linear growth in children who were born small for gestational age (SGA), we started a randomized multicenter trial in 26 age- and sex-matched prepubertal children born SGA. During the 1st year of GH therapy, all children received GH 0.23 mg/kg/week, then during the 2nd year, 13 children received the same dose (group A), and in the other 13 children, the dose of GH was doubled, i.e., 0.46 mg/kg/week (group B). During the 1st year of therapy, the growth velocity significantly (p<0.0001) increased in all patients. During the 2nd year, group A showed a significant decrease of the growth velocity (p<0.015), whereas group B maintained the growth rate. The height in group A children significantly increased during the 1st and the 2nd year of GH therapy (p<0.000002 and p<0.000001, respectively), reaching the normal range in 8 out of 13 children at the end of 2 years of GH therapy. The height in group B children significantly increased during the 1st and the 2nd year of GH therapy (p<0.000001 and p<0.000001, respectively), reaching the normal range in all 11 children who completed the GH therapy. The height gain was similar in groups A and B treated with the same GH dosage during the 1st year of therapy. A greater increase in height gain was found in children of group B treated with the higher GH dosage during the 2nd year of therapy as compared with group A (p<0.02). Significant increases in insulin-like growth factor I (p<0.0001), acid-labile subunit (p<0.0002), and bone/chronological age ratio (p<0.0001) were found after the 1st year of GH therapy, but no significant changes were observed during the 2nd year, independently of the GH dose. In conclusion, the height velocity of children born SGA significantly increases during the 1st year of GH therapy, diminishes, but can decrease during the 2nd year, if the GH dosage is not raised.