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.     

Short-term growth response to GH treatment and considerations upon the limits of short-term growth predictions

OBJECTIVES: To investigate the impact of short-term growth measurements on predicting the individual growth response to GH treatment, and to elucidate the possible reasons for the limited accuracy of current growth prediction models for GH-treated children. METHODS: Short-term growth measurements by knemometry and stadiometer in 99 short, GH-treated children (27 girls, 72 boys), aged 10.3 +/- 2.3 years, from the Children's University Hospital, Leipzig, Germany. RESULTS: GH treatment significantly accelerated the mean height velocity (HV) from 4.3 +/- 1.0 to 8.1 +/- 1.8 cm/year during the first year of treatment, the average height standard deviation score (SDS) shifted by +0.52 SD. The variation in HV also increased, from S(2) = 1.0 before to S(2) = 3.4 cm(2)/year(2) during treatment. Lower leg length (LLL) velocity accelerated from 1.6 +/- 0.7 before treatment to 3.4 +/- 1.0 cm/year during the first 8 weeks of treatment. Four coefficients of correlation appeared clinically meaningful: (1) LLL velocity vs. body HV during the first year of GH treatment (r = 0.87), indicating that GH acts simultaneously on leg and rump growth; (2) early (first 8 weeks) LLL velocity vs. 1-year body HV during treatment, with r = 0.61 (R(2) = 0.38), indicating that 38% of the variation in HV during the first year of treatment is already predictable by an initial 8-week period of knemometry; (3) early (first 8 weeks) LLL velocity vs. 1-year LLL velocity during treatment, with r = 0.63 (R(2) = 0.39), and (4) early (first 8 weeks) LLL velocity vs. later LLL velocity, up to the end of the first year, with r = 0.53 (R(2) = 0.28) indicating that the early response on lower leg growth persists for at least 1 year of GH treatment. CONCLUSIONS: (1) Thirty-eight percent of the variation in HV during the first year of GH treatment is predictable by an initial 8-week period of knemometry. This parallels early changes in biochemical markers of bone turnover after GH treatment. (2) There is evidence for a baseline variability in HV both in healthy children and in children with growth disorders that make growth prediction difficult.     

Multicenter clinical trial to evaluate the therapeutic use of recombinant growth hormone from mammalian cells in the treatment of growth hormone neurosecretory dysfunction

The efficacy and safety of a 12-month treatment with recombinant human growth hormone from mammalian cells (r-hGH, Saizen) in growth hormone neurosecretory dysfunction (GHND) are evaluated in this study. r-hGH was administered subcutaneously, at a dosage of 0.5 IU/kg/week divided into 6 equal daily doses. A total of 16 (12 M and 4 F) poorly growing patients, height -2.3 SD or more below the mean for chronological age and sex, were included in the study. r-hGH therapy significantly increased the growth velocity; from 3.57 +/- 0.85 cm/year, before therapy, to 7.09 +/- 2.29 cm/year after 12 months (p less than 0.001). Patients' height SD score rose from -3.40 +/- 0.84 SDS to -2.98 +/- 0.69 SDS (p less than 0.01). Somatomedin C increased significantly from a baseline value of 0.59 +/- 0.32 U/ml to 1.26 +/- 0.66 U/ml after therapy (p less than 0.01). Finally, r-hGH therapy improved the pretreatment adult height prediction; from an initial prognosis of -2.66 +/- 0.79 SDS to -2.17 +/- 0.81 SDS after treatment (p less than 0.01). No side effects or adverse reactions were observed during treatment. Anti-r-hGH antibody formation was not found in any of the patients included in the study.     

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.     

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.     

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.     

Efficacy and safety of long-term continuous growth hormone treatment of children born small for gestational age

Twelve years of growth hormone (GH) therapy of short children born small for gestational age (SGA) have demonstrated that GH is an effective and well-tolerated therapy. Most children will reach a normal adult height (AH). AH of 55 SGA adolescents was comparable for those treated with a GH dose of 1 or 2 mg/m2 (approximately 0.033 or 0.066 mg/kg) per day, mean (SD) AH SDS being -1.2 (0.7) and -0.8 (0.7), respectively. GH therapy had no influence on the age at onset, the progression of puberty, duration of puberty and pubertal height gain. GH therapy induced higher fasting and glucose-stimulated insulin levels after 1 and 6 years, but 6 months after GH stop, all levels returned to normal. At baseline mean systolic blood pressure was significantly increased, but both systolic and diastolic blood pressure decreased significantly during 6 years of GH and remained so after GH stop. GH therapy demonstrated a beneficial effect on serum lipid profiles, body composition, bone mineral density and head growth. Treatment with 2 mg GH/m2 per day induced mean serum IGF-I levels of +2 SDS, whereas IGF-I levels remained within the normal range with 1 mg GH/m2 per day. In conclusion, long-term GH therapy of short SGA children with 1 mg/m2 per day appears to be effective and safe. Since the future consequences of high serum IGF-I levels during long-term GH therapy with 2 mg/m2 per day are as yet unknown, it seems safer to treat short prepubertal SGA children with a GH dose of 1 mg/m2 per day when children are to be treated continuously for many years.     

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.     

Skeletal dysplasia, growth hormone treatment and body proportion: comparison with other syndromic and non-syndromic short children

Skeletal dysplasias comprise a diverse group of conditions that usually compromise both linear growth and body proportions. It is of theoretical interest to evaluate the effect of GH treatment on linear growth, body proportion and final height in the different skeletal dysplasias. Reported experience of GH treatment in short children with skeletal dysplasia is sparse and often limited to short treatment periods and knowledge of its effects on final height and body proportion is generally lacking. Formal studies are almost all confined to achondroplasia as the most common entity. First-year response is typically a 2-3 cm increase in growth velocity in prepubertal children, or a gain of about 0.5 SDS or less in relative height from a baseline level of -4 to -5 SDS. GH treatment for up to 5 years in achondroplasia can produce a total height gain of about 1 SDS. Apart from achondroplasia, treatment of hypochondroplasia and dyschondrosteosis with GH has been reported in a small number of patients. Long-term data are, however, lacking. Of theoretical interest is that in many syndromic or non-syndromic short-statured children body proportion, i.e. trunk to leg length ratio, does not seem to be dependent on the degree of GH sufficiency and does not seem to be changed by GH treatment. GH treatment, at least in the prepubertal period, does seem to influence degree of disproportion.     

Effect of growth hormone on short normal children.

The growth of 26 short normal prepubertal children (mean age 8.4, height velocity standard deviation score for chronological age between +0.4 and -0.8) was studied for two years. Sixteen children were treated with somatrem (methionyl growth hormone) during the second year, and the remaining 10 children served as controls. During one year of treatment the height velocity standard deviation score for chronological age increased from the pretreatment mean of -0.44 (SD 0.33) to +2.20 (1.03). These values represented a change in height velocity from a pretreatment mean of 5.3 cm/year (range 4.6-6.9) to 7.4 cm/year (range 5.7-9.9). In the control group the height velocity standard deviation score was unchanged. Bone age advanced by 0.75 (0.33) years in the treated group compared with 0.70 (0.18) years in the control group. There was a significant increase in the height standard deviation score for bone age (0.63 (0.55] in the treated group. Multiple regression analysis of predictive factors contributing to the change in height velocity standard deviation score over the first year of treatment showed that the dose of growth hormone and pretreatment height velocity standard deviation score were important, together yielding a regression correlation coefficient of 0.80. The only metabolic side effect of treatment was an increase in fasting insulin concentration, which may be an important mediator of the anabolic effects of growth hormone. Treatment had no effect on thyroid function, blood pressure, or glucose tolerance. At the end of the treatment year seven of the 16 treated children had developed antibodies to growth hormone, but they were present in low titre with low binding capacity and in no child was growth attenuated. Biosynthetic growth hormone improved the height velocity of children growing along or parallel to the third height centile, but the effects on height prognosis need to be assessed over a longer period.     

Psychosocial functioning of adolescents with idiopathic short stature or persistent short stature born small for gestational age during three years of combined growth hormone and gonadotropin-releasing hormone agonist treatment

AIM: To examine psychosocial functioning of medically referred adolescents with idiopathic short stature (ISS) or persistent short stature born small for gestational age (SGA) during 3 years of combined growth hormone (GH) and gonadotropin-releasing hormone agonist (GnRHa) treatment. METHODS: Thirty-eight adolescents participated in a controlled trial with GH/GnRHa treatment or no intervention. Each year the adolescents and their parents completed questionnaires and structured interviews. Multilevel analysis was used to analyze data. RESULTS: The adolescents of the treatment group showed a worse outcome than the adolescents of the control group on 3 of 16 variables: perceived competence of scholastic (p < 0.01) and athletic ability (p < 0.05) and trait anxiety (p < 0.05). Adolescents in both the treatment and control groups perceived improved current height (p < 0.001) and self-appraisal of physical appearance (p < 0.05). The parents did not report changes in their children during treatment. CONCLUSION: The observation of some adverse psychological consequences as experienced by the adolescents indicates that it is useful to monitor psychosocial functioning during a combined GH/GnRHa treatment in adolescents with ISS or SGA. It is uncertain whether the hypothesized positive effects of the expected gain in final height by adulthood can sufficiently counterbalance possible short-term negative effects.     

Auxological and endocrine evolution of 28 children with Prader-Willi syndrome: effect of GH therapy in 14 children

We report on the auxological and endocrine evolution of 28 patients presenting with Prader-Willi syndrome. Half of them received growth hormone (GH) therapy (group 2). The spontaneous auxological evolution was analyzed in the two groups from 2 to 8 years; the mean SDS for height remained stable (-0.6 +/- 0.6) in group 1 and decreased (from -2.0 +/- 0.9 to -2.7 +/- 0.6) in group 2. Magnetic resonance imaging showed marked pituitary hypoplasia in the two groups. In group 2, the mean GH peak after two provocative tests was 3.8 +/- 2.4 microg/l, the mean SDS values for insulin-like growth factor I levels were -2.0 +/- 1.5 (range from -0.5 to -5.0). The mean duration of GH treatment was 3.6 +/- 2.9 (range 1-9.3) years. 14 children completed 1 year of treatment. The two groups had opposite evolutions in Delta SDS for height (-0.8 +/- 0.8 vs. +1.1 +/- 0.8), for growth velocity (-1.9 +/- 2.2 vs. +2.9 +/- 2.7), and for Z score of the body mass index (+0.37 +/- 1.3 vs. -0.14 +/- 0.76; group 1 vs. group 2). This retrospective study shows that, in children with Prader-Willi syndrome and true GH deficiency, long-term GH therapy is effective in increasing growth velocity and in maintaining body mass index.     

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.     

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.     

Long-term evolution of endocrine disorders and effect of GH therapy in 35 patients with pituitary stalk interruption syndrome

We report long-term evolution of endocrine functions and the results of GH treatment in 35 patients (26 male and 9 female) with pituitary stalk interruption. At diagnosis, mean chronological age was 4.8 +/- 2.7 years, mean SDS for height -3.1 +/- 0.8 with a bone age retardation of 2.3 +/- 1.3 years and a mean SDS for growth velocity of -0.5 +/- 1.1; 80% presented complete GH deficiency (GHD) and 20% partial GHD; thyroid deficiency was present in 47.1% of children with complete GHD but absent in all partial GHD. Diagnosis was made during the first months of life in only 2 patients while 23% presented with severe neonatal distress; neonatal signs were only observed in the group with pituitary height below 2 mm (45.7% of patients). GHD was isolated in 40.6% of patients below 10 years while multiple hormone deficiencies was consistent at completion of growth in all patients. Height gain was significantly higher in patients who started GH treatment before 4 years (p = 0.002). GH treatment is very effective: in 13 patients, final height was -0.4 +/- 1.0, total height gain 3.2 +/- 1.2 and distance to target height -0.3 +/- 1.6 SDS.     

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.     

Long-term treatment of growth hormone insensitivity syndrome with IGF-I. Results of the European Multicentre Study. The Working Group on Growth Hormone Insensitivity Syndromes.

A total of 33 patients (17 female, 16 male) with Laron syndrome (n = 31) or hGH-1 gene (n = 2, type IA deletion) from 22 centres in 12 countries were enrolled in a study conducted by Pharmacia & Upjohn, Stockholm, which was designed to test the efficacy, in terms of growth promotion and safety, of IGF-I (Igef(TM)). The patients were treated with 40-120 microg/kg IGF-I s.c. twice daily after meals. After the study ended, the patients continued to be treated on an individual basis. The results of 17 patients, who were treated for 48 months or longer were available for the present analysis. Six patients were treated for up to 72 months. When treatment started, the mean age of these patients (8 female, 9 male) was 9.1 (3.7-13.5) years and mean height was -6.5 +/- 1.3 SDS. At the end of the observation period, the mean age of the 17 patients was 14.2 (9.1-17. 7) years and mean height was -4.9 +/- 1.9 SDS. All patients showed a significant increase in growth during the final year on IGF-I, with two of them reaching the age-corresponding 3rd centile. The total gain in height (DeltaHT) was 1.7 +/- 1.2 SDS. DeltaHT SDS correlated negatively with age at onset of treatment (R(2) = -0.78, p < 0.02). BMI was 0.6 +/- 1.8 SDS at start of treatment and 1.8 +/- 1.5 SDS at the end of observation. Total DeltaHT SDS correlated positively with total DeltaBMI SDS (R(2) = 0.59, p < 0.01). Long-term treatment of patients with GHIS thus proved to be effective in promoting growth. If treatment is started at an early age, there is considerable potential for achieving height normalisation. The treatment modalities need to be optimized with respect to the growth-promoting and metabolic effects of IFG-I.     

Greater efficiency of human growth hormone therapy in children below five years of age with growth hormone deficiency. A 5-year follow-up study

The effect of human growth hormone (hGH) therapy was studied in 39 prepubertal children with growth hormone deficiency (24 with isolated growth hormone deficiency; 15 with multiple pituitary hormone deficiencies) who had been treated for 2-5 years. They were divided into two groups according to age at the initiation of therapy: group A (n = 21), 0.7-4.8 years (mean chronological age, 2.9 +/- 1.4 years, and bone age, 1.2 +/- 0.9 years); group B (n = 18), 5.2-9.9 years (mean chronological age, 7.4 +/- 1.3 years, and bone age, 4.0 +/- 1.5 years). hGH was given at an initial dose of 2-4 IU 3 times/week, raised to 4-6 IU 3 times/week when growth velocity slowed. In the first year, the mean height SDS gain was 1.7 for group A and 0.8 for group B, and in the second year, 1.1 and 0.1, respectively. Subsequently this remained consistent. Bone age advancement was significantly slower in the younger group (3.8 vs. 5.8 years during 5 years) although this group had a greater catch-up response to therapy. It is concluded that hGH therapy is significantly more effective in achieving normalization of height when treatment is initiated at an early age.     

Final height in children with idiopathic growth hormone deficiency treated with recombinant human growth hormone: the Belgian experience

BACKGROUND: The growth response to recombinant hGH (rhGH) treatment and final height of 61 Belgian children (32 boys) with idiopathic growth hormone deficiency (GHD) were studied. PATIENTS/METHODS: Two patient groups were compared: Group 1 with spontaneous puberty (n = 49), Group 2 with induced puberty (n = 12). The patients were treated with daily subcutaneous injections of rhGH in a dose of 0.5-0.7 IU/kg/week (0.17-0.23 mg/kg/week) from the mean +/- SD age of 11.9 +/- 3.1 years during 5.1 +/- 2.1 years. RESULTS: rhGH treatment induced a doubling of the height velocity during the first year and resulted in a normalisation of height in 53 (87%) patients. Final height was -0.7 +/- 1.1 SDS, being 170.4 +/- 7.2 cm in boys and 158.0 +/- 6.4 cm in girls. Corrected for mid-parental height, final height was 0.0 +/- 1.1 SDS. Ninety-two percent of the patients attained an adult height within the genetically determined target height range. Although height gain during puberty was smaller in the patients with induced puberty (boys: 17.1 +/- 7.0 cm vs. 27.5 +/- 6.6 cm (p < 0.005); girls: 9.6 +/- 7.4 cm vs. 22.2 +/- 6.1 cm (p < 0.005)), no differences in final height after adjustment for mid-parental height were found between patients with spontaneous or induced puberty. CONCLUSIONS: We conclude that patients with idiopathic GHD treated with rhGH administered as daily subcutaneous injections in a dose of 0.5-0.7 IU/kg/week reach their genetic growth potential, resulting in a normalisation of height in the majority of them, irrespective of spontaneous or induced puberty.     

Treatment of growth failure in juvenile chronic arthritis

We retrospectively assessed linear growth and final height in a group of 24 patients suffering from juvenile idiopathic arthritis (JIA) during childhood, receiving steroid therapy. In these patients, a significant loss of height (-2.7 +/- 1.5 SDS) occurred in the first years of the disease which was positively correlated with prednisone therapy duration. After remission of the disease and prednisone discontinuation, most of the patients (70%) had catch-up growth but 30% had a persistent loss of height. Their mean final height was strongly correlated with their mean height at the end of steroid therapy and was significantly different between the group of patients with catch-up growth (-1.5 +/- 1.6 SDS) and the group without catch-up growth (-3.6 +/- 1.2 SDS). This pattern of growth observed in JIA patients should help us to define strategies of GH treatment in these patients in order to improve their final height. We have previously reported the beneficial effects on growth and body composition of a 1-year GH treatment in a group of 14 growth-retarded patients suffering from juvenile idiopathic arthritis, receiving glucocorticoid therapy. These patients (n = 13) were treated again with GH at the same dosage (0.46 mg/kg/week) for another 3-year period. GH treatment markedly increased growth velocity in these patients, but had a minor effect on SDS height suggesting that these children will remain short at adult age. Using GH earlier in these patients during the course of their disease may prevent growth deterioration and metabolic complications induced by chronic inflammation and long-term steroid therapy.