Predicting and monitoring of growth in children with short stature during the first year of growth hormone treatment.

Fifteen prepubertal short stature children (10 girls, 5 boys), mean age 9.6 years (range 5.2-12.7 years), with normal response to growth hormone stimulation tests (group A) or partial growth hormone deficiency (GHD) of idiopathic nature (group B) were included in a controlled longitudinal study for evaluation of predictive parameters for the long-term growth response after administration of biosynthetic human growth hormone (B-hGH). The average knee-heel length velocity for the first 3 months was significantly correlated to total body height velocity during the following 9 months (p less than 0.0008). By contrast, this association could not be found for height velocity during the same period. The increase in serum values of alkaline phosphatase and insulin-like growth factor I (IGF-1) during the first month of treatment was not significantly correlated to height velocity during the first year. During one year of treatment with B-hGH the mean height velocity for groups A and B increased from 4.4 cm/year (range 2.5-6.5) to 7.6 cm/year (range 4.7-10.6). Bone age advanced by 1.08 +/- 0.60 per chronological year. The ratio between total height and knee-heel length prior to treatment was 3.34 +/- 0.10 and after one year 3.33 +/- 0.10, suggesting a proportional linear growth. An inverse relationship was observed between the ratio and chronological age. In conclusion, early knee-heel measurement may be a useful non-invasive predictor of long-term linear growth in children during treatment with growth hormone, and the ratio of total height to lower leg length may be of importance in detecting dysproportional growth.     

Prediction of the growth response of short prepubertal children treated with growth hormone

The aim of this study was to identify predictors of the growth response to growth hormone (GH) during the first 2 years of GH treatment, using auxological data and the maximum GH response (GH_max) to provocation tests. The patients were 169 prepubertal short children (27F, 142M), with Gmax values ranging from 0 to 65 mU/1. Their mean age (± SD)was8.3 ± 2.4 years (range 3-13 years), mean height SDS –3.0 ± 0.7 (range –1.5 to –6.0SDS) and mean pretreatment height velocity was normal (± 0.0 SDS) (range -1.6 to + 0.9 SDS). The increase in height SDS during the first 2 years of GH treatment (0.1 U/kg/day) varied from 0.10 to 3.75 SDS, with younger children having a better growth response. Individual growth responses correlated (p < 0.001) with GH_max (r =–0.37), age (r= -0.35), 1-year pretreatment delta SDS (r = -0.25), mid-parental height SDS (r = 0.34), height SDS at start of treatment (r =–0.22) and difference between height SDS of an individual child at the onset of GH treatment and mid-parental height expressed in SDS (diff SDS) (r = –0.43). In a multiple stepwise linear regression model, diff SDS and log GH_max were found to be the strongest predictors of the magnitude of the growth response. In the short children in this study who exhibited a broad range of GH_max values, 33% of the growth response during the first 2 years of treatment could be predicted.     

Recombinant Human Growth Hormone Treatment of Children with Chronic Renal Failure: Update 1990

ABSTRACT. Nine children with growth retardation due to chronic renal failure were treated with recombinant human growth hormone (rhGH) for 12-36 months. Results demonstrated a significant increase in height velocity at each 12-month interval compared with that achieved during the year prior to treatment. However, the increase in bone age was no greater than the increase in chronological age during the period of treatment. The mean calculated creatinine clearance did not decrease significantly during the 36 months of treatment; however, two patients required institution of dialysis at 18 and 30 months following initiation of rhGH treatment. There was no exacerbation of the glucose intolerance of uraemia following treatment. Currently, 6 of 7 patients who have been treated for more than 24 months have achieved sufficient acceleration in height velocity to attain an SDS of less than -2.00 and are above the 5th centile for chronological age on the growth curve. These updated data indicate that rhGH treatment of growth retarded children with chronic renal failure continues to result in accelerated height velocity during the second and third year of treatment, and demonstrate the potential for such children to achieve normal stature (±2 SD) for chronological age despite the continued presence of chronic renal failure.     

Effect of combined treatment with gonadotropin releasing hormone analogue and growth hormone in patients with central precocious puberty who had subnormal growth velocity and impaired height prognosis

Growth hormone-insulin-like growth factor-I status and response to growth hormone therapy (0.6 IU/kg/week sc, six times a week for 12 months) were evaluated in 12 girls (chronological age 9.4 ± 1.6 years) suffering from central precocious puberty with growth velocity less than 4 cm/year and no substantial increase or decrease in predicted adult height during gonadotropin releasing hormone (Gn-RH) analogue treatment (D-Trp⁶-LH-RH, 60 μg/kg im/28 days). At baseline, large variations were observed in nocturnal growth hormone (GH) means (pathological values (< 3.6μg/l) 33.3%), stimulated levodopa GH peaks (pathological values (<10.0 μg/I) 28.6%) and serum insulin-like growth factor-I (IGF-I) levels. Neither GH nor IGF-I levels were correlated with growth velocity. During recombinant GH therapy, growth velocity increased significantly (baseline 3.0 ± 0.9 cm/year; 6 months 6.4 ± 1.9cm/year, p < 0.001 versus baseline; 12 months 6.0 ± 1.3cm/year, p < 0.001 versus baseline). There was a significant increase in height SDS for bone age (baseline –1.6 ±0.5 SDS; 12 months -1.04 ± 0.6SDS; p < 0.002) and in predicted adult height (baseline 152.0 ± 3.6cm; 12 months 155.9 ± 3.4cm; p < 0.002). Our results suggest that combined therapy with Gn-RH analogues and recombinant GH can improve growth velocity and predicted adult height in girls with central precocious puberty and impaired height prognosis during Gn-RH analogue treatment.     

Treatment of Growth Hormone Deficient Patients with Recombinant Somatropin for 1 year: Results of a Chinese Multicentre Trial

ABSTRACT. Fifty-nine patients with idiopathic growth hormone deficiency were included in a Chinese multicentre trial of recombinant somatropin, 0.5-0.7 IU/kg/week s.c. given in six or seven divided doses. The height velocity increased from 2.8 ±1.0 cm/year to 13.1 ± 2.5 cm/year during 1 year of treatment, and typical catch-up growth was observed. The increase in height SDS for chronological age was significant, but the increase in height SDS for bone age was not statistically significant. No adverse reactions to the treatment were recorded. Recombinant somatropin was shown to be very effective and safe during the first year of therapy in patients with growth hormone deficiency.     

Growth Response in Prepubertal Children with Idiopathic Growth Hormone Deficiency During the First Two Years of Treatment with Human Growth Hormone. Analysis of the Kabi Pharmacia International Growth Study

From the large database of patients enrolled in the Kabi Pharmacia International Growth Study (KIGS), 289 prepubertal patients with idiopathic growth hormone deficiency (GHD), treated for 2 years with growth hormone (GH) substitution therapy, were selected. A multiple regression analysis was performed to determine both the auxological factors characterizing the patients at the beginning of the first and second years on GH therapy and the respective treatment modalities relevant to the magnitude of the growth response. It was observed that during the first year on GH therapy the magnitude of the growth response was negatively correlated with chronological age and height SDS, and positively correlated with target height SDS, GH dose (IU/kg/week) and frequency of GH injections. During the second year the growth response was negatively correlated with chronological age and the first-year GH dose (IU/kg/week), and positively correlated with height velocity during the first year, GH dose (second year), and injection frequency (second year). The data suggest that the forces of'catch-up'- auxologically entrenched within the distance between target height SDS and height SDS - no longer prevail during the second year of GH therapy. The inverse influence of the first-year GH dose in the two yearly phases of growth suggests that optimizing GH treatment must be attempted by analysing growth in response to GH over longer periods of time and considering that the growth process is influenced by interactive factors.     

Effects of Short-Term Growth Hormone Therapy in Short Children without Growth Hormone Deficiency

ABSTRACT. Evaluation of 24-hour endogenous growth hormone (GH) secretion was carried out in 62 children, aged 7-16 years, who did not have classic GH deficiency (GHD). The mean 24-hour GH concentration, determined at 20-minute intervals over 24 hours, was variable, ranging from 1.28 to 11.39 μg/l with a mean of 4.95 ± 2.55 μl (± SD). There was a positive correlation between mean 24-hour GH concentration and plasma insulin-like growth factor I (IGF-I) values ( r = 0.54; p < 0.01). Recombinant human GH, 0.1 IU/kg/day was administered to 30 of the 62 children for 6 months followed by 6 months'observation without treatment. Thereafter, GH was administered at the same dose for a further 6 months to 16 children. The mean height velocities before, during, and after the first treatment period were 4.3 ± 0.9, 7.3 ± 1.9 and 4.9 ± 2.0 cm/year (mean ± SD), respectively. The height velocity during treatment was greater than pre- and post-treatment values ( p < 0.001). The height velocity Increased again during the second treatment period to a mean of 8.5 ± 2.0 cm/year ( p < 0.001). Nine other children were treated continuously in a similar manner for 1 year and their height velocity increased significantly from 4.1 ± 1.4 to 6.0 ± 1.9 cm/year ( p < 0.001). According to our criteria, 29 of the 39 children (74.4%) who were treated for 6-12 months showed a GH-dependent height increase during therapy. There were no differences between the children who responded to GH treatment and those who did not in terms of Chronological age, bone age, plasma IGF-I level, maximal GH level to insulin-induced hypoglycaemia, or mean 24-hour plasma GH concentration. These data indicate that some short children without GHD respond to GH treatment with an increased height velocity. Further investigations are required to determine the effect of GH on final height.     

Growth and Growth Hormone Therapy in Hypochondroplasia

ABSTRACT. The growth of 84 patients with hypochondroplasia (56 male, 28 female) was studied. A wide spectrum of severity was found from quite severe short limbed dwarfism to short apparently normal prepubertal children who manifested disproportion only at puberty when growth failed. The onset of puberty was at the normal time but the pubertal growth spurt appeared not to materialize and it is this lack which resulted in severely compromised adult heights of 145-165 cm in boys and 133–151 cm in girls. Twenty (12 M, 8 F) hypochondroplastic children aged between 4.3 and 12.8 years were recruited to a study of the effects of biosynthetic growth hormone. All had normal growth hormone responses (> 15 mU/I) to a pharmacological test of growth hormone secretion. Biosynthetic growth hormone in doses between 12-32 u/m²/week produced a significant acceleration in height velocity standard deviation score (SDS) for chronological age (CA) from a pretreatment mean of - 1.66 (SD 1.36) to + 1.62 (SD 1.52) ( p < 0.001). Significant increases were also observed in the height SDS for bone age (BA), sitting height (SH) SDS and subischial leg length (SILL) SDS. A longer period will be required to assess the effect of treatment on adult height prognosis.     

Chronic Growth Retardation with Normal Growth Hormone Response to Provocative Stimuli and Low Somatomedin Activity

ABSTRACT. Four prepubertal children with chronic growth retardation (growth velocities ≤4 cm/yr), normal growth hormone (GH) response to provocative stimuli and low basal but increased somatomedin activity values after GH administration, received continuous GH-therapy (4 IU/three times a week) for an 18–24-month period. Growth velocity doubled during the first 12 months of therapy and remained 4–6 cm/yr until the end. Bone age progressed according to chronological age and adult height predictions improved. No thyroid function or carbohydrate and lipid metabolism anomalies were observed. After completion of this GH-therapy period, patients remained off treatment during the following six months. Growth velocities were similar to pre-GH-treatment values in two patients, lower in the third and higher in the fourth, who was by then pubertal. Thus, in these patients, long-term GH-therapy promoted growth and improved adult height prediction.     

Growth velocity and serum aminoterminal propeptide of type III procollagen in precocious puberty during gonadotropin-releasing hormone analogue treatment

Growth velocity and serum aminoterminal propeptide of type III procollagen (P-III-NP) were evaluated in 11 girls (age 3.8–8.5 years) with central precocious puberty during luteinizing hormone releasing hormone (LH-RH) analogue treatment (D-Trp⁶-LH-RH, 60 μg/kg im for 28 days, n = 7; D-ser(TBU)⁶-LH-RH, 1600 μg/day intranasally, n = 4). Before treatment, growth velocity (10.2 ± 1.9 cm/ year) and P-III-NP concentrations (12.8 ± 4.3 μg/l) were in the pubertal range. During therapy, growth velocity significantly decreased to the prepubertal levels. P-III-NP concentrations decreased significantly after six months of therapy (7.9 ± 3.7 μg/l, p < 0.001). Three girls with low growth velocity (< 4 cm/year), stimulated growth hormone peak < 10 μg/l, and altered 12-h nocturnal growth hormone secretion at 12 and/or 18 months of treatment, had a more marked decrease in P-III-NP concentrations (patient 3: −65.9%; patient 5: −58.7%; patient 10: −61.0%) after 6 months of therapy. Our results suggest that LH-RH analogue treatment in central precocious puberty may impair growth. In these cases, measurement of serum P-III-NP levels may be an additional marker to- monitor growth.     

Demography, auxology and response to recombinant human growth hormone treatment in girls with Turner's syndrome in the Kabi Pharmacia International Growth Study

Demographic and auxological data were analysed from 818 girls with Turner's syndrome treated with recombinant human growth hormone (GH) and entered into the Kabi Pharmacia International Growth Study. Size at birth was low and correlated with the heights of both parents. The median age at start of GH treatment was 11.4 years and the parents had a median height SDS of -2.9. Height SDS at the start of treatment correlated with parental heights. Height velocities conformed to Turner-specific standards. The weight-for-height index increased sharply above 9 years of age. The frequency of spontaneous appearance of Tanner breast stage 2 was high (34.1% of girls > 10 years of age). Bone age (Greulich and Pyle) data were described by the equation: bone age = 1.61 (chronological age) -0.04(chronological age)² - 3.61. This equation was used to correct adult height predictions. The median initial dose of GH was 0.8 IUkglweek and was maintained during the first 3 years of treatment. The median frequency of injections was six/week. Height velocity increased from 4.1 to 6.8 cm/year in the first year, and height velocity SDS for chronological age remained positive for 4 years. The height prediction corrected for bone age increased over the first 2 years only. Differences in demography and auxology were described according to karyotype and country of origin. A greater height velocity SDS was observed at higher GH doses and when oxandrolone was used concomitantly.     

Growth Hormone Treatment in Turner's Syndrome

ABSTRACT. A total of 21 patients with Turner's syndrome were treated with pituitary hGH and/or somatrem for 1–2 years. Plasma non-esterified fatty acid increased significantly from 0.52 ± 0.06 to 1.30 ± 0.09 mEq/litre at 4 hours after injection of hGH, 4 IU (mean ± SEM, p < 0.001). Basal plasma IGF-1 levels were within the normal range; however, they increased significantly at 24 hours after the first three daily injections of hGH, 4 IU (basal, 0.92 ± 0.14 units/ml; 24 hours, 1.39 ± 0.16 units/ml; 48 hours, 1.68 ± 0.19 units/ml; 72 hours, 1.91 ± 0.22 units/ml; p < 0.001). For long-term treatment, patients were given hGH, 4–16 IU for 1–2 years. Their height velocity increased to 5.5 ± 1.2 cm/year and 5.1 ± 0.6 cm/year in the first and second year of the treatment, respectively. These values were greater than the pretreatment value of 3.6 ± 0.8 cm/year (p < 0.001). Antibody against hGH was observed in 60% of the patients at the end of 12 months of somatrem treatment. Otherwise there were no significant changes in physical, blood or urine examinations. These results indicate that hGH treatment is useful for the acceleration of growth velocity in patients with Turner's syndrome.     

Growth hormone therapy in pre-pubertal children with Noonan syndrome: first year growth response and comparison with Turner syndrome

We studied the growth-promoting effect of treatment with recombinant human growth hormone in 23 prepubertal children with Noonan syndrome, aged between 5. 4 and 14. 3 y, and all with a height < 1. 4 SD for Tanner standards. The growth response and skeletal maturation after 1 y of recombinant human growth hormone treatment (0. 15 U/kg/day given by daily injection) in the Noonan syndrome patients was compared with the auxological changes observed in a group of 17 girls with Turner syndrome with a comparable age and height deficit who were treated with recombinant human growth hormone in a similar way. During 1 y of treatment, the mean ± SD height velocity increased by 4. 0 ± 1. 6 cm/y in the Noonan syndrome group and by 3. 6 ± 1. 3 cm/y in the Turner syndrome group. Height SDS for chronological age in the Noonan syndrome group increased by 0. 53 ± 0. 46 ( p < 0. 001). In the Noonan syndrome patients the changes in height velocity were positively related to birthweight ( r = 0. 48, p < 0. 05). The changes in height velocity or height SDS were not related to the age, height deficit or a delay in bone age maturation at start of treatment. In neither the patients with Noonan syndrome nor Turner syndrome was an acceleration of bone maturation found. We conclude that treatment with recombinant human growth hormone in pre-pubertal NS patients induces an increase in height velocity and height SDS comparable to that observed in Turner syndrome girls.     

Assessment of the Usefulness of Weekly Knemometric Measurements in Growth Studies

ABSTRACT. In 31 healthy children the variability of lower leg length growth over 12 weekly measuring sessions, each consisting of 6 measurements, was assessed with a knemometer. The average SD of 6 measurements was 0.12 mm. In many cases not only a rising trend, but also a zig-zag pattern was observed. The linear regression was not significant ( p >0.05) in 1 child. The average (±SD) lower leg length velocity (LV) was 0.36±0.14 mm/week, and the average statural growth velocity 1.27±0.54 mm/week. The median ratio was 3.3. The range of both velocities was greater than the range of annual height velocities. When LV over the first 6 weeks was compared with LV over the next 6 weeks, a significant difference was found in 5 children. If the effect of growth-promoting or -inhibiting drugs were to be analyzed over such periods, a difference of 0.37 mm/week over two 6-week-periods would be necessary for significance at a 5% level. This would be equivalent with a statural growth response of at least 6.3 cm/year. In conclusion, short-term knemometric growth response cannot be used as a reliable predictor of long-term statural growth response.     

Gonadotrophin-Releasing Hormone Agonist Treatment of Central Precocious Puberty: an Analysis of Growth Data in a Developmental Context

ABSTRACT. Growth and skeletal maturation was assessed in 83 girls with central precocious puberty (CPP) during pituitary—gonadal suppression induced by treatment with a gonadotrophin-releasing hormone agonist (GnRHa). The mean pretreatment chronological age (CA) was 6.3 years and the mean bone age (BA) was 10.6 years. During the suppression of gonadal sex steroid secretion, mean height velocity (HV) decreased from a pretreatment value of 10.8 cm/year to 5.9 (year 1, n = 83), 4.9 (year 2, n = 72), 4.2 (year 3, n = 49, and 4.4 (year 4, n = 23) cm/year. During each interval, there was a negative correlation between HV and the pretreatment BA. In addition, the rate of skeletal maturation was reduced during GnRHa treatment (ΔBA/ΔCA = 0.6 ± 0.1 over 3 years, n = 45). The rate of skeletal maturation during therapy was also negatively correlated with pretreatment BA. Predicted adult stature, based upon z -scores of height for BA, increased significantly and progressively during therapy but the changes in height SDS for BA varied significantly. Since HV, ΔBA/ΔCA, and the change in height SDS for BA (ΔHT SDS for BA) during pituitary—gonadal suppression all correlated with the initial degree of skeletal maturation, the effect of GnRHa therapy on Final adult height in children with CPP will be best understood if growth data are assessed within a developmental framework.     

Gonadotrophin-Releasing Hormone Analogues as Therapeutic Probes in Human Growth and Development: Evidence from Children with Central Precocious Puberty

ABSTRACT. Statural growth and skeletal development were assessed in 87 girls with idiopathic central precocious puberty (CPP) during gonadotrophin-releasing hormone analogue (GnRHa)-induced suppression of gonadarche. Before the start of therapy, mean chronological age (CA) was 6.3 years and mean bone age (BA) was 10.6 years. During up to 6 consecutive years of complete suppression of gonadal sex steroid secretion, the mean height velocity decreased from 10.8 cm/year to prepubertal rates. At each interval height velocity was found to be inversely and negatively correlated with BA such that girls with advanced BAs grew at rates well below prepubertal norms but appropriately for their degree of skeletal maturation. Skeletal maturation similarly slowed during prolonged GnRHa administration (ABA/ACA = 0.6 ± 0.1 over 3 years, mean ± SD, n = 66) and was also negatively correlated with the BA before the start of therapy. Predicted adult height increased progressively during therapy; however, when analysed as changes in height SDS(BA), the impact of treatment was variable and correlated positively with the initial degree of skeletal maturation. The effect of GnRHa therapy on growth in children with CPP requires long-term study and is best analysed by employing a developmental perspective.     

Growth Response in Prepubertal Children with Idiopathic Growth Hormone Deficiency during the First Year of Treatment with Human Growth Hormone. Analysis of the Kabi International Growth Study.

ABSTRACT. In order that children with growth hormone deficiency (GHD) reach the goal of normal adult stature, treatment modalities need to be optimized. From the large database of patients enrolled in the Kabi International Growth Study (KIGS), 257 prepubertal patients with idiopathic GHD undergoing their first year of growth hormone (GH) substitution therapy were selected. A multiple regression analysis was performed to determine both auxiological factors characterizing the patients and the factors related to the chosen treatment modalities which are of significance for the observed magnitude of the growth response. Due to the structure of the data, pretreatment height velocity and bone age-derived auxiological data were not considered. It was observed that the magnitude of the growth response was inversely correlated with chronological age and relative height (HT SDS) at the start of GH treatment but was positively correlated with mid-parental height. The growth response was also positively correlated with the GH dose (IU/kg/week) and the frequency of GH injections per week. A regression equation using these five parameters was derived, allowing the growth response of these patients to be predicted. The extension of this analytical approach in the future will allow the treatment of patients with GHD to be tailored to individual requirements.     

A Controlled Trial of Methionyl Growth Hormone Therapy in Prepubertal Children with Short Stature, Subnormal Growth Rate and Normal Growth Hormone Response to Secretagogues

ABSTRACT. Thirty short and slowly growing children with normal plasma growth hormone (GH) responses to standard provocation tests were randomly assigned to either a group ( n = 20) undergoing treatment with methionyl GH (somatrem), 2IU per m² body surface s.c. daily, or a control group ( n = 10). Twelve out of 18 children who completed the first year of treatment showed a height velocity increment of more than 2 cm/year. The mean (SD) growth velocity of the treatment group increased by 3.0 (1.9) cm/year over the first year, compared with -0.2 (0.7) cm/year in the control group. Neither parameters of endogenous GH secretion nor plasma IGF-I levels showed a significant correlation with the growth response. Of the auxological variables studied, pre-treatment growth velocity ( r = 0.8) and the short-term height velocity increment ( r = 0.7–0.9) showed significant correlations with the growth response in the first year of treatment. Somatrem therapy was without side effects, except in one child who developed anti-GH antibodies in combination with a poor growth response.     

Long-Term Results with a Slow-Release Gonadotrophin-Releasing Hormone Agonist in Central Precocious Puberty

ABSTRACT. As part of an ongoing international multicentre study, 19 children (14 girls, 5 boys) with central precocious puberty (CPP) were treated with a slow-release gonadotrophin-releasing hormone (GnRH) agonist, triptorelin, for 4 years. After 3 years of treatment, height velocity stabilized at 4.0 cm/year. Predicted adult height (mean ± SD) increased from 158.9 ± 6.8 to 164.9 ± 6.6 cm in girls (n = 14, p < 0.01), and from 174.4 ± 18.5 to 184.3 ± 17.1 cm in boys (n = 4, p < 0.05). In 12 additional girls who had started the multicentre study but discontinued triptorelin treatment after 2.2 ± 0.5 years, menses started 9.8 ± 3.7 months after cessation of treatment in all but one patient. Height velocity increased over the first 6 months after discontinuation of treatment, from 3.6 ± 0.1 to 5.4 ± 2.5 cm/year, and remained higher than pretreatment values in the second 6 months, but decreased subsequently. Bone maturation increased, and no significant improvement in predicted adult height was observed. For auxological reasons, therefore, it may be advisable to continue triptorelin treatment for as long as possible. Concomitant growth hormone (GH) therapy was initiated in three girls with CPP with height velocities of 3.2–3.6 cm/year after 3 years of treatment with triptorelin and predicted adult heights of less than the third centile for Dutch girls. Prior to the administration of GH, all patients had subnormal 24-hour GH profiles and GH responses to arginine provocation. GH treatment increased height velocity markedly in all girls, and improved predicted adult height. It is concluded that triptorelin therapy improves predicted adult height. In children with CPP and genetic short stature, with a markedly decreased height velocity during triptorelin therapy, concomitant administration of a GnRH agonist and GH may have advantages. Further extensive studies are required.     

Three-year data from a comparative study with recombinant human growth hormone in the treatment of short stature in young children with intrauterine growth retardation

Growth acceleration and bone maturation were studied for 3 y in 69 children with severe short stature and a history of intrauterine growth retardation (IUGR), to determine the effect of treatment with recombinant human growth hormone (r-hGH). The patients were enrolled in an open, multicentre trial and were randomly allocated to either the treated group (Group 1) or the control group (Group 2). The children in Group 1 were treated daily with 0.2 IU/kg/body weight (0.067 mg/kg) s.c, during 3 y and the children in Group 2 started the study with a 1-y observation period followed by a 3-y treatment period. At birth, their mean weight standard deviation score (SDS) was -2.5 and their mean length SDS -3.5. At baseline, the patients were prepubertal, non-GHdeficient, with no known dysmorphic features. Mean age was 4.5 y, bone age was 3.3 y, height SDS was -3.4, height velocity (HV) SDS was -1.6, and body mass index SDS was -1.4. After 1 y of treatment, linear HV in Group 1 increased in comparison with the pre-treatment period (from 5.7 ± 2.0 to 10.1 ± 1.7cm/y; p < 0:001)and with the firstyear of observation in Group2( p < 0:001). Increased HV was sustained during the second and third year of treatment and was significantly higher than at baseline. A similar growth pattern was seen during the 3y of GH treatment in Group 2. Mean height SDS for chronological age increased by 2.0 ± 0.7 in the two groups after 3 y of treatment. HV after 1 y of treatment was negatively correlated with growth velocity at baseline. Bone age remained retarded but increased with a mean of almost 4 y after 3y of treatment in both groups. Even at a dose that is three times the replacement dose treatment with r-hGH was well tolerated. From these results, we conclude that r-hGH treatment over 3 y can induce sustained catch-up growth in young children with severe short stature and a history of IUGR. Long-term studies are needed to assess ultimate effects on final height.