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.     

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.     

One-year treatment with recombinant human growth hormone of children with meningomyelocele and growth hormone deficiency: a comparison of supine length and arm span.

Growth retardation and precocious puberty are frequently found in children with meningomyelocele (MMC). Lower limb contractions, spasticity and kyphoscoliosis may lead to disproportionate short stature. Most of these patients have structural brain defects or hydrocephalus which can cause growth hormone deficiency. In this study, 19 children aged between 3.5 and 12.8 years with MMC and growth hormone (GH) deficiency were treated with recombinant human GH for a period of 12 months. Supine length, arm span and growth velocity were compared before, and after 6 and 12 months of treatment with rhGH (daily dose 2.0 IU/m2 BSA s.c.). Mean supine length standard deviation score (SDS) increased by +0.8 SDS after 6 months and +1.2 SDS after 12 months of therapy. Mean arm span standard deviation score increased by +0.9 SDS and +1.3 SDS. Growth velocity increased in supine length from 3.3 cm/yr (-2.1 SDS) to 8.4 cm/yr (+2.4 SDS) and in arm span from 4.8 cm/yr (-1.3 SDS) to 8.6 cm/yr (+3.1 SDS) in the first 6 months and was 8.1 cm/yr (+2.4 SDS) and 8.3 cm/yr (+2.6 SDS) after 12 months of therapy. Linear correlation between SDS growth velocity supine length and SDS growth velocity arm span during one year of treatment was excellent (r = 0.65, p < 0.0025). We surmise that body proportions do not deteriorate when growth velocity is stimulated in MMC patients. Both supine length and arm span measurements are necessary to document growth in children with spinal dysraphism.     

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.     

Height prognosis of children with true precocious puberty and growth hormone deficiency: effect of combination therapy with gonadotropin releasing hormone agonist and growth hormone.

We evaluated height prognosis and therapeutic efficacy of long-term, combination therapy with gonadotropin releasing-hormone agonist and growth hormone (GH) in five children (three girls) with coexistent precocious puberty and GH deficiency. Their clinical characteristics and growth response were compared with those of 12 girls with idiopathic true precocious puberty and eight prepubertal GH-deficient children (one girl). Precocious GH-deficient subjects were older than the precocious GH-sufficient children (9.5 +/- 1.8 years vs 6.5 +/- 1.3 years; mean +/- SD), but bone ages were comparable (12 +/- 3.7 years vs 10 +/- 0.9 years); their chronologic age was similar to that of the prepubertal GH-deficient children (9.6 +/- 2.1 years), but bone age was significantly more advanced (6.9 +/- 2.3 years). The mean height velocity of the prepubertal GH-deficient children (3.8 +/- 1.5 cm/yr) was lower than that of the precocious GH-deficient subjects (6.7 +/- 1.6 cm/yr) and the precocious GH-sufficient children (9.5 +/- 2.9 cm/yr). Baseline adult height prediction z scores were significantly lower in the precocious GH-deficient children (-3.7 +/- 1.0) than in either the precocious GH-sufficient children (-2.2 +/- 1.0) or the prepubertal GH-deficient subjects (-1.5 +/- 0.8). During therapy with gonadotropin releasing-hormone agonist, growth rates slowed to an average of 3.7 cm/yr in the precocious GH-deficient children but increased after the addition of GH to 7.4 cm during the first year of combination therapy. After 2 to 3 years of combination therapy, height predictions increased an average of 10 cm, compared with an increase of 2.8 cm in the precocious GH-sufficient group treated with gonadotropin releasing-hormone agonist alone. We conclude that combination treatment with gonadotropin releasing-hormone agonist and GH improves the height prognosis of children with coexistent true precocious puberty and GH deficiency, but falls short of achieving normal adult height potential.     

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.     

Growth hormone deficiency impedes the rise in plasma insulin-like growth factor I levels associated with precocious puberty

We tested the hypothesis that growth hormone (GH) mediates the rise in insulin-like growth factor I (IGF-I) concentrations in children with precocious puberty. We studied three groups of patients. Group 1 included six children with GH deficiency and precocious puberty (precocious GH-deficient); group 2 included 10 GH-sufficient patients with idiopathic true precocious puberty (precocious GH-sufficient); and group 3 included 9 prepubertal children with GH deficiency (prepubertal GH-deficient). Growth rates, pubertal status, and plasma IGF-I concentrations were determined at regular intervals. The precocious children with GH deficiency had a mean (+/- SD) growth rate of 7.2 +/- 2.1 significantly below that of the precocious GH-sufficient patients (10.5 +/- 2.5 cm/yr, p less than 0.05) but above that of the prepubertal GH-deficient children (3.9 +/- 1.4 cm/yr, p less than 0.05). The mean IGF-I concentration in the precocious GH-deficient children was 0.77 +/- 0.39 U/ml, significantly lower than the mean level of 2.2 +/- 0.67 U/ml in the precocious GH-sufficient patients (p less than 0.01). However, precocious GH-deficient patients had significantly higher IGF-I values than the prepubertal GH-deficient children (0.24 +/- 0.10 U/ml, p less than 0.05). IGF-I values did not rise with the onset of precocious puberty in four of the precocious GH-deficient children evaluated before and after the development of precocious puberty. However, three patients who began GH treatment did have a rise in plasma IGF-I concentrations to levels of 1.2, 3.4, and 3.7 U/ml, respectively. These findings are compatible with the concept that sex steroids increase IGF-I levels in precocious puberty primarily by increasing GH production. A small but direct effect of sex steroids on IGF-I production may also exist. The onset of precocious puberty in children with organic GH deficiency may mask the abnormal growth pattern of these children and delay diagnosis; determinations of plasma IGF-I concentrations may be helpful in assessing the GH status of these patients.     

Physical effects of growth hormone treatment in children with Prader-Willi syndrome

A randomized, controlled study of 54 children (age, 4-16 years) with Prader-Willi syndrome was conducted to assess the potential beneficial effects of growth hormone (GH) treatment. After observation for 6 months, the children were randomized to receive GH at a dose of 3 IU/m²/day (1 mg/m²/day) ( n = 35) or no intervention ( n = 19). The effects of GH treatment on linear growth, body composition, muscle strength, pulmonary function and resting energy expenditure were assessed. The levels of GH secreted in resonse to clonidine stimulation were universally low, and mean (± SD) insulin-like growth factor I SDS was -1.2 ± 0.8 pretreatment. In children treated for 1 year, mean height velocity SDS significantly increased from -1.0 ± 2.5 to 4.6 ± 2.9 ( p < 0.0001), mean percentage body fat decreased from 46.3 ± 8.4% to 38.4 ± 10.7% ( p < 0.001), mean lean body mass increased from 20.5 ± 6.3 kg to 25.6 ± 4.3 kg ( p <0.01) and respiratory muscle function and physical strength imporved. Mean respiratory quotients significantly decreased from 0.81 to 0.77 ( p < 0.001); however, resting energy expenditure did not change. Therefore, GH therapy appears to reduce some of the physical disabilities experienced by children with Prader-Willi syndrome.     

Growth hormone therapy in Silver Russell Syndrome: 5 years experience of the Australian and New Zealand Growth database (OZGROW)

Data were analysed on 33 children (22 males) with Silver Russell syndrome treated with growth hormone for periods up to 5 years. Baseline data (medians) at commencement of growth hormone (GH) therapy were age 6.7 years, bone age delay 1.7 years, height standard deviation score (SDS)-3.2, weight SDS –3.1, and growth velocity 5.7 cm/ year. All were prepubertal. Median birth weight SDS for gestational age was –3.2. GH was commenced at 14 IU/m² per week and subsequently adjusted according to response. Growth velocity and growth velocity SDS for chronological age (CA) improved over baseline and gains in height SDS for CA were 1.0, 1.5 and 1.8 SD over 3, 4 and 5 years respectively (P < 0.001). No significant increase in height SDS for bone age was observed. Increased GH doses were required after the 1st year to maintain growth rates. Mean bone age advancement was 3.1 years after 3 years of treatment, and 6.0 years after 5 years treatment. Younger age was a predictor of the growth response over the 1st year. Predictors of response after 3 years were catch-up growth, low weight SDS at birth and low height SDS for CA. Age at onset of puberty was normal, but height at onset of puberty was lower than normal means. Conclusion We have demonstrated significant improvement in growth in Silver Russell syndrome after 3 years of GH therapy, however data on estimated mature height and final height are insufficient to conclude final outcomes. Further follow up is required to assess the long-term benefit. Received: 19 July 1995 Accepted: 4 March 1996     

Noonan's syndrome: abnormalities of the growth hormone/IGF-I axis and the response to treatment with human biosynthetic growth hormone

Auxological and endocrine data from 6 children (3 male, 3 female) aged 8.5-12.8 years with Noonan's syndrome and the results of treatment with human biosynthetic growth hormone (hGH) are presented. All the children were short (Ht SDS -3.5 to -2.3) and height velocity SDS ranged between -1.76 and +0.03. The maximum plasma growth hormone (GH) response to standard provocation tests ranged from 17 to 52 mU/l, yet, plasma insulin-like growth factor I (IGF-I) concentrations were low or low normal. Overnight GH secretory profiles were normal in all but 2 children who had disordered pulsatility with high trough concentrations. In 5 children who have completed one year of hGH therapy mean height velocity increased from 4.8 to 7.4 cm/year and the height velocity SDS ranged from +0.2 to +3.75. This improvement was associated with an increase in plasma IGF-I in three subjects. These results suggest that a defect of the GH/IGF-I axis may be present in some children with Noonan's syndrome and hGH therapy may have a role in the management of the short stature in these children.     

Final height after combined growth hormone and GnRH analogue treatment in adopted girls with early puberty

Background: Girls adopted from developing countries often have early or precocious puberty, requiring treatment with gonadotrophin-releasing hormone (GnRH) analogues. During such treatment, decreased growth velocity is frequent. Aim: To study whether the addition of growth hormone (GH) to GnRH analogue treatment improves final height in girls with early or precocious puberty. Methods: Forty-six girls with early or precocious puberty (age ≤9.5 y) adopted from developing countries were randomized for treatment for 2-4 y with GnRH analogue, or with a combination of GH and GnRH analogue. Results: During treatment, the mean growth velocity in the GH/GnRH analogue group was significantly higher compared to the control group. Combined GH/GnRH analogue treatment resulted in a higher final height: 158.9 cm compared to 155.8 cm in the GnRH analogue-treated group. Three out of 24 girls (13%) in the combined group and nine of the 22 girls (41%) treated with GnRH analogue alone attained a final height below -2 standard deviation scores (SDS).

Conclusion: The difference between the two groups is statistically significant, and possibly of clinical importance. A future challenge is to identify a subgroup with clinically significant advantage of GH addition to GnRH analogue treatment. Being very short on arrival in Sweden and being short and young at start of treatment are possible indicators.     

Combination growth hormone and gonadotropin releasing hormone analog therapy in 11beta-hydroxylase deficiency

Diagnosis of 11beta-hydroxylase deficiency was made in a boy at the age of 2 1/2 years on the basis of peripheral precocious puberty, growth acceleration (height standard deviation score +4.4) with advanced skeletal maturation (bone age 8.4 years) and elevated deoxycortisol levels. Glucocorticoid supplementation led to normalization of blood pressure but was associated with progression to central precocious puberty and increase in bone age resulting in decrease in predicted adult height to 133.7 cm (target height 163 cm). The child was started on GnRH analog (triptorelin 3.75 mg every 28 days), which led to improvement in predicted adult height by 3.1 cm over 15 months. Addition of growth hormone (0.1 IU/kg/day) resulted in improvement in predicted adult height (151 cm) and height deficit (12 cm) over the next 3.6 years. Final height (151 cm) exceeded predicted height at the initiation of GnRH analog treatment by 17.3 cm. This report suggests that combination GH and GnRH analog treatment may be useful in improving height outcome in children with 11beta-hydroxylase deficiency and compromised final height.     

Predictors of first-year growth response to a fixed-dose growth hormone treatment in children born small for gestational age: results of an open-label, multicenter trial in the United States

BACKGROUND: Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM: To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS: 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS: Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION: GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.     

Growth hormone treatment during suppression of early puberty in adopted girls

Girls adopted from developing countries often have early or precocious puberty, requiring treatment with gonadotropin-releasing hormone (GnRH) analogues. During such treatment decreased growth velocity is frequent. The aim of this investigation was to study whether the addition of growth hormone (GH) to GnRH analogue treatment improves height velocity and final height in girls with early or precocious puberty. Forty-six girls with early or precocious puberty adopted from developing countries were randomized for treatment with GnRH analogue or a combination of GH and GnRH analogue. After 2 y of treatment the mean growth in the GH/GnRH analogue group was significantly higher, 14.6 cm, compared to 10.9 cm in the control group. The increase in bone age did not differ, while the difference in predicted adult height increased by 2.7 cm in favour of the combination group. Although data on final height are not yet available, combined GH/GnRH analogue treatment for 2 y resulted in a higher growth velocity and predicted final height compared to GnRH analogue treatment alone.     

Treatment of precocious puberty using an intranasal luteinizing hormone-releasing hormone analogue: Buserelin

Abstract Fourteen patients with precocious puberty were treated for 1-3 years with 900-1800 μg/day of intranasal (i.n.) Buserelin. The peak luteinizing hormone and follicle-stimulating hormone responses to intravenous luteinizing hormone-releasing hormone were reduced significantly 4 weeks after starting treatment and remained suppressed while the patients were on treatment. Two patients were withdrawn because of drug non-compliance. Three patients showed regression of pubertal changes, four patients showed no progression and five patients showed progression of breast size or pubic hair staging after 1.5-2 years of treatment.
Treatment was changed to the subcutaneous route in two patients because of hormonal escape and accelerated skeletal maturation. The mean growth velocity decreased from 10.78 cm/year (s.e.m. = 0.64) to 7.06 cm/year (s.e.m. = 0.85) after 1 year of treatment ( P < 0.005). After an increase in dosage (from 900 μg/day to 1800 μg/day) in most patients, further significant falls in growth velocity to 5.29 cm/year (s.e.m. = 0.45), 4.63 cm/year (s.e.m. = 0.8) and 5.06 cm/year (s.e.m. = 0.5) were observed at 18, 24 and 30 months, respectively, compared with the pretreatment value ( P < 0.001). With treatment, the increased rate of skeletal maturation normalized. In 10 patients who had completed 2 years of treatment, the height standard deviation score for bone age improved from a pretreatment value of -2.42 ± 0.42 to -1.6 ± 0.42 after 2 years of treatment ( P < 0.01), indicating an improvement in height prognosis. It is concluded that i.n. Buserelin at a dose of 1800 μg/day is effective in the treatment of most but not all patients with precocious puberty.     

Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably

We have compared the growth and the body composition in children with Prader-Willi syndrome (PWS) with and without growth hormone treatment (recombinant GH 0.1 IU/kg/day) after a 1-y period. Twenty-nine prepubertal children with PWS, with mean body mass index (BMI) SDS of 2.2, and 10 (control) healthy obese children with mean BMI SDS of 5.6, underwent 24-h frequent blood sampling. Both PWS and control obese children had low and similar GH levels (0.7 /ng/l ± 0.4 SD). Serum IGF-I levels, however, were significantly lower in children with PWS (-1.5 SDS ± 0.8 SD vs -0.2 SDS ±0.8 SD). The 29 PWS children were randomized into 2 groups of 15 and 14 subjects for GH treatment and no treatment, respectively. Height velocity increased from -1.9 SDS to + 6.0 SDS in the treated group ( p < 0:001) and decreased from -0.1 SDS to -1.4 SDS in the control PWS group during the study year. BMI decreased significantly for the treated group (+3.0 SDS to + 2.0 SDS). Relative fat mass decreased significantly, while fat-free mass increased ( p < 0:001) for the treated group. No significant changes were noticed in body composition in the control PWS group. In conclusion, the low spontaneous 24-h GH secretion, regardless of body weight, and the exceptional response to growth hormone treatment together with the finding of low IGF-I levels suggest that growth hormone deficiency is a common feature of PWS, as a result of hypothalamic dysfunction. Treatment with growth hormone is beneficial for the majority of PWS children.     

Short-term therapy with recombinant growth hormone in polytransfused thalassaemia major patients with growth deficiency

Growth failure is commonly described in polytransfused thalassaemia major patients (Th) with or without growth hormone (GH) releasing hormone-GH axis impairment. We have investigated the efficacy of short-term recombinant GH (rhGH) therapy (Saizen [Serono] 0.1 IU/kg/day 6 evenings/week administered s.c. for 12 months) on growth and predicted final height in 28 (19M, 9F) regularly transfused Th with growth deficiency (aged 14.8 +/- 2.0 yr) on long term desferrioxamine s.c. therapy. All Th had no evidence of congestive heart failure, hypothyroidism or impaired glucose tolerance; in all patients the GH peak (evaluated during both insulin and clonidine test) was < or = 20 mIU/l; hypergonadotropic hypogonadism was excluded in Th with delayed puberty. At the start of therapy height age (HA)/bone age (BA) ratio was 0.92 +/- 0.12. Bone age delay was positively correlated to chronological age (CA), serum ferritin levels (mean of the last three years), the age at the start of chelation therapy, growth velocity calculated for CA during the last year; a positive correlation was also found between circulating IGF-I levels and age at the start of chelation therapy. After 1 year on rhGH therapy there was a significant increase of height calculated for CA (not for BA), of growth velocity calculated for both CA and BA and of circulating IGF-I levels; the HA variation/BA variation ratio was 1.85 +/- 1.71, without any significant difference between predicted final height at the start (-1.08 +/- 1.28 SDS) and at the end of rhGH therapy (-0.88 +/- 1.13). The variation of height calculated for CA was positively correlated to both CA and growth velocity during the last year before rhGH therapy (calculated for CA) and negatively to the height at the start (calculated for CA). There were no side effects and haematological parameters did not show significant changes. In conclusion, our data, obtained in a relatively large group of Th, confirm the emerging results of short-term (12 months) rhGH therapy on growth, as shown by the increase of both growth velocity and height calculated for CA. With regard to final height, although the mean variation of HA/variation of BA ratio was 1.85, no significant increase of the predicted final height was found between the start and the end of rhGH therapy. We are evaluating the effect of long-term rhGH therapy on growth in these patients.     

Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls

A survey to identify children and adolescents with primary growth hormone insensitivity syndrome (GHIS) yielded 38 patients who were positively identified using a scoring system that included five criteria: height, basal growth hormone (GH), GH binding protein, basal insulin-like growth factor 1 (1GF-I) and the increase of IGF-I after 4 days of GH administration (IGF generation test). Because of an overlap of the accepted and excluded groups with respect to points scored, an attempt was made to improve the scoring system. The new criteria were: height below –3 SDS, basal GH 4 mU/I or above, GH binding below 10%, basal IGF-I and basal IGF binding protein-3 (IGFBP-3) below the 0.1 centile for age, an increase of IGF-I in the IGF generation test less than 15 μg/1, and the increase of IGFBP-3 less than 0.4 mg/1. With this scoring system, a clear separation between the accepted and the excluded groups was obtained. IGFBP-3 was included to give the GH-dependent parameters of the IGF system more weight and because the accuracy of IGFBP-3 in the IGF generation tests was greater than the accuracy of IGF-I, when the group of patients with GHIS was compared with a group of patients with GH deficiency. Unexpectedly, the IGF generation test was unable to segregate both cohorts completely. In the GHIS-positive group, a significant correlation was found between basal IGF-I or IGFBP-3 levels corrected for age (SDS) and height SDS ( r = 0.49, p < 0.002 and r = 0.61, p < 0.0001, respectively). There was also a significant correlation between the changes of IGF-I or IGFBP-3 in the IGF generation test and height SDS. That is, the patients with a slight response to GH were those with the least growth retardation, suggesting the existence of partial GH insensitivity.     

Responses of bone turnover markers and bone mineral density to growth hormone therapy in children with isolated growth hormone deficiency and multiple pituitary hormone deficiencies

Growth hormone deficiency (GHD) is an important cause of decreased bone mass in childhood and adolescence. The role of other pituitary hormone deficiencies on bone mass is still a query in children. Thirty-nine children (28 with isolated GHD [IGHD] and 11 with multiple pituitary hormone deficiency [MPHD]) were investigated to show the effects of IGHD vs MPHD on bone status. Bone turnover markers (calcium, phosphate, alkaline phosphatase [ALP] Bone ALP [BALP], osteocalcin [OSC], carboxyterminal propeptide of type-1 collagen [CPP-I], parathyroid hormone [PTH]) were measured before and every four months during growth hormone (GH) therapy; bone mineral density (BMD) of the lumbar spine was measured before and every six months during therapy. All bone turnover markers except calcium and PTH increased significantly during 1 year of GH therapy. There were no differences in the levels of bone turnover markers between children with IGHD and MPHD at baseline, and after 4, 8 and 12 months of therapy. Lumbar spine BMD SDS of all patients increased significantly during 1 year of therapy (p = 0.035 after 6 months and p <0.001 after 12 months compared with baseline). BMD SDS of both IGHD and MPHD groups were similar at baseline and after 6 and 12 months of therapy (p = 0.235, p = 0.295 and p = 0.384). Height SDS (HtSDS) at baseline was the most important predictor of baseline BMD SDS in children with GHD (t = 4.166, p <0.001). DeltaHtSDS was also positively related to deltaBMD SDS after 1 year of GH therapy. In conclusion, there was no difference in bone status of the patients with IGHD and MPHD at baseline. GH therapy yielded similar increases in bone mass in both groups. Increase in height contributed to increase in BMD during 1 year of GH therapy.     

Efficacy of recombinant human growth hormone in children with juvenile rheumatoid arthritis and growth failure

Ten patients with juvenile rheumatoid arthritis (JRA) and growth failure were treated with recombinant human growth hormone (GH) for 1 to 3 years at a dosage of 0.57 IU/kg/wk. All the patients had been on prednisone at a mean dosage of 4.12 mg p.o. daily. GH was low in one patient, two patients had a borderline level and seven patients had adequate response to provocative tests or post-sleep measurement. Serum IGF-I was found to be low in five of six patients. Mean growth velocity increased from 2.45 cm/yr to 4.79 cm/yr after 1 year's treatment with GH (P<0.004). Six patients continued on GH treatment for a second year and continued to have a better growth velocity, with a mean of 5.43 cm/yr (P<0.014). Two patients entered puberty during the second year of GH treatment. This study demonstrates the potential beneficial effect of GH treatment in patients with JRA with growth failure of systemic onset or polyarticular onset who are on prednisone. Further study is needed to determine the long-term effect of GH treatment on ultimate height.