Differential effects of hGH and IGF-I on body proportions

The differential growth effects of hGH and IGF-I on the upper/lower (U/L) body segment in relation to height (Ht) were analyzed in 15 patients with isolated Growth hormone deficiency (IGHD,:7M, 8F) mean age 5.0 +/- 3.2 (SD) years treated with hGH; 21 patients with multiple pituitary hormone deficiency including growth hormone (MPHD: 14M, 7F) aged 10.0 +/- 3.8, treated with hGH; 9 patients with Laron Syndrome (LS) (4M,5F) aged 6.9 +/- 5.6 years treated with IGF-I; 9 boys with intrauterine growth retardation (IUGR) aged 6.3 +/- 1.25 years treated by hGH; and 22 boys with idiopathic short stature (ISS) aged 8.0 +/- 1.55 years treated by hGH. The dose of hGH was 33 microg/kg/day, that of IGF-I 180-200 microg/kg/day. RESULTS: the U/L body segment ratio in IGHD patients decreased from 2.3 +/- 0.7 to 1.1 +/- 0.7 (p <0.001), and the Ht SDS increased from -4.9 +/- 1.3 to 2.3 +/- 1 (p < 0.001) following treatment. In MPHD patients the U/L body segment decreased from 1.1 +/- 1.1 to -0.6 +/- 1.0 (p < 0.001), and the Ht SDS increased from -3.3 +/- 1.4 to -2.5 +/- 1.0 (p < 0.009). In the LS group the U/L body segment ratio did not change with IGF-I treatment but Ht improved from -6.1 +/- 1.3 to -4.6 +/- 1.2 (p < 0.001), The differential growth response of the children with IUGR and with ISS resembled that of the children with LS. CONCLUSIONS: hGH and IGF-I act differentially on the spine and limbs.     

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.     

Final height in patients with idiopathic short stature and high growth hormone responses to stimulation tests

Children with idiopathic short stature (ISS) may have normal or increased growth hormone (GH) responses to provocation tests and achieve a final height (FH) below -2.0 standard deviation score (SDS) if untreated. FH of subjects with high stimulated GH levels has not been studied in detail. AIM: It was the aim of this study to analyse FH in ISS patients with high GH peak responses to the provocation test. PATIENTS AND METHODS: We studied 16 patients (9 pre-pubertal) with ISS and a GH peak >or=40 mU/l to insulin-induced hypoglycaemia. The patients were recalled at age 19.7 +/- 2.5 years for measurement of FH when blood samples were obtained for serum insulin-like growth factor (IGF)-I, IGF binding protein 3, acid-labile subunit and GH binding protein measurements. GH bioactivity was determined using the Nb2 bioassay. RESULTS: FH was -3.1 +/- 1.0 SDS, being significantly lower than target height (TH). At FH, IGF-I levels were within -1.5 and +1.5 SDS for age and sex in 10 patients and higher than +1.5 SDS in 6 patients. IGF binding protein 3, acid-labile subunit, GH binding protein levels and GH bioactivity values were normal. SUMMARY: These data suggest that patients with ISS and high GH levels during a GH stimulation test may have a more compromised FH. The association of severe ISS with a peak GH >40 mU/l might suggest a degree of insensitivity for the GH-IGF-I axis.     

Physiological growth hormone secretion in children with short stature and intra-uterine growth retardation

31 prepubertal children with short stature [mean height standard deviation score (SDS) -2.84] and low birth weight (mean -2.82 SDS) were studied. Mean age was 6.0 years and mean height velocity SDS was -0.76. Patients were classified as having either the clinical characteristics of Russell-Silver syndrome (RSS) (4 F, 13 M) or not (4 F, 10 M). All children had an overnight profile of spontaneous growth hormone (GH) secretion. 4 children achieved a maximum GH concentration of less than 20 mU/l. 9 children with RSS secreted only one large GH peak during the night. Most of the non-RSS group had normal GH pulse frequency but 3 boys had a fast-frequency pattern. Abnormal GH secretion may contribute towards growth failure in children with low birth weight/RSS.     

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.     

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.     

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.     

Height, bone mineral density and bone markers in congenital adrenal hyperplasia.

AIM: To evaluate height, bone growth, areal bone mineral density (aBMD), volumetric bone mineral density (vBMD) and markers of bone turnover in a group of patients affected by congenital adrenal hyperplasia (CAH). PATIENTS: There were 50 patients (23 males, 27 females), aged 1-28 years, affected by CAH due to 21-hydroxylase deficiency: 27 with the salt-wasting (SW); 14 with the simple virilizing (SV), and 9 with the nonclassical (NC) forms. METHODS: Bone morphometry was evaluated with the metacarpal index (MI) and lumbar aBMD and vBMD (L2-L4) by dual energy X-ray absorptiometry. Serum osteocalcin was used as a marker of bone formation, while urinary cross-linked N-telopeptides of type-I collagen and free deoxypyridinoline levels were evaluated as indexes of bone resorption. RESULTS: The height standard deviation score (SDS) was -0.41 +/- 1.4 in SW patients, -0.01 +/- 1.9 in SV patients, and -0.01 +/- 2.3 in NC patients. There was no significant difference among groups and against zero. The MI SDS was also not different between groups and against zero. aBMD was significantly lower in the pubertal patients compared with normal values, but only when patients with the SW and SV forms were considered together (p < 0.05). vBMD was significantly reduced in all patients with the classical form. Bone markers were not different in patients and controls. CONCLUSION: Our study shows that normal height can be attained in CAH patients; however, an impairment in bone growth and mineralization may be found in adolescents and young adults affected by the classical form.     

Predicting therapeutic response and degree of pituitary tumour shrinkage during treatment of acromegaly with octreotide LAR

BACKGROUND/AIMS: The efficacy of transsphenoidal surgery in the treatment of patients with acromegaly is largely dependent on tumour size. A reduction in pituitary tumour volume by medical therapy might therefore improve subsequent surgical cure rates. This study prospectively determined the effects of the depot somatostatin analogue octreotide LAR on pituitary tumour size, GH and IGF-I levels and clinical symptoms in a cohort of previously untreated patients with acromegaly. METHODS: Six patients newly diagnosed with acromegaly (mean age 53 years; range 42-76 years) received intramuscular octreotide LAR every 28 days for 6 months. The initial dose of LAR was 20 mg, but increased to 30 mg after the initial 3 injections if mean GH levels were >5 mU/l. Prior to commencing LAR therapy, each patient received 3 injections of subcutaneous octreotide (50, 100 and 200 mug) in a randomized order on separate days, and the serum GH response was measured. Pituitary tumour volume was calculated from MRI or computed tomography scans at baseline, then 3 and 6 months after initiation of treatment, and assessed by a 'blinded' radiologist in random order. At baseline, 4 patients had a macroadenoma and 2 patients had a microadenoma. For the latter, the whole gland volume was measured. RESULTS: Serum GH levels decreased from 29.6 +/- 19.2 mU/l (mean +/- SD) at baseline to 12.1 +/- 10.5 mU/l at 3 months and 10.4 +/- 9.3 mU/l at 6 months. Three patients achieved a mean serum GH level of <5 mU/l. In these patients, the serum GH had declined to <5 mU/l in response to a single 100 mug subcutaneous octreotide injection. Serum IGF-I levels decreased by a mean of 45 +/- 7.4%. Tumour volume decreased in all patients: mean baseline volume 2,175 mm(3) (range 660-6,998) decreasing to 1,567 mm(3) (range 360-4,522) at 3 months (p < 0.05) and 1,293 mm(3) (range 280-4,104) at 6 months (p < 0.002). The mean percentage decrease in size was 29% (range -54 to +4%) at 3 months (p < 0.02) and 47% (range 21-97%) at 6 months (p < 0.002). There was no statistically significant correlation between GH response and tumour shrinkage. CONCLUSIONS: A single test dose of subcutaneous octreotide may be useful in predicting the subsequent efficacy of octreotide LAR. Octreotide LAR results in significant shrinkage of pituitary tumours of newly diagnosed patients with acromegaly. Whether its administration to such patients for 6-12 months can improve the efficacy of subsequent transsphenoidal surgery will require further study.     

Final height after growth hormone therapy in peripubertal boys with a subnormal integrated concentration of growth hormone.

The aim of this study was to test the effect of growth hormone (GH) therapy on final height in peripubertal boys with idiopathic short stature in whom a subnormal integrated concentration of GH (< 3.2 micrograms/l) was found. Twenty-eight peripubertal children were studied. Height was below 2 SD for age, growth velocity was < 4.5 cm/year, bone age was more than 2 SD below mean for age and GH response to provocative tests was more than 10 micrograms/l. Eleven subjects (group B) were treated with recombinant GH 0.75 unit/kg/week, divided into 3 weekly doses for 2 years, and then the same weekly dose divided into daily injections was administered until final height was attained. Seventeen untreated children (group A) who were followed until cessation of growth served as controls. The GH-treated patients reached their target heights (-2.1 +/- 0.5, mean +/- SD in SDS) and predicted heights (-1.8 +/- 0.8) determined by the Bayley and Pinneau method, while the final heights of the untreated patients were significantly lower than their target heights and their predicted final heights (-2.7 +/- 0.7, -1.8 +/- 1.0 and -2.7 +/- 0.7, respectively). The main effect of GH was observed during the 1st year of treatment when height velocity was significantly higher in the GH-treated group than in the untreated one (9.3 +/- 2.1 vs. 5.3 +/- 1.1, respectively, p < 0.001). The high cost of the treatment in this specific age group should be weighed against the results.     

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

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

A comparison of subcutaneous and intramuscular administration of human growth hormone (hGH) and increased growth rate by daily injection of hGH in GH deficient children

Plasma human growth hormone (hGH) profiles and biological activities of recombinant hGH were compared after im and sc injection in 8 normal volunteers. The time to reach maximal plasma GH and plasma hGH concentrations and the areas under the curve of hGH profiles did not differ significantly after im and sc injections. The biological effect of hGH in increasing nonesterified fatty acid and insulin-like growth factor-I (IGF-I) was the same after both im and sc injections. During 6 months of daily sc administration of recombinant hGH in 20 naive patients, their height increased between 5 and 16.5 cm with a mean of 11.0 +/- 3.0 cm/year. In 27 patients who switched from hGH injections of 2-4 times/week to daily injections, the height increased between 5.3 and 16.5 cm with a mean of 8.3 +/- 2.2 cm/year. These values were greater than those observed in a previous study in which the same amount of hGH was injected in 2-4 doses per week. Plasma IGF-I increased more with daily sc administration than with 2-4 doses per week. The rate of appearance of an antibody to hGH was low (0.5%) and there were no notable changes in blood cell count, urinalysis and/or routine chemistries during the 6 months of daily recombinant hGH treatment. These results show that sc daily administration of hGH is safe, has a greater growth promoting effect, and can be recommended for the treatment of patients with GH deficiency.     

Precocious or early puberty and growth failure in girls treated for acute lymphoblastic leukaemia

We have studied 41 children with early or precocious puberty who have been treated for acute lymphoblastic leukaemia with prophylactic cranial irradiation (1,800-2,400 cGy) accompanied by intrathecal methotrexate and systemic chemotherapy. Mean age at radiotherapy was 3.9 years (range 1.7-7.7) in the girls and 4.8 years (range 2.6-7.8) in the boys. Mean age at the onset of puberty was 8.6 years (range 6.7-9.7) in the girls and 9.3 years (range 7.8-10.3) in the boys. Of the 41 children with early puberty (greater than 1.4 SD from the mean) 36 were females and 5 were males. 21 of the 36 girls had an absent or inadequate growth acceleration of puberty. 7 of 12 girls who had a pharmacological test of growth hormone (GH) secretion had GH insufficiency (peak level less than 20 mU/l). Early or precocious puberty combined with GH insufficiency may produce severe growth failure and we have used a treatment regimen of a gonadotrophin-releasing hormone analogue, in order to reduce the rate of epiphyseal maturation, combined with biosynthetic GH to increase or sustain growth rate. We have treated 4 girls in this manner. During a mean treatment period of 0.86 years, height SDS for bone age rose from a mean of -1.06 to -0.59. Longer treatment periods will be required to assess the effect on final height.     

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.     

Total pubertal growth and markers of puberty onset in adolescents with GHD: comparison between mathematical growth analysis and pubertal staging methods

Two methods of determining puberty onset (Preece- Baines model 1 (PB1) and Tanner staging) were used to calculate total pubertal growth (TPG) in adolescents with growth hormone deficiency (GHD). PATIENTS AND METHODS: 34 patients (11 girls) met the following inclusion criteria: isolated GHD, >2 years growth hormone therapy prior to puberty onset, regular weight-adjusted GH dosage, known final height (age >21 years or height velocity <0.5 cm/year), no induction of puberty. PB1 was used to define age and height at onset of the pubertal growth spurt ("take-off"). RESULTS: The results (mean +/- SD) were as follows: in girls, mean age at take-off was 9.8 years; 2.0 +/- 1.1 years before breast stage B2. In boys, mean age at take-off was 11.3 years; 1.4 +/- 0.8 years before testes volume >3 ml. Height at take-off was lower than at Tanner stage 2 by 12.4 +/- 7.6 cm in girls and 7.7 +/- 5.3 cm in boys. TPG was thus markedly greater (p < 0.001) using the PB1 method, as compared with Tanner stage2. Peak height velocity was normal. Final height was -0.5 +/- 0.7 SDS in females and -0.4 +/- 0.9 SDS in males. CONCLUSIONS: The method of measuring TPG from take-off is more objective, and has potentially greater implications for GH therapeutics than the Tanner stage method. In our study, 40% of TPG occurred before "breast stage B2" was attained in GHD girls; whereas 23% of TPG occurred before "testes >3 ml" in GHD boys.     

The capacity to increase GH secretion at puberty reflects the severity of GH deficiency.

This study evaluates the effect of the spontaneous pubertal increase in sex steroids on GH secretion in GH-deficient patients. Fifteen patients (10 boys, 5 girls) with idiopathic isolated GH deficiency diagnosed before puberty (GH peak < 8 micrograms/l after 2 arginine insulin stimulation tests) were reevaluated for their GH secretion using the same test after completion of their hGH therapy and puberty. Their ages at diagnosis and at the last evaluation were 8.2 +/- 0.7 (SE) (range 4.9-14.9) and 17.8 +/- 0.3 years (15-23), respectively. The data at diagnosis and at last evaluation showed that (1) the mean height increased from -4 +/- 0.3 to -2.5 +/- 0.3 SD (p < 0.01), (2) the mean GH peak increased from 4.4 +/- 0.3 (1.6-8) to 7.6 +/- 0.8 micrograms/l (2-13.2, p < 0.01); at the last evaluation, 8/15 patients had GH peak > 8 micrograms/l and (3) the mean plasma insulin-like growth factor I increased from 0.28 +/- 0.05 to 0.42 +/- 0.03 U/ml (n = 6, p < 0.05). The mean increase in the GH peak was 3.2 micrograms/l (-3 to 10.6). It was negatively correlated with the degree of growth retardation at diagnosis (r = -0.74, p < 0.005). We conclude that the increase in the GH peak at puberty in patients with GH deficiency reflects the severity of GH deficiency and that a corrective factor of the cutoff number is necessary for the diagnosis of GH deficiency in puberty.     

Final height in children with idiopathic growth hormone deficiency treated with a fixed dose of recombinant growth hormone

There is no consensus regarding the optimal dosing of recombinant human growth hormone (rhGH) for children with growth hormone deficiency (GHD). Our objective was to evaluate the final adult height (FAH) in children with idiopathic GHD treated with a fixed rhGH dose of 0.18 mg/kg/week. We reviewed all charts of patients with idiopathic GHD treated with rhGH since 1985 who reached FAH. Ninety-six patients were treated for an average of 5.4 years. The mean age was 11.9 years, the mean height -2.87 standard deviation score (SDS) and the mean FAH was -1.04 SDS. Females had a lower predicted adult height than males at the initiation of therapy (-2.0 vs. -1.01 SDS; p = 0.0087) but a higher FAH - predicted adult height (1.08 vs. 0.04 SDS; p = 0.0026). In multiple regression analysis, the FAH SDS was positively related to the midparental height SDS, the height SDS at GH initiation and growth velocity during the first year of therapy, and negatively correlated with peak GH and bone age at initiation (r(2) = 0.51; p < 0.005). Treatment of children with idiopathic GHD with a fixed dose of 0.18 mg/kg/week rhGH is sufficient to reach FAH within 2 SDS of the normal population range (84%) with an average FAH within -0.5 SDS of midparental height.     

Serum prolactin in patients with Laron-type dwarfism: effect of insulin-like growth factor I.

Prolactin (PRL) secretion was studied in Laron-type dwarfism (LTD) patients (8 children and 9 adults) in basal condition, after acute insulin-like growth factor (IGF-I) or TRH injections and during 2 months of daily IGF-I treatment. Basal PRL was repeatedly higher (12.6 +/- 1.6 micrograms/l) than that in control subjects (7.6 +/- 1.2 micrograms/l, p < 0.05). Acute IGF-I injection caused an immediate slight decrease in serum PRL and growth hormone (GH), followed by a progressive rise to mean peak levels of 33.3 +/- 4.5 micrograms/l again parallel to serum hGH which rose to 86 +/- 20 micrograms/l--a response to the IGF-I-induced hypoglycemia. Intravenous TRH in LTD children induced a marked response in serum PRL, similar to that registered in estrogenized adult females. Serum PRL did not show consistent changes during chronic IGF-I treatment. It is suggested that the higher-than-normal PRL levels and release in LTD patients are due to a drift phenomenon of the mammosomatotropes which produce large amounts of hGH.     

Clinical and endocrine characteristics in atypical and classical growth hormone insensitivity syndrome

OBJECTIVE: Classical growth hormone insensitivity syndrome (GHIS) comprises a dysmorphic phenotype, extreme short stature (height SDS < 3), normal GH and low IGF-I and IGFBP-3. Wide clinical variation is recognised with classical and atypical forms. We aimed to delineate features of the milder "atypical" GHIS phenotype, and to determine whether this correlates with milder auxological and biochemical features. METHODS: Fifty-nine patients from a European series of 82 patients with GHIS, with strict diagnostic criteria of GHIS, were studied and assigned to classical or atypical GHIS groups according to facial phenotype, i.e. "classical" required 2 of 3 recognized GHIS features (frontal bossing, mid-facial hypoplasia and depressed nasal bridge), "atypical" required 0 or 1 of these facial features. Classical and atypical GHIS groups were compared in terms of (1) phenotypic features, including high-pitched voice, sparse hair, blue sclera, hypoglycaemia, microphallus, (2) birth length, height SDS, and (3) basal IGF-I, IGF-II, IGFBP-1, IGFBP-3, GHBP and increase in IGF-I on IGF-I generation testing. RESULTS: Fifty patients [24 males, 26 females, aged 8.6 +/- 4.6 years (mean +/- SD)] had "classical GHIS", 9 patients (7 males, 2 females, aged 7.8 +/- 4.1 years) had "atypical GHIS", 7 with normal facies. Atypical GHIS patients had lesser height deficit (Ht SDS -4.0 +/- 1.4) compared to classical GHIS (-6.7 +/- 1.4), less reduction in IGFBP-3 SDS (atypical -5.5 +/- 3.3; classical -8.6 +/- 2.4), and more had normal GHBP (>10% binding). Other variables were also less frequent in atypical GHIS patients: high-pitched voice 11% (70% classical), sparse hair 11% (42% classical), blue sclera 0% (38% classical), hypoglycaemia 11% (42% classical), and microphallus 14% (1 of 7 males), compared to 79% of classical (19 of 24 males). CONCLUSIONS: Atypical GHIS patients, with relatively normal facial appearance, demonstrate less height defect and biochemical abnormalities compared to classical patients. GH insensitivity may be present in children with short stature and an otherwise normal appearance.     

Effects of acute intravenous injection of two growth hormone-releasing hormones (GHRH 1-40 and 1-29) on serum growth hormone and other pituitary hormones in short children with pulsatile growth hormone secretion

We administered two different growth hormone-releasing hormones (GHRH) to 20 short, prepubertal children who had spontaneous secretion of growth hormone (GH), assessed from 24-hour GH secretion profiles (72 sampling periods of 20 min). We compared one i.v. injection of 1 microgram/kg of GHRH 1-40 with that of GHRH 1-29 regarding serum concentrations of GH, prolactin, luteinizing hormone, follicle-stimulating hormone and IGF-I. The children were allocated to two groups without statistical randomization. Both groups were given both peptides, with at least 1 week in between. The first group started with GHRH 1-40, the other with GHRH 1-29. The peptides both induced an increased serum concentration of GH of the same magnitude: mean maximal peak of 89 +/- 12 mU/l after GHRH 1-40 and 94 +/- 10 mU/l after GHRH 1-29 (n.s.). The mean difference in maximum serum GH concentration in each child after injection was 52 +/- 9 mU/l, range 1-153 mU/l. GHRH 1-29 also induced a short-term, small increase in the concentrations of prolactin (p less than 0.05), luteinizing hormone (p less than 0.01) and follicle-stimulating hormone (p less than 0.05). We conclude that the shorter sequence GHRH 1-29, when given in a dose of 1 microgram/kg, gives a rise in serum concentration of GH similar to that after the native form GHRH 1-40.