Promotion of tyrosinase folding in COS 7 cells by calnexin

To evaluate the role of serum free or unbound insulin-like growth factor I (IGF-I) on bone growth, we measured serum free IGF-I levels in 354 healthy children and adults (193 males and 161 females, aged 0-40 yr) and in 21 prepubertal GH-deficient (GHD) children (complete GHD, n = 5; partial GHD, n = 16) using a recently developed immunoradiometric assay. We obtained the following results. 1) In the normal children, the serum free IGF-I levels were low in infancy (<1 yr of age; males, 0.71 +/- 0.26 microg/L, mean +/- SD; females, 1.05 +/- 0.49 microg/L), increased during puberty (males, 5.84 +/- 2.18 microg/L; females, 5.80 +/- 1.49 microg/L), and declined thereafter. 2) Free IGF-I in the serum occupied about 0.95-2.02% of the total IGF-I values, with the highest ratio occurring in infancy (males, 1.77 +/- 0.60%; females, 2.02 +/- 0.87%). 3) The SD scores of serum free IGF-I in the 21 GHD children ranged from -3.30 to 0.30, and the 5 complete GHD children had free IGF-I values more than -2 SD below those of age-matched normal subjects. 4) There was a significant correlation between the SD scores of free IGF-I and those of total IGF-I (r = 0.715; P < 0.0005) in the GHD children. 5) In the 16 partial GHD children receiving GH treatment, the serum free IGF-I levels were elevated to 209% of pretreatment levels after 1 month of GH treatment and remained high during GH therapy. The GH-induced increase in the serum free IGF-I levels was significantly higher than those of the total IGF-I and IGF binding protein-3 levels. 6) The percent increase in the serum free IGF-I level after 1 month of GH treatment showed a significant positive correlation with that of the GH-induced improvement in the percent increase in the height velocity during 1 yr of GH therapy (r = 0.526; P < 0.05). These results show that free IGF-I in the serum has an essential role in bone formation because the higher free IGF-I levels were observed when the growth rate accelerated. The measurement of serum free IGF-I may become a useful tool for both diagnosing GH deficiency and predicting growth responses to long term GH therapy.     

Catch-up growth after childhood-onset substitution in primary hypothyroidism: is it a guide towards optimal growth hormone treatment in idiopathic growth hormone deficiency?

Catch-up growth was analyzed in 20 prepubertal children with primary hypothyroidism (PH) starting treatment at an age of 4.4 (1.2-10.1) years and a height (HT) SD score (HT SDS) of -3.1 (+/-0.8). All patients were followed for at least 3 prepubertal years. HT velocity was 12.3 +/- 2.3, 9.0 +/- 1.8 and 7.5 +/- 2.2 cm/year, and change in HT SDS was 1.60 +/- 0.56, 0.57 +/- 0.33 and 0.28 +/- 0.38 during the 1st, 2nd and 3rd year, respectively. The 11 children followed to adult height reached a HT SDS of -0.11 +/- 1.1, all within their target HT range. HT gain (DeltaHT SDS) during the 1st year was correlated with the degree of catch-up growth (r2 = 0.78, p < 0.001). While catch-up growth in childhood-onset PH is complete, this is not the case in GH deficiency (GHD). Based on the auxological characteristics of the patients with PH, HT velocities during the first 2 years were predicted applying prediction models devised for prepubertal children with idiopathic GHD. The modalities of GH treatment observed in the models were used to calculate predicted HT velocities of the PH patients. Observed HT velocities in PH were higher than predicted HT velocities during the 1st (10.67 +/- 1.37 cm/year, p < 0.01) and 2nd (8.35 +/- 0.86 cm/year, p = 0.128) year. The data show that catch-up potential in idiopathic GHD of childhood onset is reduced compared to PH. Since early catch-up as well as total HT recovery in children with GHD are often not reached by present treatment modalities, catch-up growth in PH may serve as a model towards optimizing GH treatment. The data suggest that initial GH doses of 1.0 IU/kg/week, rather than the presently recommended 0. 6 IU/kg/week, need to be given in GHD in order to achieve the degree of early catch-up observed in PH and to consequently improve the final outcome.     

Intradermal transgenic expression of granulocyte-macrophage colony-stimulating factor induces neutrophilia, epidermal hyperplasia, Langerhans'' cell/macrophage accumulation, and dermal fibrosis

Bone age maturation and growth velocity were analyzed longitudinally by the TW2 RUS method standardized for Japanese children in 45 GH-treated boys with idiopathic GH deficiency (GHD). The patients were divided into three groups: Group I consisted of four isolated GHD patients who underwent spontaneous puberty without gonadotropin suppression treatment (GST) and had a mean final height of 151.9 cm; Group II consisted of 24 GHD patients with associated gonadotropin deficiency who received sex hormone replacement treatment (GRT) and had a mean final height of 165.3 cm; Group III consisted of 17 isolated GHD patients who underwent spontaneous puberty and had a mean final height of 158.3 cm after being treated with combined GH and GST. Bone age matured along with chronological age in Group I, whereas bone age in Group II decelerated significantly after a bone age of 12 years and did not reach a bone age of 14 years. Bone age maturation in Group III showed an intermediate pattern between Groups I and II; bone age decelerated significantly after a bone age of 12 years but mean bone age advanced beyond a bone age of 14 years. Height velocity in Group I during GH treatment decelerated rapidly after the pubertal growth spurt, as usually seen in normal puberty. A definite pubertal growth spurt was not observed in the height velocity of Group II during GH treatment before receiving GRT; the mean height velocity gradually declined, remaining at 3.5-4.5 cm/year even after 18 years. Mean height velocity in Group III during GH treatment and GST showed a similar tendency as Group II, but it declined more rapidly. Since a growth velocity of around 3 cm/year was preserved with GH treatment despite the decline in growth velocity, the slower the advance of bone age, the longer the treatment period and, therefore, the taller the final height achieved by GST compared to Group I. It is recommended to start GST at a bone age between 11.5 years and 13 years. The timing, namely when to start GRT in GHD with gonadotropin deficiency or when to stop GST in isolated GHD, can be estimated according to the patient's desired final height and bone age-growth potential.     

GH and GnRH analog treatment in children who enter puberty at short stature

It is well known that height at the onset of puberty is closely related to final height. To improve final height of short children who enter puberty at short stature, twenty-one short boys and six short girls were treated with a combination of GH and GnRH analog. The boys started the combination treatment at a mean age of 12.0 years when their mean height was 128.5 cm (-2.74 SD) and the girls at a mean age of 10.68 years when their mean height was 126.4 cm (-2.23 SD). The boys discontinued GnRH at a mean age of 16.88 years after a mean treatment period of 4.89 years when their height was 153.7 cm (-2.75 SD), and the girls at a mean age of 13.89 years after a mean treatment period of 3.20 years when their height was 143.3 cm (-1.94 SD). Bone age maturation significantly decelerated during the combination treatment. Bone age rarely exceeded 14 years in boys and did not exceed 13 years in girls. Bone age maturation during combination treatment decelerated after bone age 12 years in boys and 10.5 years in girls. On average, bone age matured at a mean rate of 0.48 years a year in boys and 0.56 years a year in girls during the combination treatment. During the combination treatment, height velocity did not decelerate rapidly and remained at 3-5 cm/year for a longer duration because of the bone age deceleration, although a definite pubertal growth spurt was not observed. As a consequence, the mean projected height SDS for bone age increased 1.50 (+/- 0.76) SD in boys and 1.24 (+/- 0.49) SD during the combination treatment. Although most of the patients have not yet reached their final height, combined GnRH analog and GH treatment should increase the pubertal height gain and the adult height in short children who enter puberty early for height, when the post-GST growth is taken into account. The combination treatment seems more effective in boys than in girls. This improvement is attributed to the lengthening of the treatment period by slower bone maturation and maintained growth velocity.     

Effects of physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency

GH replacement of adults with acquired GH deficiency (GHD) results in body composition changes including increases in lean mass and bone mineral density. However, the effects of long-term GH therapy on cognitive function are largely unknown, and there are conflicting data regarding quality of life. We performed a randomized, double-blind, placebo-controlled study of GH replacement in adults with GHD and measured cognition and sense of well-being using standardized psychometric tests before and after therapy. Forty men (median age 51 yr, range 24-64 yr) with a history of pituitary disease were randomized to GH therapy (starting dose, 10 +/- 0.3 micrograms/kg per day: mean treatment dose, 4 +/- 2 micrograms/kg per day) vs. placebo for 18 months, and GH doses were adjusted according to serum insulin growth factor-I levels. At baseline, the patients displayed a full-scale intelligence quotient (IQ) score nearly 1 SD above the normal mean. Mean scores on all cognitive tests fell within normal limits, and on many tests, fell above the mean. On tests of verbal learning and delayed visual memory, mean test scores fell below the mean (although within normal limits), suggestive of a relative compromise in the area of memory performance. Following 18 months of GH replacement therapy, there were no significant changes in cognitive function or quality of life. We conclude that acquired GHD in adult men is not associated with significant alterations in cognitive function as assessed by standardized tests, and chronic low-dose GH replacement therapy does not result in significant beneficial effects on cognitive function or quality of life. Although previous studies have suggested that GH replacement in adults with acquired GHD may improve quality of life, our data do not support the use of physiological GH replacement in GHD men for this indication.     

Effects of luteinizing hormone-releasing hormone analog-induced pubertal delay in growth hormone (GH)-deficient children treated with GH: preliminary results

To study the effect of delaying epiphyseal fusion on the growth of GH-deficient children, we studied 14 pubertal, treatment naive, GH-deficient patients (6 girls and 8 boys) in a prospective, randomized, placebo-controlled trial. Chronological age was 14.5 +/- 0.5 yr, and bone age was 11.6 +/- 0.3 yr (mean +/- SEM) at the beginning of the study. Patients were assigned randomly to receive GH and LH-releasing hormone (LHRH) analog (n = 8) or GH and placebo (n = 6) during 3 yr, with planned continuation of GH treatment until epiphyseal fusion. Patients were measured with a stadiometer and had serum LHRH tests, serum testosterone (boys), serum estradiol (girls), and bone age performed every 6 months. Patients treated with GH and LHRH analog showed a clear suppression of their pituitary-gonadal axis and a marked delay in bone age progression. We observed a greater gain in height prediction in these patients than in the patients treated with GH and placebo after 3 yr of treatment (mean +/- SEM, 14.0 +/- 1.6 vs. 8.0 +/- 2.4 cm; P < 0.05). These preliminary findings suggest that delaying epiphyseal fusion with LHRH analog in pubertal GH-deficient children treated with GH increases height prediction and may increase final height compared to treatment with GH alone.     

Arm span as measurement of response to growth hormone (GH) treatment in a group of children with meningomyelocele and GH deficiency

Children with meningomyelocele (MMC) frequently have impaired linear growth. A number have associated structural brain defects with resultant GH deficiency (GHD). Reproducible measurements of height or length in MMC patients are often hampered by lower limb contractures, spasticity, and scoliosis. Arm span has been proposed as a more reproducible measure of linear growth. Five MMC children documented to have GHD were treated with recombinant human GH (hGH) for 1-3 yr. Their height, arm span, and growth velocity were compared with 32 children with idiopathic GHD treated similarly with hGH. These measures are compared with normal children by being expressed as standard deviation scores. The results of this study indicate that arm span measurements in GHD MMC patients are almost identical to height measurements in idiopathic GHD patients both before and during hGH therapy. The physical condition of children with MMC makes reproducible longitudinal height measurements difficult. Routine determinations of arm span measurements for children with MMC will assist in recognizing growth failure as well as monitoring treatment results.     

Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency

Adults with childhood onset GH deficiency (GHD) have reduced bone mass, increased fat mass, and disorders of lipid metabolism. The aim of the present study was to evaluate bone mineral density (BMD), bone metabolism, body composition, and lipid metabolism in GHD children before and during 2-3 yr of GH treatment (GHRx). Forty children with GHD, mean age 7.9 yr, participated in the study of bone metabolism and body composition; and an additional group of 17 GHD children, in the study of lipid metabolism. Lumbar spine BMD, total body BMD, and body composition were measured with dual-energy x-ray absorptiometry. Volumetric BMD (bone mineral apparent density, BMAD) was calculated to correct for bone size. BMD, BMAD, lean tissue mass, bone mineral content, fat mass, and percentage body fat were expressed as SD scores (SDS), in comparison with normative data of the same population. Lumbar spine BMD and BMAD and total body BMD were all decreased at baseline. All BMD variables increased significantly during GHRx, lumbar spine BMD SDS, already after 6 months of treatment. Lean tissue mass SDS increased continuously. Bone mineral content SDS started to increase after 6 months GHRx. Fat mass SDS decreased during the first 6 months of GHRx and remained stable thereafter. Biochemical parameters of bone formation and bone resorption did not differ from normal at baseline and increased during the first 6 months of GHRx. Serum 1,25 dihydroxyvitamin D increased continuously during GHRx, whereas PTH and serum calcium remained stable. Lipid profile was normal at baseline: Atherogenic index had decreased and apolipoprotein A1(Apo-A1) had increased after 3 yr of treatment. In conclusion, children with GHD have decreased bone mass. BMD, together with height and lean tissue mass, increased during GHRx. GHRx had a beneficial effect on lipid metabolism.     

Growth hormone secretion, puberty and adult height after cranial irradiation with 18 Gy for leukaemia

The dose of prophylactic cranial irradiation given to patients for acute lymphoblastic leukaemia has been decreased from 24 to 18 Gy, but the beneficial effect of this decrease on growth is controversial. This study compares the growth hormone (GH) secretion and growth of 35 patients (20 boys) given 18 Gy at 3.7+/-0.3 (SE) years, and routinely evaluated 5.4+/-0.4 years after irradiation to define the indications for GH treatment in these patients. Of these, 63% had a low GH peak (< 10 microg/l) after one (22 cases) or two (17 cases) stimulation tests. The plasma concentrations of insulin-like growth factor I and its GH-dependent binding protein were normal for age in all but two cases. The height changes between irradiation and evaluation were correlated with the GH peaks (P < 0.03) and were concordant, except in patients with early puberty. This occurred in 16 patients including all 12 girls irradiated before 4 years of age. A significant (P < 0.03) reduction in height (SD) between irradiation and adult height occurred in untreated GH-deficient patients (-1+/-0.3, n=6), but not in GH-deficient patients given GH (-0.6+/-0.3, n=8) or in those with normal GH peak (-0.4+/-0.3, n=7). CONCLUSION: In children irradiated for acute lymphoblastic leukaemia, GH deficiency is frequent after 18 Gy but its impact on adult height is smaller than after higher doses. We suggest that the indications for gonadotropin releasing hormone analogue therapy should be broad in patients with early or rapidly progressing puberty and those for GH therapy in those patients with a below average constitutional height before irradiation.     

Urinary growth hormone (GH), insulin-like growth factor I (IGF-I), and IGF-binding protein-3 measurements in the diagnosis of adult GH deficiency

The diagnosis of GH deficiency (GHD) in the elderly is based at present on the peak GH concentration during a stimulation test. We have now evaluated the performance of urinary GH (uGH), urinary insulin-like growth factor I (uIGF-I), and urinary IGF-binding protein-3 (uIGFBP-3) in the diagnosis of GHD in this group. Twenty GHD elderly patients with a history of pituitary disease and a peak GH response to arginine stimulation of less than 3 ng/mL (15 men and 5 women; age, 61.1-83.4 yr) and 19 controls (12 men and 7 women; age, 60.8-87.5 yr) were studied. GH secretion was assessed by 24-h profile and expressed as the area under the curve (AUCGH). Serum (s) IGF-I and sIGFBP-3 were measured in a single morning, fasted sample. Urinary GH, uIGF-I, and uIGFBP-3 were measured in a 24-h urine sample collected over the same interval as the GH profile, and results were expressed as total amount excreted in 24 h (tuGH24, nanograms; tuIGF-I24, nanograms; tuIGFBP-3(24), micrograms). Data are presented as the mean +/- SD, except for AUCGH, tuGH24, and tuIGFBP-3(24), which are presented as the geometric mean (-1, +1 tolerance factor). AUCGH, sIGF-I, and sIGFBP-3 were significantly lower in GHD subjects than in controls. Total uGH24 was lower in GHD subjects, but tuIGF-I24 and tuIGFBP-3(24) excretion were not different in the two groups. AUCGH provided the best separation between GHD and control subjects, whereas there was substantial overlap for sIGF-I, sIGFBP-3, and tuGH24. In both groups sIGF-I was correlated to sIGFBP-3 (GHD, r = 0.75; controls, r = 0.65; both P < 0.01), whereas tuIGF-I24 was not correlated to tuIGFBP-3(24) in either group. Moreover, tuIGF-I24 and tuIGFBP-3(24) were not related to their respective serum concentrations in either group. Total uGH24 was correlated with AUCGH only in controls (r = 0.54; P < 0.05). These data demonstrate that urinary GH and urinary and serum IGF-I and IGFBP-3 are not suitable diagnostic markers for GHD in elderly subjects.     

Selective incorporation of 111In-labeled PHOTOFRIN by glioma tissue in vivo

BACKGROUND: This study was to evaluate the efficacy, safety and immunogenicity of recombinant human growth hormone (rhGH) in treatment of children with growth hormone deficiency (GHD). METHODS: We selected 15 children with GHD for a 12-month clinical trial and separated them into three groups with each 5 patients receiving one of the 3 tested rhGH (Saizen by Serono, Aubonne, Switzerland; Genotropin by KabiVitrum, Stockholm, Sweden and Humatrope by Eli Lilly, Indianapolis, USA). RESULTS: In Saizen group, 3 boys and 2 girls with a mean chronological age (CA) of 10.6 +/- 1.7 yrs and bone age (BA) of 6.7 +/- 1.2 yrs, at dose of 0.2 IU/kg sc tiw, gained an average BA of 2.1 +/- 1.3 yrs. The mean height velocity (HV) increased from 3.7 +/- 1.2 to 11.1 +/- 3.3 cm/yr. The height standard deviation score (SDS) increased from -4.2 +/- 3.1 to -3.1 +/- 2.9. In Genotropin group, 2 boys and 3 girls with a mean CA of 9.2 +/- 2.3 yrs and BA of 5.6 +/- 2.1 yrs, at dose of 0.1 IU/kg sc qd, gained an average BA of 0.8 +/- 0.2 yr. The mean HV increased from 3.4 +/- 0.7 to 11.3 +/- 2.0 cm/yr. The height SDS increased from -4.0 +/- 0.5 to -2.7 +/- 0.7. In Humatrope group, 4 boys and 1 girl with a mean CA of 10.3 +/- 3.5 yrs and BA of 5.8 +/- 2.9 yrs, at dose of 0.1 IU/kg sc qd, gained at average BA of 0.8 +/- 0.7 yr. The mean HV increased from 4.0 +/- 1.3 to 9.4 +/- 1.9 cm2yr, and the height SDS increased from -2.9 +/- 0.7 to -2.2 +/- 1.0. Very low titers of anti-rhGH antibodies were noted only in two patients, one in Saizen group (titer = 1:10) and the other in Genotropin group (titer = 1:6). Their HV was not affected (Saizen: 13.3 cm/yr, Genotropin: 11.2 cm/yr). One patient evolved subclinical hypothyroidism whereas no side effect at all was noted in the rest of patients. CONCLUSIONS: Three tested GH (Saizen, Genotropin, Humatrope) produced by recombinant DNA technology appear to make no significant difference in this clinical trial, and rhGH therapy is an effective and safe treatment for prepubertal GHD children.     

Clinical trials of GH treatment in patients with Turner's syndrome in Japan--a consideration of final height. The Committee for the Treatment of Turner's Syndrome

Clinical trials of human GH (hGH) therapy in Turner's syndrome were started in 1986. Between 1986 and 1990. 362 patients were enrolled; 115 were treated for more than 6 years. The age at the start of treatment ranged from 5 to 18 years (mean 10 years). Fifty-one patients received hGH at a weekly dosage of 0.5 IU/kg and 64 received 1.0 IU/kg by daily s.c. injection. Both treatment groups showed a statistically significant growth increase during the initial 4 years of treatment. The rate of increase in height was significantly greater for the initial 2 years with the high dose than with the low dose. The increases in height over 6 years of treatment (expressed by S.D. score for chronological age) were 1.48 +/- 0.8 with 0.5 IU/kg per week and 1.80 +/- 1.0 with 1.0 IU/kg per week. To date, 260 patients have stopped GH therapy. In 32% of them, the height attained was above the -2 S.D. value for normal girls. In 27%, the growth rate was not sufficient when they stopped treatment. The mean final height (growth rate < or = 1.0 cm/year) of patients treated for more than 6 years was 142.2 +/- 6.5 cm (n = 15) with 0.5 IU/kg per week, and 144.3 +/- 3.9 cm (n = 15) with 1.0 IU/kg per week. The adult height was improved by GH treatment, although final height did not differ statistically between the two dose regimens. No remarkable adverse events occurred during the treatment. These results indicate that hGH treatment improves the final height in patients with Turner's syndrome.     

The treatment with biosynthetic growth hormone (GH) of familial short stature

The effect of growth hormone (GH) treatment in non-GH deficient subjects has been amply studied over the past few years. Although the results of these studies are encouraging, there are still no definitive data since the findings are not comparable due to the different characteristics of the populations examined. In the present study the authors examined the following parameters: stature, height SDS, growth rate, bone age and final height prediction according to Tanner, pubertal stage, before and after treatment with biosynthetic GH at a dose of 1.4 IU/kg of bodyweight for 12 months. The population treated consisted of 10 subjects (5 males and 5 females) aged between 7.3 and 9.5 years old, all prepubertal, with "familial short stature", selected according to the following criteria: stature below the 3rd centile, normal growth rate, normal GH response to stimuli using clonidine and insulin, correlation with parental stature between 25th and 75th centile, bone age correlated to chronological age, absence of other pathologies. After 12 months height SDS moved from -2.75 +/- 0.26 to -2.23 +/- 0.25 (p < 0.5); the growth rate changed from 5.75 +/- 0.63 to 6.66 +/- 0.56 (p < 0.05). No abnormal acceleration of bone age as observed: it moved from 8.2 +/- 0.62 to 9.5 +/- 0.72; all subjects continued to be prepubertal. The expected final stature changed from 154 +/- 2.38 to 159 +/- 0.7 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The relationship of partner support to outcomes for teenage mothers and their children: a review

OBJECTIVE: To examine the growth response over 3 years of growth hormone deficient (GHD) and non-GHD children who have received growth hormone (GH) in Australia. METHODOLOGY: A retrospective study of a group of patients (1362 children) who commenced GH prior to 1 September 1990. Data were collected at 12 growth centres located in major cities throughout Australia. The data were transferred after informed consent to the national OZGROW database located at the Royal Alexandra Hospital for Children, Sydney, NSW. Of the 1362 children, 898 had received 3 years or more GH therapy and were eligible for this analysis. This cohort was then categorized by diagnosis. Growth response was assessed using height standard deviation score, estimated mature height, growth velocity (GV), GH dose and bone age (years). RESULTS: For children who completed 3 years therapy, the baseline characteristics among diagnostic groups were similar with mean height standard deviation score (SDS) less than -3 SDS (except for the malignancy group) and mean GV ranging from 3.5 to 4.4cm/year. The GV during the first year improved in all groups (7.7-9.4cm/year)followed by an attenuated response during the second and third years of therapy. After 3 years GH therapy the GHD group with peak levels <10 mU/L demonstrated the greatest change in estimated mature height and height SDS. The GHD group with peak levels between > or = 10 but <2OmU/L had a growth response similar to the non-GHD children for all outcome parameters. Change in bone age ranged from 3.1 to 3.8 years with no differences being noted between the diagnostic groups, nor consistently with pubertal status. CONCLUSIONS: Australian GH guidelines have targeted very short children when compared to other series. This large cohort of non-GHD children has demonstrated short-term benefits of GH therapy; however, the long-term benefit remains unclear until these children reach final adult height.     

The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency

Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.     

Treatment of glucocorticoid-induced growth suppression with growth hormone. National Cooperative Growth Study

Growth failure is common during long term treatment with glucocorticoids (GC) due to blunting of GH release, insulin-like growth factor I (IGF-I) bioactivity, and collagen synthesis. These effects could theoretically be reversed with GH therapy. The National Cooperative Growth Study database (n = 22,005) was searched for children meeting the following criteria: 1) pharmacological treatment with GC and GH for more than 12 months, 2) known type and dose of GC, and 3) height measurements for more than 12 months. A total of 83 patients were identified. Monitoring of glucose, insulin, IGF-I, IGF-binding protein-3, type 1 procollagen, osteocalcin, and glycosylated hemoglobin levels was performed in a subset of patients. Stimulated endogenous GH levels were less than 10 microg/L in 51% of patients and less than 7 microg/L in 37% of patients. The mean GC dose, expressed as prednisone equivalents, was 0.5 +/- 0.6 mg/kg day. Baseline evaluation revealed extreme short stature (mean height SD score = -3.7 +/- 1.2), delayed skeletal maturation (mean delay, 3.1 yr), and slowed growth rates (mean, 3.0 +/- 2.5 cm/yr). After 12 months of GH therapy (mean dose, 0.29 mg/kg x weeks), mean growth rate increased to 6.3 +/- 2.6 cm/yr, and height SD score improved by 0.21 +/- 0.4 (P < 0.01). During the second year of GH therapy (n = 44), the mean growth rate was 6.3 +/- 2.0 cm/yr. Prednisone equivalent dose and growth response to GH therapy were negatively correlated (r = -0.264; P < 0.05). Plasma concentrations of IGF-I, IGF-binding protein-3, procollagen, osteocalcin, and glycosylated hemoglobin increased with GH therapy, whereas glucose and insulin levels did not change. The following conclusions were reached. The growth-suppressing effects of GC are counterbalanced by GH therapy; the mean response is a doubling of baseline growth rate. Responsiveness to GH is negatively correlated with GC dose. Glycosylated hemoglobin levels increased slightly, but glucose and insulin levels were not altered by GH therapy.     

Increased proportion of circulating non-22-kilodalton growth hormone isoforms in short children: a possible mechanism for growth failure

Current knowledge about the interaction between GH and its receptor suggests that the molecular heterogeneity of circulating GH may have important implications for growth. The aim of this study was to investigate the proportion of circulating non-22-kDa GH isoforms in prepubertal children with short stature (height less than -2 SD score) of different etiologies. We have also evaluated the relationships among the ratio of non-22-kDa GH isoforms, auxology, and spontaneous GH secretion. The study groups consisted of 17 girls with Turner's syndrome (TS), aged 3-13 yr, 25 children born small for gestational age (SGA) without postnatal catch-up growth, aged 3-13 yr; and 24 children with idiopathic short stature (ISS), aged 4-15 yr. The results were compared with those from 23 prepubertal healthy children of normal stature (height +/- 2 SD score), aged 4-13 yr. Serum non-22-kDa GH levels, expressed as a percentage of the total GH concentration, were determined by the 22-kDa GH exclusion assay, which is based on immunomagnetic extraction of monomeric and dimeric 22-kDa GH from serum and quantitation of non-22-kDa GH using a polyclonal antibody-based GH assay. All samples were selected from spontaneous GH peaks in 24-h GH profiles. The median proportion of non-22-kDa GH isoforms was increased in children born SGA (9.8%; P = 0.05) and girls with TS (9.9%; P = 0.01), but not in the group of children with ISS (8.9%), compared with that in normal children (8.1%). Individually, increased proportions of non-22-kDa GH isoforms, with values more than 2 SD above the mean for the normal group, were observed in 5 girls with TS, 5 children born SGA, and 4 children with ISS. In children born SGA, the proportion of non-22-kDa GH isoforms was directly correlated with different estimates of spontaneous GH secretion [mean 24-h GH concentration (r = 0.41; P = 0.04), area under the curve over baseline (r = 0.41; P = 0.04), and GH peak area (r = 0.61; P = 0.003)], whereas it was inversely correlated with height SD score (r = -0.42; P = 0.04). In conclusion, an increased proportion of circulating non-22-kDa GH isoforms was observed at spontaneous GH peaks in some non-GH-deficient short children. Our results suggest that the ratio of non-22-kDa GH isoforms in the circulation may have important implications for normal and abnormal growth.     

Synchrony in telomere length of the human fetus

We measured serum tumour necrosis factor-alpha (TNF-alpha) as well as interleukin-1betta (IL-1beta) and GH concentrations in 15 children with isolated growth hormone deficiency (GHD), age range 5.1-13.9 years, before and 4 and 24h after the first GH injection (0.1 IU/kg s.c.). No differences were found in basal concentrations of serum TNF-alpha and IL-1beta between GHD children (10.01 +/- 1.55 pg/ml and 2.14 +/- .16 ng/ml respectively) and sex- and age-matched controls (11.57 +/- 2.16 pg/ml and 3.78 +/- 1.46 ng/ml respectively). In GHD children, serum TNF-alpha and IL-1beta values had significantly increased (P < 0.002) 4h (26.75 +/- 5.57 pg/ml and 2.99 +/- 0.21 ng/ml respectively) and decreased again 24 h after GH administration. Likewise, serum GH levels had significantly increased 4 h (from 1.29 +/- 0.69 to 48.71 +/- 13.35 ng/ml, P < 0.001) and decreased to basal values 24h after GH administration. A significant correlation was found between basal serum concentrations of GH and those of both TNF-alpha (P < 0.01) and IL-1beta (P < 0.05). However, no correlation was found between serum GH concentration and either TNF-alpha or IL-1beta levels 4 and 24h after GH administration. Our data suggest that GH plays a role in modulating TNF-alpha and IL-1beta release in humans.     

Skeletal effects of two years of treatment with low physiological doses of recombinant human growth hormone (GH) in patients with adult-onset GH deficiency

A low bone mass in adults with childhood-onset GH deficiency (GHD) is likely to be caused by deficient bone accretion during childhood and early adulthood, whereas a decreased bone mass in patients with adult-onset GHD is likely to be caused by an imbalance in bone remodeling. Data on bone mineral density (BMD) and biochemical parameters of bone metabolism and data on response of these parameters to treatment with GH are scarce in patients with adult-onset GHD. It has been suggested that in patients with GHD, GH at the relatively high dose originally used may have beneficial effects on the skeleton. To address the question as whether lower, more physiological doses would have similar effects on the skeleton, we studied 47 patients with adult-onset GHD (27 women and 20 men, range 26-70 yr) randomized to receive one of three recombinant human GH (rhGH) dose regimens: 0.6 IU/day, 1.2 IU/day, or 1.8 IU/day as part of a study examining optimal GH dose replacement therapy. After 24 weeks of treatment, the dose of rhGH was individually adjusted to maintain the concentration of serum insulin growth factor-I within the normal laboratory reference range. Biochemical parameters of bone metabolism were measured at baseline and after 24 and 52 weeks and 2 yr of treatment. BMD of the lumbar spine was measured at baseline and after 52 weeks and 2 yr of treatment. Parameters of bone metabolism generally fell within the low-normal range and increased in a dose-dependent manner at 24 weeks of treatment. Between 24 and 52 weeks of rhGH treatment, mean serum osteocalcin levels and alkaline phosphatase activity further increased, whereas mean 24-h urine hydroxyproline/creatinine and N-telopeptide/creatinine excretion remained unchanged. After 52 weeks of treatment, serum alkaline phosphatase activity and 24-h urine hydroxyproline/ creatinine excretion decreased, although not to pretreatment levels. Mean BMD at the lumbar spine (Z-score) was normal at baseline (-0.20 +/- 0.16) and increased during treatment (at 2 yr of treatment: 0 +/- 0.20; P < 0.005). Our data suggest that a low physiological dose of rhGH, individually adjusted to maintain serum insulin-like growth factor I levels within the normal laboratory reference range, increased bone turnover in favor of bone formation, as suggested by the significant, albeit small increase in BMD observed after 2 yr of treatment. Further studies are required to establish whether in patients with adult-onset GHD the preservation and/or increase in bone mass observed with the use of physiological doses of rhGH could be maintained with longer-term treatment.     

Effect of acute pharmacological reduction of plasma free fatty acids on growth hormone (GH) releasing hormone-induced GH secretion in obese adults with and without hypopituitarism

In obesity, there is a markedly decreased GH secretion. The diagnosis of GH deficiency (GHD) in adults is based on peak GH responses to stimulation tests. In the severely obese, peak GH levels after pharmacological stimulation are often in the range that is observed in hypopituitary patients. To distinguish obese subjects from GHD patients, it will be necessary to demonstrate that reduced GH responsiveness to a given test is reversible in the former, but not in the latter, group. Recent studies have shown that reduction of plasma free fatty acids (FFA) with acipimox in obese patients restores their somatotrope responsiveness. There are no data evaluating GH responsiveness to acipimox plus GHRH in obese adults with hypopituitarism. The aim of the present study was to evaluate the effect of acute pharmacological reduction of plasma FFA on GHRH-mediated GH secretion in obese normal subjects and obese adults with hypopituitarism. Eight obese patients with a body mass index of 34.2+/-1.2; eight obese adults with hypopituitarism, with a body mass index of 35.5+/-1.9; and six control subjects were studied. All the patients showed an impaired response to an insulin-tolerance test (0.15 U/kg, i.v.), with a peak GH secretion of less than 3 microg/L. Two tests were carried out. On one day, they were given GHRH (100 microg, i.v., 0 min), preceded by placebo; and blood samples were taken every 15 min for 60 min. On the second day, they were given GHRH (100 microg, i.v., 0 min), preceded by acipimox (250 mg, orally, at -270 min and -60 min); and blood samples were taken every 15 min for 60 min. The administration of acipimox induced a FFA reduction during the entire test. Normal control subjects had a mean peak (microg/L) of 23.8+/-4.8 after GHRH-induced GH secretion; previous acipimox administration increased GHRH-induced GH secretion, with a mean peak of 54.7+/-14.5. In obese patients, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 3.9+/-1; previous administration of acipimox markedly increased GHRH-mediated GH secretion, with a mean peak of 16.0+/-3.2 (P < 0.05). In obese adults with hypopituitarism, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 2+/-0.7; previous acipimox administration did not significantly modify GHRH-mediated GH secretion, with a mean peak of 3.3+/-1.1 (P < 0.05). The GH response of obese patients and obese adults with hypopituitarism was similar after GHRH alone. In contrast, the GH response after GHRH plus acipimox, was markedly decreased in obese adults with hypopituitarism (mean peak, 3.3+/-1.1), compared with obese patients (mean peak, 16.0+/-3.2) (P < 0.05) and control subjects (mean peak, 54.7+/-14.5) (P < 0.01). In conclusion, GH secretion, after GHRH-plus-acipimox administration, is reduced in obese adults with hypopituitarism patients, when compared with obese normal patients. Testing with GHRH plus acipimox is safe and is free from side effects and could be used for the diagnosis of GHD in adults.