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.     

Adult height in growth hormone (GH)-deficient children treated with biosynthetic GH. The Genentech Growth Study Group

Near-adult height (AH) was determined in 121 children (72 males and 49 females) with GH deficiency (GHD) who were prepubertal when they began treatment with recombinant DNA-derived preparations of human GH. AH as a SD score was -0.7 +/- 1.2 (mean +/- SD), significantly greater than the pretreatment height SD score (-3.1 +/- 1.2), the predicted AH SD score (-2.2 +/- 1.2; Bayley-Pinneau method), and the height SD score at the start of puberty (-1.9 +/- 1.3). In contrast to studies of GH treatment outcome, which used pituitary-derived GH (pit-GH) in lower doses, we found that males did not have a higher AH SD score than females, spontaneous puberty did not diminish AH, and AH was significantly greater than that predicted at the start of GH treatment. In a multiple regression equation, the statistically significant variables (all P < 0.0001) related to AH (r2 = 0.70) were the following: duration of treatment with GH, sex (males were taller than females, as expected for the normal population), age (younger children had a greater AH) and height at the start of GH, and growth rate during first year of GH. For the AH SD score (r2 = 0.47), pretreatment predicted AH, duration of GH, and bone age delay were significant (P < 0.0002) explanatory variables. Bone age delay (chronological age-bone age) had a negative impact on the AH SD score. Target height, etiology of GHD, previous treatment with pituitary GH, and the presence or absence of spontaneous puberty did not significantly improve the prediction of AH. Early diagnosis of GHD and continuous treatment with larger doses of GH to near AH should improve the outcome in children with short stature due to GHD.     

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.     

Bone alkaline phosphatase and collagen markers as early predictors of height velocity response to growth-promoting treatments in short normal children

OBJECTIVE: A number of long-term research studies are in progress to evaluate the effects of treatment with GH on growth and final height in children with short stature but no demonstrable abnormality of GH secretion. Such treatment is invasive, expensive and carries some risk to the child. An early indication of growth response would allow restriction of treatment to those children most likely to benefit, but anthropometric measurements are relatively subjective, insensitive and imprecise. The aim of this study was to evaluate bone alkaline phosphatase, procollagen Type I C-terminal propeptide, procollagen Type III N-terminal propeptide and the cross-linked carboxy-terminal telopeptide of Type I collagen as early biochemical predictors of height velocity response to growth-promoting treatments in short normal children. DESIGN: A prospective intervention study, partially placebo controlled on a double blind basis. PATIENTS: Fifty healthy children with familial short stature or constitutional delay in growth and puberty (8 girls, 42 boys, ages 5.5-16.5 years and all either prepubertal (45) or in very early puberty (5 boys) at the start of treatment) were treated with placebo (6), GH alone (32), GH plus oxandrolone (8) or GH plus testosterone (4). MEASUREMENTS: Bone alkaline phosphatase and the collagen markers were measured at the start of treatment and 3 months later. Height velocity was calculated at the start of treatment and again after one year. RESULTS: Pre-treatment biochemical marker concentrations did not predict height velocity response after one year. Increments in all markers after 3 months were significantly correlated with height velocity increments after one year of treatment, the highest correlations being observed for bone alkaline phosphatase (r = 0.67, P < 0.0001) and procollagen Type III N-terminal propeptide (r = 0.57, P < 0.0001). Highly significant correlations (P < 0.0001) were also observed between bone alkaline phosphatase and procollagen Type I C-terminal propeptide (r = 0.55) and between procollagen Type III N-terminal propeptide and the cross-linked carboxy-terminal telopeptide of Type I collagen (r = 0.62). Multiple linear regression with stepwise selection of variables identified bone alkaline phosphatase and procollagen Type III N-terminal propeptide as the only two independent variables that contributed significantly to the prediction of height velocity response after one year (analysis of variance, P < 0.0001). Together they predicted 59% of the variability in height velocity response after a year. CONCLUSIONS: The best early predictors of height velocity response were bone alkaline phosphatase (a protein found in hypertrophic chondrocytes in the epiphyseal growth plate, in calcifying matrix vesicles and in mature osteoblasts) and procollagen Type III N-terminal propeptide, a marker of interstitial fibril biosynthesis in soft tissues. Using these markers, GH treatment could be targeted to those children most likely to benefit in the medium term.     

Risk of uterine leiomyomata among premenopausal women in relation to body size and cigarette smoking

Growth acceleration and bone maturation were studied for 3 y in 69 children with severe short stature and a history of intrauterine growth retardation (IUGR), to determine the effect of treatment with recombinant human growth hormone (r-hGH). The patients were enrolled in an open, multicentre trial and were randomly allocated to either the treated group (Group 1) or the control group (Group 2). The children in Group 1 were treated daily with 0.2 IU/kg/body weight (0.067 mg/kg) s.c., during 3 y and the children in Group 2 started the study with a 1-y observation period followed by a 3-y treatment period. At birth, their mean weight standard deviation score (SDS) was -2.5 and their mean length SDS -3.5. At baseline, the patients were prepubertal, non-GH deficient, with no known dysmorphic features. Mean age was 4.5 y, bone age was 3.3 y, height SDS was -3.4, height velocity (HV) SDS was -1.6, and body mass index SDS was -1.4. After 1 y of treatment, linear HV in Group 1 increased in comparison with the pre-treatment period (from 5.7 +/- 2.0 to 10.1 +/- 1.7 cm/y; p < 0.001) and with the first year of observation in Group 2 (p < 0.001). Increased HV was sustained during the second and third year of treatment and was significantly higher than at baseline. A similar growth pattern was seen during the 3 y of GH treatment in Group 2. Mean height SDS for chronological age increased by 2.0 +/- 0.7 in the two groups after 3 y of treatment. HV after 1 y of treatment was negatively correlated with growth velocity at baseline. Bone age remained retarded but increased with a mean of almost 4 y after 3 y of treatment in both groups. Even at a dose that is three times the replacement dose treatment with r-hGH was well tolerated. From these results, we conclude that r-hGH treatment over 3 y can induce sustained catch-up growth in young children with severe short stature and a history of IUGR. Long-term studies are needed to assess ultimate effects on final height.     

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.     

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.     

Final height in Turner syndrome patients treated with growth hormone

The first treatment trials on patients presenting with Turner syndrome were successful in accelerating growth velocity. It is therefore essential to know the final height of the patients who were treated in order to ascertain whether or not growth hormone treatment increases final height. We are reporting on a group of 117 patients with Turner syndrome whose growth hormone treatment was initiated in 1986. The mean growth hormone dose was 0.74 IU/kg/week for an average period of 4 years. At the start of treatment, the patients' chronological age was 129/12 years, height -3.8 +/- 1.0 standard deviation scores (SDS) and bone age 10.5 +/- 2.1 years. Mean final height was 147.7 +/- 5.6 cm, i.e. a gain of 1.5 SDS. We noted no significant difference due to the type of chromosomal abnormality, nor to oxandrolone or estrogen-associated treatment. A significant correlation was found between final height, mean parental height, the duration of the treatment, height SDS at the start of treatment and growth hormone peak during pharmacological stimulation tests. However, there was no correlation between growth hormone dosage, chronological age and bone age at the start of treatment. These results show that the growth hormone treatment improves the final heights of patients with Turner syndrome.     

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.     

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.     

Interrelation of the therapeutic effects of growth hormone and testosterone on growth in hypopituitarism

The present study evaluates the modifying effect of growth hormone on the growth-promoting action of testosterone in boys at pubertal bone age. Growth and bone maturation were analyzed in 42 boys with primary or secondary Leydig cell insufficiency who had been treated with testosterone in an attempt to induce puberty and the accompanying growth spurt. The dosage given was considered normal or high for physiologic replacement therapy at puberty. Sixteen boys had normal GH secretion (seven had isolated gonadotropin deficiency, nine had congenital anorchia); 26 were GH and Gn deficient (20 idiopathic, six craniopharyngiomas). Of the GH-deficient patients, 12 received hGH simultaneously, while 14 received only testosterone. Results from each group were compared with the normal pubertal growth spurt in 15 untreated healthy boys. In isolated Gn deficiency and in congenital anorchia, the growth rates increased to above normal during the first six months of treatment, indicating that the testosterone dosage was probably too high for the beginning of puberty. During two subsequent six-month treatment periods, the rates leveled off close to normal. The same was true in the GH- and Gn-deficient patients on adequate hGH replacement. For contrast, there was minimal or no stimulation of growth when an even higher testosterone dose was given to GH- and Gn-deficient boys without hGH therapy. Bone maturation was normal in the boys with normal GH secretion or with hGH replacement, but was subnormal in the GH-deficient boys not treated with hGH. We conclude that testosterone exerts its full growth-promoting action only in the presence of normal endogenous GH secretion or with sufficient hGH replacement and that both hormones should be continued simultaneously until final adult height is achieved.     

Association of HLA phenotype and response to interferon-alpha in patients with chronic myelogenous leukemia

OBJECTIVES: Bone metabolism is an important target for GH replacement therapy. However, in adults, treatment periods exceeding 12 months are required for a positive effect of GH on bone mineral density. Thus, to detect an early effect of GH on bone, markers of bone turn-over are important. Pyridinoline (PYR) and deoxypyridinoline (DPYR) are well-defined sensitive markers of bone resorption, but to date only urinary assays have been available. We report the use of a novel assay to measure changes in serum PYR and DPYR in GH deficient (GHD) adults during GH replacement therapy. STUDY DESIGN: The study consisted of a 6-month randomized, double-blind, placebo-controlled study of the administration of GH (Genotropin) (0.25 IU/Kg/week (0.125 IU/kg/week for the first four weeks)) followed by a 6-month open phase of GH therapy. PATIENTS: Thirty-five GHD adults (17 women; mean age 39.8 years; range 21.1-59.9) on conventional hormone replacement therapy as required, were studied. MEASUREMENTS: Bone formation was analysed using serum bone alkaline phosphatase (BAP) and serum osteocalcin (OC). Bone resorption was analysed using serum pyridinoline (PYR) and serum deoxypyridinoline (DPYR). Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry (DEXA). RESULTS: After 6 months placebo treatment there were no significant changes in any of the bone markers analysed, nor in BMD. In the active arm of the study there was a significant increase in serum OC, BAP, PYR and DPYR (P = 0.03, P = 0.004, P = 0.003 and P = 0.01, respectively), remaining significantly elevated over their baseline levels for the subsequent 6 months of treatment (P = 0.04, P = 0.009, P = 0.003 and P = 0.04, respectively). No changes were observed in BMD in any of the groups after 6 months GH treatment. In the active arm of the study, after 12 months GH treatment there was a significant increase in BMD at both the lumbar spine and femoral neck (P = 0.01 for both sites). CONCLUSIONS: In summary, the present study confirms that administration of GH treatment to GHD adult patients significantly activates bone remodelling, with the effect of GH both in bone formation and bone resorption markers being maximal after 6 months of treatment. The serum assay for PYR and DPYR has a number of practical and theoretical advantages over the urine assay and gave similar results to those previously reported for the urine assay.     

Relative importance of growth hormone and sex steroids for the growth at puberty of trunk length, limb length, and muscle width in growth hormone-deficient children

We have followed the growth of stature, sitting height, skinfolds, muscle widths measured radiologically, and skeletal maturity in growth hormone-deficient patients in whom hGH was given and withheld in alternating three-month periods throughout puberty (referred to as "off-hGH" and "on-hGH" periods). Six boys and four girls had true isolated GH deficiency and developed puberty spontaneously. Two boys had gonadotrophin deficiency plus GH deficiency, and five boys had multiple deficiencies; in these boys the signs of puberty were induced by hormone treatment. Boys with true isolated deficiency grew about two-thirds as much in height in the off-hGH periods as in the on-hGH periods; their total gain in height during the adolescent spurt would have been about 20 cm, instead of 30 cm, if hGH had been discontinued at the beginning of puberty. The effect of hGH was entirely on growth in leg-length, however, which virtually ceased during the off-hGH periods. Growth in sitting height altered little when hGH was withdrawn. Growth in limb muscles, however, was GH dependent throughout puberty; during the majority of periods when hGH was withheld, muscle was actually lost; this occurred in the boys who were receiving large doses of testosterone as well as in those producing their own normal amounts. Subcutaneous fat diminished when hGH was given and increased when it was withdrawn; this occurred independently of administration of testosterone. There was little evidence that growth of pubic and axillary hair progressed faster during on-hGH periods, except perhaps in patients with multiple deficiencies. There was some evidence, however, that bone age progressed less rapidly during on-hGH periods than during off-hGH periods in the patients with isolated deficiency. The results in the girls agreed with those in boys so far as stature was concerned, but the relationship with sitting height and leg length appeared to be different; the reasons for this are discussed. We conclude that all children with GH deficiency should continue on treatment with hGH throughout puberty, ideally until growth ceases.     

Yearly stepwise increments of the growth hormone dose results in a better growth response after four years in girls with Turner syndrome. Dutch Working Group on Growth Hormone

To optimize the growth promoting effect of growth hormone (GH), 65 previously untreated girls with Turner syndrome (TS), chronological age (CA) 2-11 yr, were randomized into 3 dosage regimen groups: A, B, and C, with a daily recombinant-human GH dose during 4 study years of 4-4-4-4, 4-6-6-6, and 4-6-8-8 IU/m2 b.s. The first GH dosage increase in groups B and C resulted in a significantly higher mean height velocity (HV) compared with constant dose group A. During the third year, when the dose was raised again only in group C, mean HV was significantly higher in groups B and C than in group A, and in group C compared with group B. In year 4 only group C mean HV remained significantly higher than group A. The pattern of change in HSDSCA (Dutch-Swedish-Danish Turner references) was identical; however, in year 4 mean delta HSDSCA in group B also remained significantly higher than group A. After 4 yr GH treatment, the following was determined. 1) The mean delta HSDSCA was significantly higher for groups B and C compared with group A, but not significantly different between groups B and C. 2) Although significantly higher compared with estimated values for untreated Dutch girls with TS, bone maturation of the GH treated girls was not significantly different between groups. 3) It was positively related with the degree of bone age (BA) retardation at start of study and negatively with baseline CA. 4) Both the modified Index of Potential Height (mIPHRUS) and a recently developed Turner-specific final height (FH) prediction method (PTSRUS), based on regression coefficients for H, CA, and bone age, showed significant increases in mean FH prediction, without significant differences between groups. PTSRUS values were markedly higher than the mIPHRUS values. Dose dependency could be shown for the area under the curve (AUC) for GH, but delta HSDSCA was not linearly related with AUC. Baseline GH binding protein (BP) levels were in 84% of the cases within the normal age range; the decrease in mean levels after 6 months GH was not significant. Mean insulin-like growth factor I (IGF-I) and IGFBP-3 plasma levels increased significantly, without significant differences between groups. delta HSDSCA during GH was dependent on IGF-I plasma levels at baseline and during the study period, beta-0.002 and beta-0.0004. Thus, a stepwise GH-dosing approach reduced the "waning" effect of the growth response after 4 yr treatment without undue bone maturation. FH prediction was not significantly different between treatment groups. Irrespective of the GH dose used, initiation of GH treatment at a younger age was beneficial after 4 yr GH when expressed as actual cm gained or as gain in FH prediction, but was not statistically significant when expressed as delta HSDSCA over the study period.     

Growth charts, growth velocity and bone development in childhood obesity

OBJECTIVE: To compare the growth charts of obese subjects (4-18 years) with the Tanner's growth curves and to analyze the growth velocities and bone age of obese children in prepuberty and adolescence. Moreover to compare the relationship between the serum insulinemic and glycemic levels and height standard deviation score (HSDS). DESIGN: Growth charts: this study included 1250 obese subjects (669 males, 581 females) observed between 1981 and 1993 and divided into seven age categories (4-6, 7-8, 9-10, 11-12, 13-14, 15-16, 17-18 years). Growth velocities: yearly growth velocities of 579 obese subjects (325 males, 254 females) were compared to growth velocities of 473 controlled children of the same sex, chronological age and pubertal stage. Bone age (BA) of 846 obese subjects (470 males, 376 females) was estimated. Blood analysis: insulin secretion of 70 obese children was considered and compared to 70 lean controls of equal chronological age and sex. MEASUREMENTS: Growth rate, standardized height and other physical characteristics of the children were measured by trained examiners. All subjects were evaluated singularly for at least 4 years with a follow-up every 6 months. BA was estimated by radiograph of the left hand and wrist using the Tanner-Whitehouse II system by a single observer. For the insulin secretion study and glycemic levels oral glucose tolerance test (OGTT) was performed using a glucose load of 1.75 g/kg per body weight. Plasma insulin was assessed by a double antibody radioimmunoassay. RESULTS: In adipose children the growth charts, referred to 97th centile, 50th centile and 3rd centile, were superior to those of the normal population up to the age of 13 and 12.5 years for male and for female respectively; growth decreases at the above age in both sexes. The obese subjects were equal in height to the non obese subjects as they reached their 18th birthday. The growth velocity (cm/yr) of the obese child, in the age range considered here, does not show differences when compared with the lean child in the prepubertal status (P not significant) but decreases during Tanner's stage II, III IV in boys and girls (P < 0.0001). BA is more advanced over chronological age (delta BA-CA) in both sexes. The increase of BA over CA does not show a remarkable difference during pubertal maturation in boys (P not significant); whereas in girls the delta BA-CA decreases with advancing sexual maturation (P < 0.0001). Our obese subjects have significantly higher plasma insulinemic levels compared with the lean controls (P < 0.0001). Moreover there is a positive correlation between plasma insulinemic levels and HSDS (r = 0.881, P < 0.0001). We did not observe a correlation between serum glycemic levels and HSDS. CONCLUSION: Our data demonstrate that the growth increase in an obese child starts in the first years of life. The statural advantage acquired in the first years of life would be exploited and maintained up to the beginning of puberty and with a growth velocity equal to that of the lean subject. Skeletal maturation is strongly increased in both sexes. Bone age remained advanced during the entire period of pubertal development. During puberty obese subjects demonstrate a less notable growth spurt when compared with lean subjects. The growth advantage gradually decreases and final adult height of obese and normal subjects is equal.     

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.     

High-dose growth hormone treatment of short children born small for gestational age

The effect of GH administration was evaluated over 2 yr in 50 short, prepubertal, non-GH deficient children born small for gestational age, who had been randomly allocated to a group receiving no treatment or daily sc GH treatment at a dose of 0.2 or 0.3 IU/kg. At the start of the study, mean age was 5.2 yr, bone age was 4.0 yr, height SDS was -3.5, height velocity SDS was -0.8, weight SDS was -2.7, and body mass index SDS was -1.9. Catch-up growth was observed in none of the untreated and all of the treated children. The response to GH treatment included a near doubling of growth velocity and of weight gain and a mean height increment of more than 2 SDS. GH treatment was associated with a distinct acceleration of bone maturation. The differences between the growth responses evoked by the two GH doses were minor. The prepubertal GH-induced catch-up growth was associated with elevated serum concentrations of insulin, insulin-like growth factor-I, insulin-like growth factor binding protein-3, and osteocalcin, whereas insulin-like growth factor-II levels remained unaltered. GH treatment was well tolerated. In conclusion, high-dose GH administration over 2 yr is emerging as a potential therapy to increase the short stature that results from insufficient catch-up growth in young children born small for gestational age. The long-term impact of this approach remains to be delineated.     

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.     

Synthesis, structure and antitumor activity of a new water-soluble platinum complex, (1R,2R-cyclohexanediamine-N,N'')[2-hydroxy-4-oxo-2-pentenoato(2-)-O2] platinum(II)

Patients with thalassemia major require multiple blood transfusions leading to hemochromatosis. These patients often have pubertal delay and growth failure, the etiology of which has not been fully elucidated. We performed an extensive endocrine evaluation which included measurements of spontaneous and stimulated levels of gonadotropins, GH, thyroid hormone, and adrenal hormones in 17 patients between the ages of 12 and 18 yr with hemochromatosis receiving desferoxamine therapy. All of the 17 patients had at least one endocrine abnormality, and 12 had more than one abnormality. Abnormalities of the hypothalamic-pituitary-gonadal axis were the most common. Six patients had clinical evidence of delayed puberty with spontaneous and stimulated gonadotropin and sex steroid levels appropriate for their delayed pubertal stage. All 14 children in puberty LH pulsatility index below the mean for pubertal stage compared to normal children. Six of the 14 had LH pulsatility index more than 2 SD below the mean for pubertal stage. This may be an indicator of abnormal pituitary function. Six patients failed either the provocative GH tests (peak GH < 7 micrograms/L) or had a mean spontaneous GH less than 1 microgram/L. The 4 patients who failed provocative tests had growth velocities more than 2 SD below the mean for bone age. Three patients had evidence of primary hypothyroidism. We conclude that all patients with hemochromatosis need periodic careful endocrine evaluations because the incidence of endocrine dysfunction is substantial and they may benefit from hormonal therapy.