Favorable Impacts of Growth Hormone (GH) Replacement Therapy on Atherogenic Risks in Japanese Children with GH Deficiency

Growth hormone (GH) affects body composition and atherogenic risk factors. Severehyperlipidemia may develop in GH-deficient adults as a consequence of continuous GHdeficiency. We investigated changes in lipid profiles in 158 Japanese children (103 boysand 55 girls) with GH deficiency who had been enrolled in the Pfizer International GrowthDatabase Japan during 3 yr of GH replacement therapy to evaluate whether GH treatment hasbeneficial effects on atherogenic risk factors. Total cholesterol (TC), high-densitylipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC) and atherogenicindex were evaluated before treatment and then once a year during treatment. The meanbaseline TC was within the normal range in both boys and girls. Seventeen (16.5%) of the103 boys and 18 (32.7%) of the 55 girls, however, had a TC level over 200 mg/dl beforetreatment. The mean TC level showed a significant decrease in girls. In a separateanalysis, patients of both sexes with a TC level > 200 mg/dl showed significantlydecreased TC. LDLC decreased significantly only in girls, while HDLC showed no change ineither sex. The atherogenic index decreased significantly in girls. GH replacement therapyin children with GH deficiency had beneficial effects on lipid metabolism and atherogenicrisk in both sexes. Early GH treatment would produce lipid metabolism benefits in thesepatients.     

Effect of Growth Hormone Treatment on Quality of Life in Japanese Children with Growth Hormone Deficiency: An Analysis from a Prospective Observational Study

The aim of this study was to assess changes in quality of life (QoL) in Japanese children with GH deficiency (GHD) after 12 mo of GH treatment or with idiopathic short stature (ISS) after 12 mo without treatment. Children with GHD were treated with GH after enrollment. Outcome measures included the parent-rated Child Behavior Checklist (CBCL), the Youth Self-Report Form (YSR), and height standard deviation scores (SDS). Total CBCL scores significantly decreased in children with GHD (n = 152, mean change (standard deviation [SD]) = –3.42 [11.21]) and ISS (n = 129, mean change = –4.82 [10.09]) after 12 mo (p < 0.001). Total YSR scores (mean change = –9.21 [14.07]) and height SDS (mean change = 0.35 [0.38]) significantly decreased in children with GHD (p < 0.001), but were unchanged in children with ISS. The change in total YSR score was significantly correlated with the change in height SDS in children with GHD (r = –0.516, p = 0.003). Our findings demonstrate that GH treatment can improve QoL in Japanese children with GHD. The correlation between the changes in total YSR score and height SDS demonstrated that increased height resulted in improved QoL.     

Growth Hormone (GH) Treatment in Achondroplasia*

ABSTRACT Achondroplasia, a form of short stature with short limbs, is the most common disease among osteochondrodysplasia. The growth pattern of patients with achondroplasia is unique compared with the normal standard. At birth, patients' heights are within normal limits and height velocity is normal during the first year in most patients. Thereafter, it declines to the 3 percentile line and remains low until 8 years of age. The peak height velocity is much lower during puberty in these patients than in the normal and contributes to short stature in achondroplasts. Extremely short stature lowers quality of life, therefore, various medications have been tried to promote growth in achondroplasts but in vain. GH is now produced in sufficient quantity utilizing recombinant DNA technique. Since encouraging results have been obtained in the GH treatment of various kinds of short stature without GH deficiency, e.g., Turner's syndrome, intrauterine growth retardation, non-endocrine short stature, etc., achondroplasia has been also considered as a candidate for GH treatment. There have been only a few studies on GH treatment in achondroplasia and the number of subjects studied is small. However, satisfactory growth-promoting effects have been demonstrated in these studies although observation periods were short and side effects have not been reported. Further studies are necessary to confirm the optimal dosage and administration method on final height and side effects in long-term use of GH.     

Growth Hormone Treatment in Short Children -Short-Term and Long-Term Effects on Growth

Short children with normal GH responses to arginine-insulin provocation testing and various amounts of spontaneously secreted GH over 24 hours participated in an ongoing study with GH, 0.1 IU/kg/day. A total of 40 prepubertal children have been treated for 1 year. Their mean height velocity increased from 4.6 to 7.5 cm/year. The children with the slowest pretreatment height velocity showed the best increment. An inverse relationship was found between the endogenous GH secretion and the increment in growth; 80% of the children had an endogenous GH secretion of less than 300 milliunits/litre/24 hours, estimated as area under the curve above the calculated baseline. They all showed an increment in height above 2 cm. The remaining 20% all had an endogenous GH secretion of more than 300 milliunits/litre/24 hours, estimated as area under the curve above the calculated baseline, Twenty-four of the children were prepubertal for the following 4 years, and their GH therapy continued. Their Deight velocity changed from 4.2 cm/year before therapy to 8.1,6.7,6.0 and 4.9 cm/year for the 1st, 2nd, 3rd and 4th years on treatment. Many of them have passed their expected final height, but have still not stopped growing. Those children who were in early puberty when GH treatment started went into a rapid growth spurt and have now stopped growing. They have all reached but not improved their expected final height. In 15 of the children GH treatment was stopped after 1-3 years. Their mean height velocity for the first post-treatment year was 5.1 cm/year; thus, for the group as a whole no'catch down'was observed. Of the 15 children, only 4 decreased in height velocity despite increasing age. Further studies on the long-term results of GH treatment in larger groups of short children are needed to verify the findings in this study.     

Three-Year Follow-up Study on Serum Leptin Levels in GH Deficient Children with GH Replacement Therapy

Interactions between GH and leptin have been extensively studied. However, results of long-term GH therapy on serum leptin levels in GH-deficient children were not consistent. Moreover, no such reports were available in Japanese children with this disease. We studied 35 Japanese patients with GH deficiency (26 boys and 9 girls, mean age: 9.8 ± 6.2 yr old), of whom 6 patients with complete and 29 with incomplete GH deficiency were identified by GH provocation test. Serum leptin levels, percent of ideal body weight (%IBW) and percent fat (%fat) were determined at 0, 1, 3, 6, 12, 18, 24, and 36 mo after beginning GH therapy. Baseline levels of %fat and leptin were significantly higher in girls than boys (P<0.05), though serum leptin did not change throughout the study period in either group. Further, %IBW did not change significantly, whereas %fat exhibited significant changes after 6 mo in boys and remained virtually constant thereafter for up to 3 yr. In summary, serum leptin levels did not change in GH-deficient boys and girls during the 3-yr period after the start of GH replacement therapy, despite a decrease in %fat after 6 mo of therapy in the boys. Thus, it is conceivable that long-term GH replacement therapy can be employed without an effect on normal leptin secretion.     

Clinical Experience with Genotropin in Growth Hormone Deficient Children

The efficacy of Genotropin (recombinant somatropin, KabiVitrum AB, Sweden) was analysed in 194 children with GH deficiency, comprising a combined series of four multicentre trials. The linear height velocity increased from 3.3±1.4 to 9.3±2.6 cm/year in 149 prepubertal children with 12 months'data available. In 18 pubertal children the pretreatment height velocity was 4.0±1.2, and increased to 8.4±1.7 cm/year during 12 months of treatment. There was a positive correlation between the gain in height velocity and the weekly dose of Genotropin. Covariance analysis revealed significantly greater height velocity with 6-7 injections/week compared to 2-3 injections/week; corrections for chronological age, bone age, height SD score and dose were made. On average, a regimen of 6-7 injections/week was 25% more effective than one of 2-3 injections/week corresponding to an extra gain in height velocity of 1.8±0.6 cm/year. At 12 months, only 0.9% of the children had developed anti-GH antibodies. Very few side-effects have been reported from more than 1000 children on Genotropin.     

Improved Growth Response to GH Treatment in Irradiated Children

ABSTRACT. The growth response to two years of GH treatment was studied in fifteen children after radiotherapy for a cranial tumor. The growth response was compared to that of short children (– 2 SD) and that of children with idiopathic growth hormone deficiency (GHD) of similar ages. All children were treated with hGH 0.1 IU/kg/day s.c; which is a higher dose and frequency than previously reported for irradiated children. On this protocol the growth rate increased 5.0 ± 0.5 cm/y (mean ± SEM) the first year and 3.8 ± 0.7 cm/y the second year compared to the growth rate the year before GH-treatment. Although the net gain in growth was higher than previously reported, the first year growth response was significantly reduced ( p < 0.05) compared to that of GHD-children (7.6 ± 0.5 cm/y) but exceeded ( p < 0.05) that of short children (3.4 ± 0.3 cm/y). The median spontaneous 24 h-GH secretion was 209 mU/I in the short children, 52 mU/I in the irradiated children and 16 mU/1 in the idiopathic GHD children. Thus the growth increment varied inversely to the spontaneous GH secretion observed in the three groups.     

Evaluation of Quality of Life in Children with GH Deficiency and Idiopathic Short Stature Using the Child Behavior Checklist

The quality of life (QoL) of short children is an important issue that has been studied in Western countries, but not fully in Japan. We assessed the psychosocial profiles of Japanese children with short stature using the Japanese version of the Child Behavior Checklist (CBCL). A higher score in the CBCL means a lower QoL. A total of 116 children with idiopathic short stature (ISS) and 127 children with GH deficiency (GHD), aged 4 to 15 yr, were enrolled in the study. The total CBCL scores of the children in the GHD/ISS group were found to be higher than those of the normal children group. The QoL subscales for social problems and attention problems of the young (4–11 yr) children in the GHD/ISS group were significantly higher than those of the group of children of normal height. The proportion of children with GHD/ISS classified into the borderline/abnormal range was significantly higher than that of normal children. Children with ISS tended to have higher total scores and more subscale problems, and a greater proportion of these children was classified in the borderline/abnormal range than the children with GHD, although the difference was not significant. These results suggest that QoL is impaired in Japanese children due to short stature.     

Combined Treatment with Gonadotropin-releasing Hormone Analog and Anabolic Steroid Hormone Increased Pubertal Height Gain and Adult Height in Boys with Early Puberty for Height

Twenty-one boys with a height of 135 cm or less at onset of puberty were treated with a combination of GnRH analog and anabolic steroid hormone, and their pubertal height gain and adult height were compared with those of untreated 29 boys who enter puberty below 135 cm. The mean age at the start of treatment with a GnRH analog, leuprorelin acetate depot (Leuplin^®) was 12.3 yr, a mean of 1.3 yr after the onset of puberty, and GnRH analog was administered every 3 to 5 wk thereafter for a mean duration of 4.1 yr. The anabolic steroid hormone was started approximately 1 yr after initiation of treatment with the GnRH analog. The mean pubertal height gain from onset of puberty till adult height was significantly greater in the combination treatment group (33.9 cm) than in the untreated group (26.4 cm) (p<0.0001). The mean adult height was significantly greater in the combination treatment group (164.3 cm) than in the untreated group (156.9 cm) (p<0.0001). The percentage of subjects with an adult height of 160 cm or taller was 90.5% (19/21) in the combination treatment group, and it was 13.8% (4/29) in the untreated group (p<0.0001). Since growth of the penis and pubic hair is promoted by the anabolic steroid hormone, no psychosocial problems arose because of delayed puberty. No clinically significant adverse events appeared. Combined treatment with GnRH analog and anabolic steroid hormone significantly increased height gain during puberty and adult height in boys who entered puberty with a short stature, since the period until epiphyseal closure was extended due to deceleration of the bone age maturation by administration of the GnRH analog and the growth rate at this time was maintained by the anabolic steroid hormone.     

Plasma Growth Hormone (GH) Responses to Growth Hormone Releasing Factor (hp GRF 1–44) in Familial GH Deficiency

ABSTRACT. In four children with familial GH deficiency peak and integrated GH responses to an acute intravenous bolus of hp GRF 1–44 were lower than in 18 children with non-familial idiopathic GH deficiency and in 5 children with structural hypothalamic abnormalities. It is possible that the familial forms of GH deficiency described may be due to absence or biological inactivity of endogenous GRF or possibly GRF receptor or post receptor abnormalities.     

Discrepancies between Physician and Parent Perceptions of Psychosocial Problems of GHD Children Undergoing GH Therapy in Japan

This study examined discrepancies between the perceptions of physicians treating short children with GH deficiency (GHD) using GH replacement therapy (GHRT) and the perceptions of the parents of these children and identified the major causes of parental anxiety. Three attending pediatric endocrinologists and the parents of 31 GHD children participated in this study. The physicians and parents completed a specially designed questionnaire to rate the types and degrees of psychosocial problems that GHD children might experience. For 6 of the first 11 questions, the physicians rated psychological problems differently than the parents did, tending to over- or underestimate parental concerns. This discrepancy did not disappear with treatment. However, the difference in the perception of anxiety between the physicians and parents changed for issues regularly discussed between them. Physicians and nurses were ranked as the most reliable providers of information. The parents of children who had previously undergone GHRT were a highly desired source of information. Psychosocial problems remain largely unaddressed by endocrinologists. Endocrinologists treating short stature are encouraged to be more involved in understanding parents’ anxieties, evaluation of misperceptions concerning parents’ expectations, and addressing these issues in future communication with parents. Support by experienced psychologists may help endocrinologists with this issue.     

Therapeutic Efficacy and Safety of GH in Japanese Children with Down Syndrome Short Stature Accompanied by GH Deficiency

In this study, we investigated the effects of GH treatment in children with Down syndrome who had been diagnosed with GH deficiency (GHD). A total of 20 subjects were investigated in this study. Fourteen Down syndrome children (5 boys and 9 girls) with short stature due to GHD were treated with GH at Okayama Red Cross General Hospital, and 6 Down syndrome children (4 boys and 2 girls) with short stature due to GHD were registered in the Pfizer International Growth Database (KIGS). Height SD score (SDS) increased throughout the three-year GH treatment period. The overall mean height SDS increased from –3.5 at baseline to –2.5 after 3 yr of treatment. The mean change in height SDS during these 3 yr was 1.1. In addition, height assessment of SD score based on Down syndrome-specific growth data in the Japanese population revealed that the height SDS (Down syndrome) also increased across the 3-yr GH treatment period. The mean change in height SDS (Down syndrome) during these three years was 1.3. GH therapy was effective for Down syndrome short stature accompanied by GHD, and no new safety concerns were found in this study.     

High-Dose Growth Hormone Treatment of Non-Growth Hormone-Deficient Children: Preliminary Results after 2 Years

ABSTRACT. The growth response to high-dose growth hormone (GH) therapy was investigated in 10 short, prepubertal, slowly-growing children. Two years treatment with recombinant human GH at a dose of 0.3 IU/kg daily 7 days per week resulted in a mean height increase of 19.5 cm (range 17–23 cm). There was a slight but not significant acceleration of bone age maturation. The treatment also induced a sustained increase in insulin secretion without detectable changes in glucose tolerance.     

Long-Lasting Catch-up Growth under Bio-Methionyl Growth Hormone Treatment in an Infant with Isolated Growth Hormone Deficiency Type 1A1

ABSTRACT. This case report concerns a 7-month-old infant with severe height retardation (–5.0 SD), typical growth hormone (GH)-deficient phenotype, and undetectable GH serum levels in response to three pharmacological stimuli. Diagnosis of isolated GH deficiency type 1A was confirmed by restriction endonuclease analysis of genomic DNA which pointed out GH-N gene deletion. The introduction of bio-methionyl-GH therapy in this patient was followed by a transient and clinically irrelevant appearance of low binding capacity GH antibodies as well as by a long-lasting catch-up growth (42.2 cm) which is continuing 44 months after beginning of treatment. This atypical pattern confirms that immune and growth response to exogenous GH in isolated GH deficiency 1A may be very heterogeneous.     

Five-years growth hormone (GH) treatment in adults with Prader-Willi syndrome

AIM: We have previously shown that 1 year of growth hormone (GH) treatment to adults with Prader-Willi syndrome (PWS) has beneficial effects on body composition. The aim of the present observational study was to re-evaluate our cohort, with focus on long-term GH treatment. METHODS: Seven men and seven women, median age 31 years, were available for follow-up for 6 years. Nine were on GH treatment for 5 years. Body composition was measured with Dual Energy X-ray absorptiometry (DXA). RESULTS: In six GH treated patients with genetically verified PWS there was a substantial increase in lean body mass of 5 kg (p = 0.031) and a concomitant, however, non-significant, decrease in body fat of 5% (p = 0.156). The changes in the genetically verified patients without GH treatment were small and unsystematic. No compliance problems were reported. Only one non-GH-treated woman developed overt diabetes. CONCLUSION: Despite inherent behavioural problems it was possible to continue GH injections for 5 years with sustained favourable effects on body composition without clinically, significant side effects.     

Onset of puberty and near adult height in short children born small for gestational age and treated with GH: Interim analysis of up to 10 years of treatment in Japan

The safety and effectiveness of long-term (10-yr) GH treatment in short Japanese children born small for gestational age (SGA) were evaluated based on interim data analysis from a clinical study, including the findings concerning the influence on the onset of puberty and subjects who achieved near adult height (NAH). Sixty-one subjects were analyzed at baseline in this study. Eleven subjects (6 boys and 5 girls) achieved NAH (mean 157.4 cm and 145.5 cm, respectively), and the Δ height SDS from the start of GH treatment was +1.6 in boys and +1.8 in girls. The median age (yr) at onset of puberty was 11.4 in boys and 9.9 in girls, comparable to healthy children. However, the mean height (cm) at onset of puberty (137.0 in boys; 125.5 in girls) was shorter than that of healthy children. Treatment-related adverse events were generally mild to moderate in severity; however, adenoidal hypertrophy was observed in two subjects as a serious adverse event. One subject had jaw malformation related to GH treatment at a dose of 0.067 mg/kg/d. No notable changes in HbA1c levels were observed, and the levels remained within the reference range. We have confirmed the safety and effectiveness of long-term GH treatment through this ongoing clinical study.     

Clinical Evaluation of the Needle-free Injection System VISION? for Growth Hormone Therapy in Children

The aim of this study was to compare the therapeutic effects of rhGH administered either by subcutaneous needle-injection (pens) or subcutaneous needle-free jet-injection (VISION^®). Furthermore, a survey was carried out after using VISION^® for 12 mo. A needle-free injection group consisting of 18 subjects (11 males and 7 females, mean age 5.87 ± 2.05 yr at the start of hGH therapy) who have not used pen injectors to date, were allowed to use VISION^® in their third to fifth years of GH therapy. In addition, a group of 8 subjects who had been using pen injectors at our clinic (6 males and 2 females, mean age 6.54 ± 2.78 at the start of GH therapy) was monitored as a control. The results indicate that there are no significant differences between the mean growth rates, growth rate SD scores or height SD scores when comparing injection devices. Furthermore, the survey of VISION^® revealed that 70% of the subjects found it slightly or not painful at or after injection, 70% found VISION^® very easy or easy to use, and 80% found the weight of the device appropriate. All subjects expressed a desire to continue using VISION^® in the future. Our results suggest that there are no problems with the effectiveness of hGH treatment with VISION^®, a needle-free jet-injection device and that VISION^® is an effective device for children who have an aversion to needle injection.     

Effects of Two Years of Growth Hormone Treatment in Short Children with Renal Disease

The effect of 1-2 years of growth hormone (GH) treatment (28-30 IU/m²/week) on growth rate, bone age, renal function and metabolic parameters was studied in 61 short, slowly growing children with chronic renal disease (20 with preterminal chronic renal failure (CRF), 24 with end-stage renal failure (ESRF) and 17 with functioning renal transplants). Height velocity (2-year data) significantly increased in children with preterminal CRF from a baseline median of 4.1 cm/year to 9.2 cm/year after 1 year and to 6.6 cm/year after 2 years of treatment. In patients with transplants, the corresponding values were 2.6 cm/year before GH treatment and 8.6 and 7.2 cm/year after 1 and 2 years, respectively. This resulted in normalization of height in 8 of the 16 children who completed 2 years of treatment. The growth response after 1 year in children with preterminal CRF was significantly higher than that in children with ESRF. Bone maturation was in proportion to the increase in chronological age; the expected final height of the children therefore increased by approximately 8-10 cm. In children with preterminal CRF, the decrease in glomerular filtration rate was not affected by 2 years of treatment with GH. The incidence of acute rejection in children with transplants was low; however, a slight stimulatory effect of GH could not be excluded. The major metabolic change induced by exogenous GH was an increase in serum levels of insulin in the three treatment groups, though all glucose tolerance tests remained stable over the 2-year period.