Predictive Criteria for Successful Growth Promotion in Growth Hormone Therapy of Short Stature: A Comparison between Common Endocrine Parameters and Knemometry

ABSTRACT. Due to increased availability of growth hormone (GH) for the treatment of short stature, its use has been proposed for a number of conditions besides classic GH deficiency. We have studied growth response during a one year treatment period with 14 IU/m²/week of GH in a heterogenous group of 24 short children with various conditions associated with short stature (SDS for body height ranging between −2.2 and −4.4). Thirteen children could be classified as "responders" with growth rate increments of 2 cm/yr or more above pretreat-ment growth rates, and 11 children as "non-responders". The children were measured regularly both by stadiometry and knemometry at weekly intervals. GH stimulation by insulin, arginine and spontaneous overnight secretion of GH, and SM-C generation were evaluated in the children and found to be of no predictive value for the individual responsiveness to GH administration except in one boy with classic GH deficiency. However, serial measurements of the lower leg length provided useful information for individual predictions in 21 out of the 24 children as early as 10 weeks after the start of the GH treatment.     

Who is Treated with Growth Hormone Today?

ABSTRACT. The present demographic data from the Kabi International Growth Study (KIGS) database are summarized. Of the 2580 patients included, 85% have growth hormone deficiency (GHD) and 15% have other causes of growth failure. Idiopathic GHD is present in 78.5% of the patients, the remaining 21.5% have organic GHD. Isolated GHD is common in idiopathic GHD whereas multiple pituitary hormone deficiencies occur in at least 50% of the organic GHD patients. A preponderance of boys is observed in most groups of patients. Median chronological age (CA) at start of treatment is 10 years and median duration of therapy is 2.3 years. However, a wide range is observed. In most cases growth retardation is severe. In most patients with GHD height SDS for chronological age at start of therapy is at or below -3. The median difference between idiopathic and organic GHD is 1 SDS. Most patients have 6 or 7 injections of growth hormone (GH) per week. The median total weekly dose is approximately 0.5 IU/kg/week, but it is lower in older patients. It is concluded that steadily increasing numbers of patients with idiopathic and organic GHD are being treated with human GH (hGH). In addition, many patients with other growth disorders not necessarily associated with GHD receive hGH therapy. Chronological age at start of treatment still appears to be (too) high in most patients and growth retardation severe. The frequency of hGH injections has been increased to nearly daily administration. However, the total weekly dose appears to be low, especially in the older patients. It is hoped that KIGS will contribute to improving the efficacy of treatment and hence the quality of life for all patients with growth disorders.     

Growth Response in Prepubertal Children with Idiopathic Growth Hormone Deficiency During the First Two Years of Treatment with Human Growth Hormone. Analysis of the Kabi Pharmacia International Growth Study

From the large database of patients enrolled in the Kabi Pharmacia International Growth Study (KIGS), 289 prepubertal patients with idiopathic growth hormone deficiency (GHD), treated for 2 years with growth hormone (GH) substitution therapy, were selected. A multiple regression analysis was performed to determine both the auxological factors characterizing the patients at the beginning of the first and second years on GH therapy and the respective treatment modalities relevant to the magnitude of the growth response. It was observed that during the first year on GH therapy the magnitude of the growth response was negatively correlated with chronological age and height SDS, and positively correlated with target height SDS, GH dose (IU/kg/week) and frequency of GH injections. During the second year the growth response was negatively correlated with chronological age and the first-year GH dose (IU/kg/week), and positively correlated with height velocity during the first year, GH dose (second year), and injection frequency (second year). The data suggest that the forces of'catch-up'- auxologically entrenched within the distance between target height SDS and height SDS - no longer prevail during the second year of GH therapy. The inverse influence of the first-year GH dose in the two yearly phases of growth suggests that optimizing GH treatment must be attempted by analysing growth in response to GH over longer periods of time and considering that the growth process is influenced by interactive factors.     

GH Deficient Children Receiving GH Replacement Do not Grow during Intermittent Infectious Illness

ABSTRACT. Five growth hormone deficient children, aged 5.3 to 12.6 yrs, were measured regularly once or twice weekly by knemometry, a novel and noninvasive technique of accurate lower leg length measurement. The total period of observation was 40 months in the 5 children. During this time all children received replacement therapy with extractive human pituitary growth hormone 12 IU/m²/week by daily S.C. injections. 11 intermittent infectious illnesses occurred within the observation period of 40 months. During the infectious diseases a significant decrease of the mean lower leg growth velocity down to -0.012 mm/day was observed. During the following convalescent period (14 days) mean lower leg growth velocity rose up to +0.107 mm/day ( p < 0.001). Growth hormone substitution was not changed throughout the period of observation.     

Growth Hormone Response to Overnight Growth Hormone-Releasing Hormone Infusion and Oral Pyridostigmine in Children with Short Stature

Ross, R.J.M., Savage, M.O., Kirk, J.M.W. and Besser, G.M. (Departments of Endocrinology and Child Health, St Bartholomew's Hospital, London, UK). Growth hormone response to overnight growth hormone-releasing hormone infusion and oral pyridostigmine in children with short stature. Acta Paediatr Scand [Suppl] 349: 114, 1989.
The development of a long-acting or depot preparation of growth hormone-releasing hormone (GHRH) may have many advantages over conventional treatment (with GH) of GH-deficient children. Pyridostigmine, an acetylcholinesterase inhibitor, has been shown to augment basal GH secretion and the GH response to GHRH in short children. It may thus provide adjuvant therapy to depot GHRH. The GH response to a nocturnal subcutaneous infusion of GHRH (1–29)NH₂ in doses of 5 and 10 pg/kg/hour was investigated in five short, slowly growing children. The effect of oral pyridostigmine 60 mg on nocturnal GH secretion and the GH response to a nocturnal infusion was also examined. The subcutaneous infusion of GHRH augmented pulsatile GH release in all five children. There was a dose-related response to subcutaneous GHRH for the GH area under the curve and mean GH pulse amplitude, but no change in the number of pulses. There was a significant rise in the mean baseline GH concentration during the GHRH infusion compared with placebo. Pyridostigmine had no effect on either basal or stimulated GH secretion.     

重组人生长激素替代治疗对生长激素缺乏症患儿糖代谢的影响

目的观察国产重组人生长激素(r-hGH)替代治疗对生长激素缺乏症(GHD)患儿糖代谢的影响。方法用国产r-hGH对GHD 15例患儿治疗3个月。治疗前后行口服葡萄糖耐量试验(OGTT)及胰岛素(INS)释放试验(IRT)。分别于0、30 mun,1、2 h采静脉血行血浆葡萄糖(PG)及胰岛素(INS)测定。结果治疗前患儿糖耐量均正常,治疗3个月后OGTT空腹PG 无明显增加,但PG 30min(P<0.01)、1 h(P<0.05)、2 h(P<0.05)、血糖曲线下面积(AUCglu)(P<0.01)均明显增加;虽葡萄糖耐量曲线上移,但均未出现糖耐量损伤(IGT)或糖尿病(DM)。IRT空腹INS(P<0.05)、30 min(P<0.05)、1 h(P<0.01)、2 h(P<0.01)、INS曲线下面积(AUCins)(P<0.01)均显著增加,稳态模型胰岛素抵抗指数(Homa IR)明显上升(P<0.05)。结论GHD患儿r-hGH替代治疗3个月后INS敏感性下降,糖耐量降低,提示应用r-hGH替代治疗患儿应监测PG、INS水平     

Growth Response in Prepubertal Children with Idiopathic Growth Hormone Deficiency during the First Year of Treatment with Human Growth Hormone. Analysis of the Kabi International Growth Study.

ABSTRACT. In order that children with growth hormone deficiency (GHD) reach the goal of normal adult stature, treatment modalities need to be optimized. From the large database of patients enrolled in the Kabi International Growth Study (KIGS), 257 prepubertal patients with idiopathic GHD undergoing their first year of growth hormone (GH) substitution therapy were selected. A multiple regression analysis was performed to determine both auxiological factors characterizing the patients and the factors related to the chosen treatment modalities which are of significance for the observed magnitude of the growth response. Due to the structure of the data, pretreatment height velocity and bone age-derived auxiological data were not considered. It was observed that the magnitude of the growth response was inversely correlated with chronological age and relative height (HT SDS) at the start of GH treatment but was positively correlated with mid-parental height. The growth response was also positively correlated with the GH dose (IU/kg/week) and the frequency of GH injections per week. A regression equation using these five parameters was derived, allowing the growth response of these patients to be predicted. The extension of this analytical approach in the future will allow the treatment of patients with GHD to be tailored to individual requirements.     

Effects of Short-Term Growth Hormone Therapy in Short Children without Growth Hormone Deficiency

ABSTRACT. Evaluation of 24-hour endogenous growth hormone (GH) secretion was carried out in 62 children, aged 7-16 years, who did not have classic GH deficiency (GHD). The mean 24-hour GH concentration, determined at 20-minute intervals over 24 hours, was variable, ranging from 1.28 to 11.39 μg/l with a mean of 4.95 ± 2.55 μl (± SD). There was a positive correlation between mean 24-hour GH concentration and plasma insulin-like growth factor I (IGF-I) values ( r = 0.54; p < 0.01). Recombinant human GH, 0.1 IU/kg/day was administered to 30 of the 62 children for 6 months followed by 6 months'observation without treatment. Thereafter, GH was administered at the same dose for a further 6 months to 16 children. The mean height velocities before, during, and after the first treatment period were 4.3 ± 0.9, 7.3 ± 1.9 and 4.9 ± 2.0 cm/year (mean ± SD), respectively. The height velocity during treatment was greater than pre- and post-treatment values ( p < 0.001). The height velocity Increased again during the second treatment period to a mean of 8.5 ± 2.0 cm/year ( p < 0.001). Nine other children were treated continuously in a similar manner for 1 year and their height velocity increased significantly from 4.1 ± 1.4 to 6.0 ± 1.9 cm/year ( p < 0.001). According to our criteria, 29 of the 39 children (74.4%) who were treated for 6-12 months showed a GH-dependent height increase during therapy. There were no differences between the children who responded to GH treatment and those who did not in terms of Chronological age, bone age, plasma IGF-I level, maximal GH level to insulin-induced hypoglycaemia, or mean 24-hour plasma GH concentration. These data indicate that some short children without GHD respond to GH treatment with an increased height velocity. Further investigations are required to determine the effect of GH on final height.     

Growth Response to Human Growth Hormone Treatment in Children with Partial and Total Growth Hormone Deficiency

ABSTRACT. The growth response during the first and second years of human growth hormone (hGH) treatment was studied in 14 prepubertal children with so-called "partial" GH deficiency (peak GH between 8 and 15 mU/1) and compared to 28 prepubertal children with "total" GH deficiency (peak GH less than 8 mU/1). There was no difference in growth acceleration between children with partial and total GH deficiency, when initial covariables were taken into account. In a stepwise multiple regression analysis initial stature, pre-treatment growth velocity and skinfold thickness were shown to be most related to growth response, but after exclusion of 3 children with a genetic form of total GH deficiency and partial TSH deficiency this relationship was lost. GH levels during provocation tests and auxological criteria have a poor predictive value for growth response to hGH therapy.     

Growth Hormone Secretion and the Therapeutic Effects of Human Growth Hormone: First Japanese Results of the Kabi Pharmacia International Growth Study/International Cooperative Growth Study

Data for a total of 942 new cases of hypopituitarism, out of 3493 patients treated with recombinant human growth hormone (GH) for more than 1 year, have been analysed. The mean peak GH correlated well with clinical variables related to growth and was considered to be a good index of GH secretory capacity. Mean peak GH was correlated inversely with obesity ( r = -0.253, p < 0.01). The lower the height velocity before treatment, the mean peak GH and the height SDS, the greater was the therapeutic effect achieved. The patients with mean peak GH less than or equal to 5 ng/ml were defined as having complete GH deficiency (GHD), and those with a mean peak GH of 5-10 ng/ml as having partial GHD. The clinical entity of GH neurosecretory dysfunction could not be identified from either the clinical variables examined or the therapeutic effect. The appearance of GH antibody was considered to be of no clinical significance because its incidence and titre were both low.     

The Dosage Dependency of Growth and Maturity in Growth Hormone Deficiency Treated with Human Growth Hormone

ABSTRACT. A group of 11 pre-pubertal growth hormone deficient patients were treated with human growth hormone over a period of 4 years. In 6 of the patients the dosage was 4 IU 3 times a week and in 5, 8 IU 3 times a week. Changes in height demonstrated that the "catch up" was significantly greater and of longer duration in the second group. In spite of a more rapid increase of bone age in the second group, the prognosis of final height had improved significantly at the end of the study period. A comparative study of the plasma concentrations of T4, T SH, gonadotrophins and steroids, to see if the greater velocity of bone maturity in the second group could be due to contamination of the preparation by other could be due to contamination of the preparation by other hypophysary hormones, did not demonstrate significant differences between the groups.     

Growth Hormone Therapy of Short Stature1

ABSTRACT. Considerable progress has been made in the diagnosis and treatment of growth hormone-related short stature. Knowledge about growth hormone releasing factor (GRF) and somatomedin C has provided the possibility of distinguishing between hypothalamic and pituitary growth hormone deficiency and growth hormone resistance. It has been shown that treatment with GRF may stimulate growth in certain cases of growth hormone deficiency. Recombinant DNA techniques may, in the near future, provide sufficient amounts of GRF, growth hormone and possibly somatomedin C for clinical use. At present, many countries have prohibited the use of human pituitary growth hormone due to a possible risk of transmission of Creutzfeldt-Jakob disease. It has become increasingly clear that several short children without classical growth hormone deficiency, may increase their growth velocity during growth hormone treatment. There are many medical, psychological, ethical and economical implications involved in the extended treatment of children with short stature. It is necessary to maintain a restricted approach towards the treatment of children with short stature, and such treatment should be prescribed and controlled by a limited number of well-trained paediatric endocrinologists. This article reviews some of the present knowledge in this rapid developing field of paediatric endocrinology.     

重组人生长激素治疗颅咽管瘤术后生长激素缺乏症

目的探讨低剂量基因重组人生长激素(rhGH)治疗颅咽管瘤术后生长激素缺乏症(GHD)患儿的疗效和安全性。方法回顾性分析2008年4月-2011年4月在北京三博脑科医院内分泌门诊治疗的12例7～15岁术后病理确诊为颅咽管瘤且继发生长迟滞患儿的病例资料及随访资料。患儿均给予rhGH治疗(每晚睡前皮下注射0.1 IU.kg-1,每周5次注射),疗程3～36个月。定期检测肝功能、肾功能、激素水平等指标,并比较患儿治疗前后身高、体质量、生长速度、身高标准差计数、胰岛素样生长因子1(IGF-1)、骨龄等生长指标的改变。结果在rhGH治疗期间,12例患儿在治疗第1年生长速率增加显著,由(2.2±1.3)cm.a-1增加到(6.63±4.97)cm.a-1(P<0.01),身高标准差计数由治疗前-3.3±2.3增加到-3.2±2.8,血IGF-1治疗前为(38±64)μg.L-1,治疗后为(173±167)μg.L-1(患儿治疗后血清IGF-1水平达到正常范围),差异均有统计学意义(Pa<0.01)。治疗期间,患儿肝肾功能等均保持在正常值范围,骨龄无明显变化,随访时尚无患儿肿瘤复发。结论低剂量rhGH治疗儿童颅咽管瘤术后继发GHD是经济、有效的,在充分评估及严密监控下开展GH替代治疗是安全的。     

Dramatic Early Postnatal Growth Failure in Children with Early Onset Growth Hormone Deficiency

From the large group of patients included in the Kabi Pharmacia International Growth Study, 58 were studied who were treated with growth hormone (GH) before the age of 2 years, after diagnosis of GH deficiency (GHD). The growth parameters calculated from these infants indicate dramatic early postnatal growth failure, thus suggesting that GH could participate in early postnatal growth. The intensity of growth failure in these infants with GHD suggests that early screening on clinical grounds is possible.     

Growth and Growth Hormone Therapy in Hypochondroplasia

ABSTRACT. The growth of 84 patients with hypochondroplasia (56 male, 28 female) was studied. A wide spectrum of severity was found from quite severe short limbed dwarfism to short apparently normal prepubertal children who manifested disproportion only at puberty when growth failed. The onset of puberty was at the normal time but the pubertal growth spurt appeared not to materialize and it is this lack which resulted in severely compromised adult heights of 145-165 cm in boys and 133–151 cm in girls. Twenty (12 M, 8 F) hypochondroplastic children aged between 4.3 and 12.8 years were recruited to a study of the effects of biosynthetic growth hormone. All had normal growth hormone responses (> 15 mU/I) to a pharmacological test of growth hormone secretion. Biosynthetic growth hormone in doses between 12-32 u/m²/week produced a significant acceleration in height velocity standard deviation score (SDS) for chronological age (CA) from a pretreatment mean of - 1.66 (SD 1.36) to + 1.62 (SD 1.52) ( p < 0.001). Significant increases were also observed in the height SDS for bone age (BA), sitting height (SH) SDS and subischial leg length (SILL) SDS. A longer period will be required to assess the effect of treatment on adult height prognosis.     

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.     

Modification of 24-Hour Growth Hormone Secretion after Continuous Subcutaneous Infusion of Growth Hormone-Releasing Hormone (GHRH (1–29)NH2) in Short Children with Low 24-Hour Growth Hormone Secretion

Tauber, M.T., Pienkowski, C., Landier, F., Gunnarsson, R. and Rochiccioli, P. (Department of Paediatric Endocrinology, CHU Rangueil, Toulouse Cedex, and Kabi Laboratory, Paris, France and Kabi Peptide Hormones, Stockholm, Sweden). Modification of 24-hour growth hormone secretion after continuous subcutaneous infusion of growth hormone-releasing hormone (GHRH (1–29)NH₂) in short children with low 24-hour growth hormone secretion. Acta Paediatr Scand [Suppl] 349: 117, 1989.
Six short children with low 24-hour growth hormone (GH) secretion were treated with continuous subcutaneous infusion of GHRH (1–29)NH₂ for 3 weeks using a portable infusion pump. Restoration of pulsatile GH secretion was observed in all three children treated with 40 pg/kg/day of GHRH, but in only one of the three children treated with 20 pg/kg/day. All parameters of 24-hour GH secretion increased, but in five children the magnitude of the GH response was greater on day 1 than on day 21 of CHRH treatment. This decrease was not observed in the single child who responded to a low dose of GHRH (20 pg/kg/day); on the contrary, the response in this patient was greater after 21 days of GHRH treatment. Plasma levels of GHRH (1–29)NH₂ were significantly higher on day 21 than on day 1 of treatment, suggesting altered pharmacokinetics over time. The effect of GHRH treatment on growth could not be determined because of the short duration of the study, but the data obtained on 24-hour GH secretion and GHRH metabolism suggest that a long-acting analogue of GHRH could be useful for the treatment of GH deficient or insufficient children.