Comparison of growth hormone releasing hormone therapy and growth hormone therapy in growth hormone deficiency

Seven children with growth hormone deficiency of hypothalamic origin responded to an i.v. bolus of growth hormone releasing hormone (GHRH) (1–29)-NH2 with a mean serum increase of 10.7 ng/ml growth hormone (GH) (range 2.5–29.3 ng/ml). Continuous s.c. administration of GHRH of 4–6 g/kg twice daily for at least 6 months did not improve the growth rate in five of the patients. One patient increased his growth rate from 1.9 to 3.8 cm/year and another from 3.5 to 8.2 cm/year; however, the growth rate of the latter patient then decreased to 5.4 cm/year. When treatment was changed to recombinant human growth hormone (rhGH) in a dose of 2 U/m² daily, given s.c. at bedtime, the growth rate improved in all patients to a mean of 8.5 cm/year (range: 6.2 to 14.6). Presently GHRH cannot be recommended for the routine therapy of children with growth hormone deficiency since a single daily dose of rhGH produced catch-up growth which GHRH therapy did not.Abbreviations GH growth hormone - GHD growth hormone deficiency - GHRH growth hormone releasing hormone - hGH human growth hormone - rhGH recombinant human growth hormone - SM C/IGF I somatomedin C/insulin-like growth factor I On the occasion of the 85th birthday of Prof. Dr.Dr.h.c. mult. Adolf Butenandt     

Malignant thymoma in a patient with growth hormone deficiency during growth hormone therapy

Malignant thymoma was found in an 8-year-old Japanese boy with growth hormone (GH) deficiency who had received GH therapy for 3 years and 5 months. There may be a possible relationship between the occurrence of malignant thymoma and GH therapy.     

Arachnoid cyst with growth hormone deficiency

On clinical grounds, arachnoid cysts are usually associated with neurological dysfunction. Little is known concerning their involvement in endocrine disorders. A seven-year-old boy was admitted to the hospital for evaluation of an unprovoked afebrile seizure. His neurological examination was normal, however, he had growth retardation. Insulin tolerance and L-dopa growth hormone stimulation tests revealed an inefficient growth hormone response. An MRI of hypophysis and cranium yielded a shift of hypophysis and a large arachnoid cyst.     

Growth hormone deficiency of hypothalamic origin in septo-optic dysplasia

Hypothalamic pituitary function and growth hormone releasing hormone (GHRH) loading tests in two children with septo-optic dysplasia (SOD) revealed isolated GH deficiency in one and deficiencies of growth hormone, adrenocorticotropic hormone and antidiuretic hormone in the other. Secretion of GH was elicited in the first patient by single i.v. bolus administration of GHRH and after repetitive i.v. infusions of GHRH in the second. With these results we confirmed that the hypopituitarism in our patients with SOD was of hypothalamic origin. Both patients also had infantile spasms.     

Prediction of growth response in prepubertal children treated with growth hormone for idiopathic growth hormone deficiency

Several multiple regression models have been developed to predict the first-year growth response to human growth hormone (hGH) in children with growth hormone deficiency (GHD). It was the aim of this study to analyse the significance of various growth parameters for a height prediction model. Data from 148 prepubertal children with idiopathic GHD were evaluated. The prediction model was developed by means of univariate and stepwise linear regression analysis and an “all possible” regression approach using Mallow's C(p) statistics. Six out of eight selected variables had a significant influence on the first-year growth rate. The most important parameter was the difference between target height SDS and height SDS at the start of therapy (THSDS - HSDSC0), accounting for 23.95% and 25.74% of the variability. No other single variable or combination of variables was more informative than the variable THSDS - HSDSC0 alone. From these data, growth velocity for the first year of hGH treatment was estimated as 1.106 (THSDS - HSDSC0) + 6.8 cm/y ± 2.2 cm (SE), allowing a prediction for different intervals between THSDS and HSDSC0. This equation was validated in a small group of 18 GHD patients demonstrating a predicted vs. observed first-year growth rate of 9.4 ± 1.1 vs. 9.5 ± 2.6 cm/y. We conclude that the difference between THSDS and height SDS at the start of therapy is an important predictor of the first-year growth response in children treated with hGH for idiopathic GHD. Unlike in previous studies, additional parameters did not increase predictability.     

Rheumatoid arthritis and growth retardation in children: Treatment with human growth hormone

Twenty patients with rheumatoid arthritis or Still's disease associated with growth failure were treated with human growth hormone, 7.5 to 17 U/m² body surface per week.Five patients did not respond with better growth. In the remainder the mean growth rate increased from 1.9 cm/year (range: 0 to 3.3) to 6.2 cm/year (range: 3.6 to 12) over 5 to 7 months. Twelve patients treated for longer periods increased their mean growth rate from 2.3 cm/year (range: 0.7 to 5.7) to 6.3 cm/year (range: 2.4 to 9.7) and continued to grow during a second year of treatment. Growth velocity decreased in 6 patients when the hGH therapy was discontinued.The causes for this improvement in growth are possibly multifactorial: the growth rate is depressed by the severity of the disease and high-dose glucocorticoid therapy. Increases of growth rate occured during improvements in the disease, reduction of steroid medication, as a result of therapy with human growth hormone, and because of puberty in some patients.Human growth hormone seemed to improve the underlying condition of four of the patients but had no influence on the disease in the remaining children.On the occasion of the 75th birthday of Prof. Dr. Dr. h. c. Adolf Butenandt     

Final height and pubertal development in 55 children with idiopathic growth hormone deficiency,treated for between 2 and 15 years with human growth hormone

Sixty patients with the diagnosis of idiopathic growth hormone deficiency have been followed till final height was reached, after hGH treatment lasting between 2 and 15 (average 5.4) years. Twenty-six had total and 13 partial isolated growth hormone deficiency (IGHD); 10 had GHD plus gonadotrophin deficiency (GnD); six had multiple pituitary hormone deficiency (MPHD) and five, labelled transient prepubertal GHD, had normal responses in the insulin tolerance test when retested after the end of treatment.The final height of the patients with IGHD averaged 2.3 SD below the population mean, or 2.0SD below their midparent mean. Half the boys, but only 15% of the girls, ended above the population 3rd centile. There was no difference in final height between those with total and partial deficiency nor between patients treated prepubertally and those in whom treatment started in early puberty. In the 39 patients with IGHD the correlation of final height with midparent height was 0.72, a figure identical to that occurring in the normal population. Though final height was chiefly influenced by parental height, it was also affected by the degree of smallness when treatment began being lowered by an average of 2.5 cm for every SD that the patient's height at beginning of treatment lay below the average of all IGHD children, parents' heights being allowed for.Since untreated patients end at about 6 SD below the mean, treatment during the age span represented in these patients recovered 4SD, but failed to recover the remainder. The lost 2 SD may be due to the late start of treatment (averaging 11 years of age even in our prepubertal patients). Our findings emphasise the importance of early diagnosis, so that future patients never drop to 4 or 5 SD below mean height for age, but only to 2 or 3.Patients with IGHD plus GnD had final heights averaging 1.5 SD below the population mean and those with MPHD 1.0 SD below. This was entirely due to their developing longer legs than the patients with IGHD, the final sitting heights being the same. The long legs were due to treatment with sex steroids being started relatively late. Patients with IGHD who entered puberty spontaneously did so late in time and in the boys pubertal development was normal. In the girls there was a disturbance in the normal relationship of pubertal events and in two menarche never occurred.     

A comparative study of growth hormone (GH) and GH-releasing hormone(1–29)-NH2 for stimulation of growth in children with GH deficiency

In this study, 60 patients with proven growth hormone deficiency (GHD) of hypothalamic origin were randomized into three equal groups, and received growth hormone-releasing hormone(1–29)-NH, (GHRH(1–29)-NH,), 30 or 60 μg/kg/day, or growth hormone (GH), 0.1 IU/kg/day, for 6 months. There were no significant differences in growth between the two groups given GHRH(1–29)-NH, but growth in the GH group was significantly better than in the other two groups ( p < 0.01). Mean height velocities at 6 months were 9.2, 9.3 and 14.6 cm/year for the three groups, respectively. Plasma GHRH concentrations increased steadily over the 6-month treatment period, with higher levels in the group on the higher dose. During GHRH(1–29)-NH₂ treatment, serum concentrations of insulin-like growth factor I rose initially, but then fell to values similar to those before treatment. No GH antibodies were detected, but all 20 patients on high-dose GHRH(1–29)-NH, and 19 of 20 patients on low-dose GHRH(1–29)-NH₂ developed GHRH antibodies. These had almost disappeared by 9 months after stopping treatment. There was no correlation between antibody titres and increase in height. No serious side-effects were seen, but three patients receiving GHRH(1–29)-NH, reported mild irritation at the injection site. These results from the continuous infusion of GHRH(1–29)-NH₂ over 6 months suggest that this treatment, or the related use of a depot preparation, is unlikely to be as effective as GH for the promotion of growth in GHD.     

Effectiveness of growth hormone (GH) therapy in GH-deficient children and non-GH-deficient short children

The growth response during short-term growth hormone (GH) treatment was evaluated in eight prepubertal non-GH-deficient (non-GHD) children and compared with six prepubertal GH-deficient (GHD) patients. Standard doses of GH can improve growth rate in GHD and in some non-GHD patients. In neither group the growth response can be predicted by the acute increase in Thymidine Activity or Somatomedin-C levels. A diagnostic trial of GH treatment may be the only certain method of selecting the short non-GHD patients who may benefit from long-term GH therapy.Abbreviations GH growth hormone - GHD growth hormone deficient - Sm-C somatomedin C - TA thymidine activity     

Molecular study of human growth hormone gene cluster in three families with isolated growth hormone deficiency and similar phenotype

The growth hormone (GH) gene (hGH-N) cluster was analysed using polymerase chain reaction, Southern and polymorphism analysis in five patients (including two pairs of siblings) with extreme short stature and absence of GH secretion. Patients 1 and 2 (siblings) were homozygous for a large deletion removing four genes of the cluster: hGH-N, hCS-L, hCS-A and hGH-V Both siblings produced high anti-GH antibody levels in response to exogenous GH therapy, followed by growth arrest a few months after starting replacement therapy. In patient 3 we detected a heterozygous deletion which involved three genes of the cluster (hCS-A, hGH-V, hCS-B) and left an intact hGH-N gene. Direct sequencing of hGH-N specific amplified fragments excluded the presence of any point mutations in exons and splicing regions. In patients 4 and 5 (sisters) our study did not demonstrate any gene deletions. Analysis of polymorphic restriction patterns in this family demonstrated that both sisters inherited the same alleles from the father but different alleles from the mother, suggesting that the defect was not linked to the hGH-N gene. These results confirm the difficulty of clinical identification of subjects with hGH-N deletion and underline the importance of DNA analysis in patients with absence of GH secretion and extreme growth retardation.A preliminary report of these studies was presented at the 31st Annual Meeting of the European Society for Paediatric Endocrinology (ESPE), Zaragoza (Spain), September 6–9, 1992     

生长发育迟缓与胰岛素样生长因子的关系

目的提高由于生长激素－胰岛素样生长因子（ＧＨ－ＩＧＦ）轴异常引起的生长发育迟缓诊断的准确性。方法分别收集门诊６８例生长发育迟缓儿童运动激发试验前后２次血清和１４例住院患儿药物激发试验１０次血标本,用免疫放射计量（ＩＲＭＡ）方法测定ＩＧＦ－１,ＩＧＦ－２和ＩＧＦＢＰ－３,放免方法（ＲＩＡ）测定ＧＨ。结果药物激发试验ＧＨ水平与ＩＧＦ－１,ＩＧＦ－２和ＩＧＦＢＰ－３测定一致。运动激发试验根据运动后ＧＨ水平及身高百分位的情况将６８例分为３组：ＧＨ＜５０μｇ／Ｌ,５０～１００μｇ／Ｌ,＞１００μｇ／Ｌ。ＧＨ＜５０μｇ／Ｌ组１４例,其中１０例身高小于第３百分位,其ＩＧＦ－１,ＩＧＦ－２和ＩＧＦＢＰ－３水平分别是（３９±２０）,（２７４±１２２）,（４２０±２１０）ｎｍｏｌ／Ｌ,低于正常值（Ｐ＜００１）,ＧＨ水平与ＩＧＦ－１,ＩＧＦ－２和ＩＧＦＢＰ－３相符。结论用运动激发试验联合测定ＧＨ、ＩＧＦ－１和ＩＧＦＢＰ－３三项指标可以提高由于ＧＨ－ＩＧＦ轴异常所引起的生长发育迟缓诊断的准确性。     

Effects of growth hormone therapy in prepubertal children with short stature secondary to intrauterine growth retardation

A total of 130 short children were included in a French multicentre study and randomized between a control group (group A) and two groups treated with daily subcutaneous injections of GH at doses of 0.7 IU/kg/week (group B) and 1.4 IU/kg/week (group C) for 2 years. Height velocity was significantly increased ( p <0.0005) in groups B and C, with a greater increase in group C than in group B ( p < 0.001). The benefit after 2 years compared with controls was 4.3 cm in group B and 5.9 cm in group C. The rate of bone maturation was not affected by GH therapy. These results led to the conclusion that 2 years of treatment with GH improves final height prognosis in children with short stature secondary to IUGR, and that this effect is dose dependent. The effect on final height has still to be demonstrated.     

Excessive growth in a child with craniopharyngioma and growth hormone deficiency

In a 5-year-old boy presenting with clumsiness and excessive growth, a large craniopharngioma was diagnosed. Biochemically, there was a deficiency of growth hormone, a hypothalamic hypothyroidism and hypocorticalism, a thyroxine binding globulin elevation, an abnormal gonadotropin secretion and a mild hyperprolactinaemia. After removal of the tumour growth stopped almost completely. Plasma insulin-like growth factor (IGF)-I was in the lower normal range. Plasma IGF-II decreased after tumour removal. It is speculated that the tumour produced a growth factor causing excessive growth.Abbreviations GH growth hormone - IGF insulin-like growth factor - TSH thyroid-stimulating hormone - SDS standard deviation score - TBG thyroxine binding globulin - LH luteinizing hormone     

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.     

Crouzon综合征合并生长激素缺乏症1例报告及重组人生长激素治疗随诊

目的报告1例Crouzon综合征合并生长激素缺乏症(GHD)患儿及其重组人生长激素(rhGH)治疗结果。方法回顾分析患儿以rhGH治疗2年的临床资料。结果患儿女性,5岁4月龄时身高98.2 cm(P_3),有特殊面容(舟状头、突眼、反颌畸形等)。基因检测示FGFR2基因存在c.1061CG(p.Ser354Cys)杂合变异,源自母亲,为已知的致病变异,诊断为Crouzon综合征。同时相关检查提示患儿合并GHD。给予rhGH治疗2年,身高117 cm,平均生长速率为9.4 cm/a。治疗期间,头颅磁共振监测提示侧脑室及第三脑室略扩张等表现未进展,眼科随诊示左眼视盘水肿程度较前减轻,未发现不良反应。结论矮小可能是Crouzon综合征的表型,rhGH治疗可以改善Crouzon综合征合并GHD患儿的身高,且未引起患儿颅内压增高等不良反应。     

rhGH替代治疗对生长激素缺乏儿童糖代谢的影响

目的探讨重组人生长激素(rhGH)替代治疗对生长激素缺乏症(GHD)儿童糖和胰岛素代谢的影响以及 GH 与糖代谢平衡之间的关系。方法对44例(男28例,女16例)4.5～16.5(10.4±2.6)岁 GHD 患儿在接受 rhGH 治疗前及治疗后每3个月检测体重指数、胰岛素样生长因子-1(IGF-1)、行口服葡萄糖耐量试验,计算稳态模型胰岛素抵抗指数。结果 (1)空腹血糖和 IGF-1在治疗3个月时即显著提高,一直持续较高水平,每个随访时间点与治疗前比较,差异均有统计学意义(F=6.81,7.31,P 均<0.01);稳态模型胰岛素抵抗指数和空腹胰岛素分别在治疗3和9个月时提高(P<0.01和 P<0.05),1年后下降,治疗1年半时与治疗前比较,差异已无统计学意义(均 P>0.05)。(2)相关分析发现,稳态模型胰岛素抵抗指数与体重指数、IGF-1和治疗持续时间显著相关(r=0.251,0.437,0.281,P 均<0.001)。二次方程曲线回归分析发现,稳态模型胰岛素抵抗指数与治疗持续时间呈近似抛物线量变关系。(3)发现2例暂时性高血糖,分别在停用 rhGH 治疗后1个月和5d 血糖恢复正常,再注射 rh GH 后,行口服葡萄糖耐量试验正常。结论 GHD 儿童接受 rhGH 治疗(尤第1年内)可增加胰岛素抵抗,极少数引起短暂糖代谢紊乱。循环 IGF-1可能参与控制胰岛素的敏感性,在 GH 与胰岛素平衡间起重要作用。有必要对所有接受 rhGH 治疗者定期监测糖代谢指标和 IGF-1水平。     

Intranasal administration of growth hormone-releasing hormone(1–29)-NH2 in children with growth hormone deficiency: effects on growth hormone secretion and growth

The growth-promoting potential of growth hormone-releasing hormone(1— 29)-NH, (GHRH(1–29)- NH,) in a new formulation for intranasal use was examined in a 6-month pilot study of eight short prepubertal children. The maximal plasma concentration of growth hormone (GH) was below 12 μg/l in two stimulation tests (arginine, insulin), but above 12 (24–90) μg/l after intravenous GHRH, 1 μglkg. GHRH, 50 μg/kg, was insufflated intranasally three times per day over 6 months. On day 1, GHRHinsufflations were followed by distinct GHRH and GH plasma peaks, ranging from 1.2 to 5.4 μg/l and from 10 to 85 mIU/l, respectively. Peak amplitudes were variably reduced after 6 weeks in most patients, and further reduced at 6 months. GHRH antibodies (initially negative) were positive in three patients after 6 weeks. The mean knemometric growth rate rose from 0.24 to 0.48 mm/week after 6 weeks of treatment ( p = 0.03) and then rapidly declined; the mean 6-month stadiometric height velocity did not increase. Local tolerance was good in one patient; most others reported sneezing immediately after insufflation, rhinorrhoea and mild mucosal burning. Treatment was discontinued in two patients after 6 and 12 weeks. It is concluded that intranasal GHRH, though non-invasive, is not suitable in its present form for use in children, because of decreasing absorption and effectiveness with concomitant development of antibodies and local reactions.     

Diagnostic value of growth hormone-releasing hormone test in children and adolescents with idiopathic growth hormone deficiency

Average growth hormone (GH) peaks following an i.v. growth hormone releasing hormone (GHRH) 1–29 stimulation test were significantly lower in 48 children and adolescents with GH deficiency (GHD) than in 20 age-matched controls (15.2+12.7 vs 37.5+28.1 ng/ml, 2P<0.001). Twelve patients exhibited a low GH peak (<5 ng/ml), 27 demonstrated a normal response (>10 ng/ml) and 9 showed an intermediate rise in plasma GH (5–10 ng/ml). Six of the 12 patients with low GH response to the first GHRH stimulation failed to respond to two other tests immediately before and after a 1 week priming with s.c. GHRH. These subjects with subnormal GH increase at repeat testing had total GHD (TGHD) and multiple pituitary hormone deficiency (MPHD) and had suffered from perinatal distress. On the contrary, 26 of 27 patients with normal GH response to the first test had isolated GHD and only a minority (8/27) had signs of perinatal distress. It is concluded that perinatal injuries primarily damage pituitary structures and that a pituitary defect more probably underlies more severe forms (TGHD and MPHD) of GHD.Presented in part at the 7th Meeting of the Italian Society for Paediatric Endocrinology (Milan, 20–21 October 1989)     

Growth retardation and reduced growth hormone secretion in a boy with achalasia

A 15-year-old boy with achalasia of the oesophagus is described in whom growth retardation was the presenting and misleading symptom. Growth hormone (GH) and insulin-like growth factor-I secretion were decreased but GH therapy was unsuccessful. After pneumatic dilatation of the oesophageal sphincter catch up growth occurred.