Circulating immunoreactive growth hormone releasing hormone concentrations and growth hormone response to growth hormone releasing hormone in short children

To study the role of peripheral immunoreactive growth hormone releasing hormone (ir-GHRH) concentrations and the GHRH test in the evaluation of growth hormone (GH) secretion in short stature, 46 children with a mean age of 9.4 years (range 1.6–16.3 years) and a mean relative height score of –3.2 SD (range –5.0–2.1 SD) were investigated. The children were divided into prepubertal (n=35) and pubertal (n=11) and the prepubertal children further into three groups based on their maximal GH responses to insulin-induced hypoglycaemia (IIH) and clonidine: (1) GH deficient subjects (maximal GH<10 g/l in both test); (2) discordant responders (maximal GH<10 g/l in one test and 10 g/l in the other); and (3) normal responders (maximal GH10 g/l in both test). Peripheral ir-GHRH concentrations were measured during the IIH test by radioimmunoassay after purification of plasma samples on Sep-pak cartridges. Among the prepubertal children 10 fell into group 1, 16 into group 2 and 9 into group 3. Children in group 1 were older, than those in group 3. There were no significant differences in relative heights and weights or absolute and relative growth velocities between the groups. Subjects in groups 1 and 2 had lower maximal GH responses to GHRH than those in group 3. There were no significant differences in the basal plasma ir-GHRH concentrations between the groups. Nine children (19.6%) had somatotrophs with a poor response to a single dose of exogenous GHRH (maximal GH<10 g/l). These subjects had increased basal plasma ir-GHRH concentrations. All of them had a decreased GH response to IIH and/or clonidine. Pubertal children had higher circulating ir-GHRH levels than the prepubertal subjects. There was an inverse correlation (r=–0.46;P<0.001) between the maximal GH response to GHRH and calendar age in the whole series. These observations suggest that: (1) a substantial proportion of short children have a heterogenous GH response to pharmacological stimuli necessitating complementary evaluation of their spontaneous GH secretion; (2) a poor response to exogenous GHRH is associated with increased ir-GHRH levels in the peripheral circulation; (3) all children with normal GH responses in pharmacological tests respond normally to GHRH and (4) the pituitary sensitivity to GHRH decreases with increasing age. Peripheral ir-GHRH concentrations do not differentiate between short children with growth hormone deficiency (GHD) and those with undefined short stature. The GHRH test is of limited value in the diagnosis of GHD, since a normal GH response does not exclude GHD, although a subnormal response appears to reflect dysfunctional GH secretion.     

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     

Effects of long-term growth hormone releasing hormone 1 -29 in significantly short children

Seven children with significant idiopathic short stature (SISS) whose heights were significantly below the third percentile (SD score for height —2.5 to —3.5) and who had normal levels of growth hormone (GH) were treated with growth hormone releasing hormone (GH-RH) in a dose of 30 /μg/kg/day. Therapy was discontinued if patients failed to increase their rates of growth by more than 2.0 cm/year over their pre-therapy growth rate. Treatment was discontinued in two of the patients after 12 months but was continued in the other five for 24 months. These data demonstrate that some patients with SISS grow well during the first 2 years of treatment with GH-RH.     

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.     

Oral administration of arginine enhances the growth hormone response to growth hormone releasing hormone in short children

We have evaluated the effect of oral administration of arginine chlorhydrate on the growth hormone response to growth hormone releasing hormone in a group of nine short prepubertal children (six boys and four girls). Arginine chlorhydrate 10 g, administered orally 60 min before an iv bolus injection of growth hormone releasing hormone 1–29, 1 μg/kg, significantly enhanced the growth hormone response to the neuropeptidc, confirming the results of previous studies which used the iv route. Furthermore, our data strengthen the view that the effects of arginine chlorhydrate on growth hormone secretion are mediated by inhibition of endogenous somatostatin release.     

Oral administration of arginine enhances the growth hormone response to growth hormone releasing hormone in short children

We have evaluated the effect of oral administration of arginine chlorhydrate on the growth hormone response to growth hormone releasing hormone in a group of nine short prepubertal children (six boys and four girls). Arginine chlorhydrate 10 g, administered orally 60 min before an iv bolus injection of growth hormone releasing hormone 1–29, 1 μg/kg, significantly enhanced the growth hormone response to the neuropeptidc, confirming the results of previous studies which used the iv route. Furthermore, our data strengthen the view that the effects of arginine chlorhydrate on growth hormone secretion are mediated by inhibition of endogenous somatostatin release.     

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)     

促性腺激素释放激素类似物联合重组人生长激素对中枢性性早熟女童身高的影响

目的 研究促性腺激素释放激素类似物（GnRHa）与重组人生长激素（rhGh）联合治疗以及GnRHa单用对骨龄≥10岁的特发性中枢性性早熟（ICPP）女童成年身高的改善情况。方法 将6个医学中心确诊为ICPP符合研究条件的80例女童（年龄9.0±0.7岁,骨龄≥10岁）根据治疗方法分为GnRHa与rhGh联合治疗组（31例）及GnRHa单用组（49例）。观察治疗前后的预测成年身高、接近成年身高和身高净获等各项指标的变化。结果 两组在治疗后按骨龄的身高标准差分值均较治疗前有显著改善（P<0.01）,其中GnRHa与rhGh联合治疗组明显优于GnRHa单用组（P<0.01）。联合用药组接近成年身高（157±6 cm vs 157±4 cm）、身高净获（4.68 cm vs 3.89 cm）、停药时预测成年身高（161±5 cm vs 158±5 cm）、接近成年身高与遗传靶身高差值等指标均略高于GnRHa单用组,但差异无统计学意义（均P >0.05）。结论 GnRHa与rhGh联合治疗或GnRHa单用组均能改善骨龄≥10岁ICCP女童的成年身高,但两药联用优势不明显。对ICPP患儿预测成年身高的评估需要慎重,停药时的预测值偏高。     

GnRHa激发试验对性早熟的诊断价值探讨

目的　探讨GnRH类似物 (GnRHa)曲普瑞林 (triptorelin)激发试验对于性早熟的诊断价值。方法　将因乳房发育提前而就诊的 95例女孩 (均于就诊时行 0、30和 6 0minGnRHa激发试验 )分为 3组 :真性性早熟(CPP)组 5 0例、单纯性乳房早发育 (PT)组 32例、外周性性早熟 (PPP)组 13例。以 33例健康的青春前期女孩作为对照。比较各组血清促卵泡激素 (FSH)、促黄体生成激素 (LH)激发值和基值、FSH和LH的最大反应 (ΔFSH和ΔLH)及峰值之比 (峰LH/FSH ,免疫化学发光法测定 )。绘制诊断CPP的受试者工作特性曲线 ,确定具有较高诊断灵敏度和特异度的峰LH和峰LH/FSH的截断值。结果　PPP、PT、CPP和对照组的FSH基值以及LH基值均有明显的重迭。PPP组 3个时相的血清FSH及LH浓度无差异。PT、CPP组 3个时相的血清FSH及LH浓度均有显著差异 (P =0 0 0 )。PT组ΔFSH (8 76± 3 74 )IU/L显著高于ΔLH(2 5 7± 1 5 6 )IU/L(P =0 0 0 )。CPP组ΔLH(2 3 2 3± 19 16 )IU/L显著高于ΔFSH(10 6 0± 4 79)IU/L(P =0 0 0 )。PT组和CPP组的ΔFSH无差异 ,CPP组ΔLH和峰LH/FSH(1 6 6± 1 2 6 )显著高于PT组 (0 2 8± 0 11) (P =0 0 0 )。以LH峰值≥5 0 5IU/L为前提 ,诊断CPP的灵敏度和特异度分别为 98 0 %和 90 6 %。结论　PPP组     

Predictive factors for the effect of gonadotrophin releasing hormone analogue therapy on the height of girls with idiopathic central precocious puberty

The factors influencing the final height of central precocious puberty patients treated with gonadotrophin releasing hormone (GnRH) analogues remain a critical issue. This study compares the predicted final height before and after GnRH analogue therapy to identify predictive factors for final height. Fourteen girls with idiopathic central precocious puberty were treated with a GnRH analogue. All had an active non-regressive form before therapy, full and permanent suppression of oestrogenic activity during therapy (duration >2 years, 3.1±0.3 years, mean ±SEM), and the pubertal pituitary-ovarian axis had normalized in all of them 1 year after the cessation of therapy. The mean predicted final height increased from 152±1.8 cm before therapy to 162.2±1.2 cm (P<0.01) at the last evaluation performed 4.5±0.3 years after the onset of therapy. The mean gain in predicted final height between the onset of therapy and the last evaluation was 10.2±1.1 cm. It was correlated with the following data recorded at the onset of therapy: bone age advance over chronological age (r=0.66,P<0.02), predicted final height at the onset of therapy (r=–0.76,P<0.001), and the difference between the target height and the predicted height at onset of therapy (r=0.76,P<0.001). We conclude that GnRH analogue therapy is more likely to improve final height prognosis in girls who initially present with a markedly advanced bone age and a great difference between their target and predicted heights. Both these parameters reflect the severity of the disease at diagnosis.This work was presented in part at the international symposium on GnRH analogues in cancer and human reproduction, Geneva, November 1990. Abstract, Gynecol Endocrinol 4 [Suppl 2]:101 (1990)     

促性腺激素释放激素激动剂治疗女童性早熟的不良反应探析

促性腺激素释放激素激动剂(gonadotropin releasing hormone agonist,GnRHa)是目前临床广泛应用的相对安全的性早熟治疗药物.患儿在停药后可以正常月经来潮、怀孕、生育.GnRHa不会降低青春期后的子宫体积,停药后的黄体生成素、卵泡刺激素及性激素水平可恢复至接近或超过停药前水平.研究提示促性腺激素释放激素拟似物可能会增加罹患雄激素过多症及多囊卵巢综合征的风险,但尚缺乏较高等级的证据.现有的研究不能提供充分证据表明GnRHa对骨矿物质密度有显著和不可逆的负面影响.GnRHa可能具有增加体质量指数(BMI)的不良反应,亦有研究表明GnRHa有助于降低BMI,或不会增加BMI.     

Growth hormone treatment in a child with Williams-Beuren syndrome: a case report

Growth retardation is a consistent finding in Williams-Beuren syndrome. The cause of short stature in this syndrome is unknown. Endocrine studies have failed to reveal abnormalities in the growth hormone – insulin-like growth factor I axis. We report a boy with confirmed Williams-Beuren syndrome, who was found to have classical growth hormone deficiency and responded well to growth hormone therapy. Conclusion Although growth hormone deficiency is not likely to be a common cause of short stature in Williams-Beuren syndrome, we nevertheless recommend evaluation of the growth hormone – insulin-like growth factor I axis in all cases. Received: 14 February 1998 / Accepted in revised form: 4 April 1998     

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.     

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.     

Growth in precocious puberty

Growth in precocious puberty is a subject of concern to families and clinicians alike. The definition of precocious puberty and the role of obesity in the age of onset have also been areas of debate since the Lawson Wilkins Society recommended a lowering of the age of onset of precocious puberty in US girls. An understanding of growth patterns in normal children with earlier or later onset of puberty and the variable rate of progression between individuals with central precocious puberty as well as the imprecision in available height prediction methods are important in assessing height outcomes in this condition. In the absence of randomised controlled trials in this area, only qualified conclusions about the effectiveness of interventions can be drawn. In general, it appears that height outcome is not compromised in untreated slowly progressive variants of central precocious puberty. In rapidly progressing central precocious puberty in girls, gonadotrophin releasing hormone agonists (GnRH agonists) appear to increase final height by about 5cm in girls treated before the age of eight, but there is no height benefit in those treated after eight years. Scanly data is available to assess treatment effects in boys. GnRH agonists appear to be relatively safe. The decision to treat central precocious puberty should take into account rate of progression of pubertal changes as well as biochemical markers and may need to address other factors (for example psychosocial and behavioural issues) as well as height outcome.     

Growth hormone treatment in Turner syndrome accelerates growth and skeletal maturation

Sixteen girls with Turner syndrome (TS) were treated for 4 years with biosynthetic growth hormone (GH). The dosage was 4IU/m² body surface s.c. per day over the first 3 years. In the 4th year the dosage was increased to 61 U/m² per day in the 6 girls with a poor height increment and in 1 girl oxandrolone was added. Ethinyl oestradiol was added after the age of 13. Mean (SD) growth velocities were 3.4 (0.9), 7.2 (1.7), 5.3 (1.3), 4.3 (2.0) and 3.6 (1.5) cm/year before and in the 1st, 2nd, 3rd and 4th year of treatment. Skeletal maturation advanced faster than usual in Turner patients especially in the youger children. Although the mean height prediction increased by 5.6 cm and 11 of the 16 girls have now exceeded their predicted height, the height of the 4 girls who stopped GH treatment exceeded the predicted adult height by only 0 to 3.4 cm.     

Growth hormone treatment of Turner syndrome patients with insufficient growth hormone response to pharmacological stimulation tests

Growth before and during treatment with biosynthetic human growth hormone (hGH) was studied in 13 patients with Turner syndrome (TS) and a growth hormone (GH) response of less than 10 g/l to two standard provocative tests. During 1 year of treatment with hGH (0.15 IU/kg per day) height velocity (mean±SD) increased significantly (P<0.001) from 3.7±1.8 cm/year to 7.6±1.5 cm/year. The auxological data in these girls before and during treatment with hGH were similar to those observed in TS patients with a normal response of GH to pharmacological stimuli. It is concluded that in girls with Turner syndrome GH testing should only be performed when height velocity is below the Turner norm. In TS patients with residual growth potential a clinically significant growth acceleration can be obtained with a higher-than-replacement dose of hGH, i.e. 0.15 IU/kg per day, regardless of GH testing.     

Growth hormone studies in lysinuric protein intolerance

Our two patients with lysinuric protein intolerance, a 14-year-old boy and his 12-year-old sister, showed growth retardation and their bone ages were retarded. Growth hormone secretion responded to glucagon-propranolol and showed a good response to arginine. However, growth hormone showed little response to insulin. After the oral administration of arginine hydrochloride, growth hormone showed a good response to insulin and glucagon-propranolol, and gain in height and weight accelerated. This result may suggest that an adequate supply of arginine is effective in improving the growth retardation in lysinuric protein intolerance.     

Circulating somatomedin-C levels and the effect of growth hormone-releasing factor on plasma levels of growth hormone and somatostatin-like immunoreactivity in obese children

The effect of growth hormone-releasing factor (GRF) 1-44 on growth hormone and somatostatin release in plasma has been studied in 20 obese children. Twenty age and sex-matched children with normal weight served as controls. Mean peak growth hormone response in obese children after 1 g/kg body wt. GRF 1-44 was significantly lower than in controls (23.7±3.6 ng/ml vs. 41.1±3.0 ng/ml;P<0.01), as were mean integrated growth hormone response areas (1544±272 ng×ml^-1×2 h vs. 2476±283 ng×ml^-1×2 h;P<0.01). Mean plasma levels of somatostatin-like immunoreactivity did not change after GRF in both goups. Mean somatomedin-C levels in obese children were significantly higher compared to controls (1.6±0.4 U/ml vs. 0.86±0.4 U/ml;P<0.01). Somatomedin-C levels were not related to the integrated growth hormone responses. In conclusion there is no relation between somatomedin-C levels and the reduced growth hormone-releasing effect of GRF in obese children. GRF does not alter peripheral somatostatin-like immunoreactivity levels either in normal or obese children.Abbreviations Sm-C somatomedin C - GRF growth hormone-releasing factor - GH growth hormone - SLI somatostatin-like immunoreactivity     

The effect of gonadotrophin releasing hormone analogue on height prognosis in growth hormone deficiency and normal puberty

We have treated seven pubertal children, five (three female, two male) with growth hormone deficiency and two (one female, one male) with constitutional short stature with intranasal (D-Serine⁶) gonadotrophin releasing hormone (GnRH) analogue (Buserelin) for a mean of 0.84 years (range, 0.5–1.3). Treatment was successful in arresting pubertal development but there was no improvement in final height prognosis.Abbreviations GnRH gonadotrophin releasing hormone - GH growth hormone