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.     

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     

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     

Rapid decrease of urinary pyridinoline excretion in growth hormone deficient children following discontinuation of growth hormone therapy

In order to examine the effect of growth hormone on urinary pyridinoline excretion, 32 patients with complete or partial growth hormone deficiency had their urinary pyridinoline excretion measured while receiving growth hormone and for 14 days after it was discontinued. There was a significant positive correlation between increases in growth velocities during the first year of growth hormone administration compared to before it, and the ratio of the urinary pyridinoline excretion levels while receiving growth hormone to those after discontinuation. Therefore, urinary pyridinoline excretion rapidly decreased in patients with growth hormone deficiency when the administration of growth hormone was stopped. Exogenous growth hormone appears to stimulate bone resorption in these patients.     

Changes with growth hormone treatment in growth hormone deficient children

A total of 54 previously untreated patients (15 girls, 39 boys) with poor growth due to idiopathic growth hormone deficiency (IGHD) were treated with human growth hormone (hGH), continuously up to 4 years. All of the patients had a peak hGH level which was below 10 ng/mL after at least two pharmacological tests and/or blunted physiologic hGH secretion, and their height was below ?2.5 s.d. for age and gender. After the 1st year of therapy, height velocity (HV) increased significantly when compared with baseline (from 3.18 ±0.76 cm/year to 9.17±1.03 cm/year; P <0.001), declined during the 2nd year and then remained significantly higher than pretreatment HV. When considering improvement in height expressed by height standard deviation score (SDS), during the therapy all of the patients showed a significant gain ± 1.72±1.09 (from ?4.11±0.61 to ?2.21±0.48). The height values were significantly higher than pretreatment, but remained below ?2 s.d. after 4 years of hGH therapy in our patients. Increased height velocity has been sustained, but height improvement after therapy was inversely correlated to height SDS for chronological age of patients at the start of therapy. In conclusion post-treatment height has been shown to be related to height deficit at the beginning of therapy. Therapy was well tolerated with no local or systemic adverse effects or acceleration of bone age.     

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.     

Effect of human chorionic gonadotropin on growth velocity and biological growth parameters in adolescents with thalassaemia major

The effect of long-term human chorionic gonadotropin (HCG) therapy on the linear growth and biological growth parameters was studied in six thalassaemic boys aged 14.5–15.5 years old with hypogonadotropic hypogonadism. A significant (P<0.001) increase in growth velocity (from 3.3±0.3 to 7.6±0.6 cm/year) was found after 6–12 months of therapy, without acceleration of bone age. A striking improvement in pubertal development was observed. The treatment significantly increased growth hormone (GH) response to l-dopa administration (P<0.025) as well as sleep GH secretion (P<0.025). Serum growth factors, evaluated as thymidine activity during deep sleep, increased (P<0.001), but somatomedin C (Sm-C) levels did not. Prior to treatment, baseline and peak values of plasma growth hormone releasing hormone (GH-RH) following l-dopa were low. After HCG therapy, GH-RH response to l-dopa increased significantly (from 9.2±5.6 to 20.2±6.2 pg/ml; P<0.05), but remained (P<0.001) lower than in normal prepubertal children. This study suggests that in thalassaemia major an impaired GH-RH release can be observed, in addition to the described alteration in Sm-C generation.Abbreviations LH luteinising hormone - FSH follicle stimulating hormone - HCG human chorionic gonadotropin - GH growth hormone - GH-RH growth hormone releasing hormone - GnRH gonadotropin releasing hormone - TA thymidine activity - Sm-C somatomedin C     

重组人生长激素治疗生长激素缺乏症疗效观察

目的 观察基因重组人生长激素(rhGH)对生长激素缺乏症(GHD)患儿的疗效。方法 对15例GHD患儿应用rhGH治疗,每晚睡前皮下注射0.1 IU/kg,疗程6个月。结果 患儿身高由治疗前109.3±9.9cm增加到115.5±11.3 cm;年身高生长速度由治疗前2.8±0.6cm/年增加到11.6±3.5cm/年。治疗期间除少数患儿出现亚临床甲状腺功能低下,注射部位有轻度反应外,未发现明显副作用。结论 皮下注射rhGH是治疗儿童GHD的一种安全有效的方法。     

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。     

Rapid effect of intravenous growth hormone (GH)-releasing hormone 1–44 on plasma GH levels in children

Growth hormone releasing hormone (GHRH)-testing was performed in 24 short normal children (16 male, 8 female). Before and after administration of GHRH_1–44 (1g/kg body weight i.v.) blood samples for growth hormone (GH) determination were drawn at-30, 0, 1, 2, 3, 4, 6, 8, 10, 15, 30, 45, 60, and 90 min. Plasma GH increase was apparent 1 min after injection and in 12 patients (7 female) peak plasma GH values were reached within 15 min. In all patients plasma GH levels were greater than 10 ng/ml within the first 8 min following GHRH injection, but in 4 patients this level was not attained when considering only GH values obtained after 15 min. These results demonstrate the capability of the pituitary to rapidly secerete GH in response to GHRH_1–44 in children. Therefore, in this age group blood samples for GH determination should be taken earlier when testing with GHRH_1–44.Abbreviations GHRH growth hormone releasing hormone - GH growth hormone - SD standard deviation     

Insulin-resistant diabetes during growth hormone therapy in a child with SHORT syndrome

We report the case of a 13-year-old boy with SHORT syndrome, including lipoatrophy and insulin resistance, who developed diabetes mellitus while receiving growth hormone therapy. The diabetes persisted after cessation of exogenous growth hormone but oral hypoglycaemic therapy was successful and could be discontinued eight months later.     

Screening for growth hormone deficiency using urinary growth hormone measurement

The diagnostic approach in growth hormone deficiency (GHD) is complicated. Two or more provocative tests are essential for definitive diagnosis of GHD. However, such testing cannot be carried out routinely on all subjects with short stature because of the need for hospitalization and blood sampling. A simple screening method for GHD would be of great value. Human growth hormone (hGH) levels were measured in the early morning urine of 192 children aged 7–15 years with height 2.0 s.d. below the mean for their ages. Sixty-eight subjects were selected because they showed a urinary hGH level < 10 ng/g creatinine. They were further examined in terms of bone age and plasma insulin-like growth factor (IGF-I) levels. In 30 subjects, the ratio of bone age: chronological age was < 0.8 and/or plasma IGF-I level was < 0.7 U/mL. Finally 24 of these subjects were examined with provocative tests and other endocrinological tests. Eleven subjects proved to have poor growth hormone secretion and one subject was diagnosed as having Turner syndrome. In conclusion, 11 patients with GHD were diagnosed from 192 children with short stature using urinary hGH measurement as the first screening method. These findings suggests that urinary hGH measurement could be a useful and simple method for detecting GHD.     

Depressive tendency in children with growth hormone deficiency

Aim:   This study assessed changes in depressive tendency of children with growth hormone deficiency.
Methods:   The 41 children with growth hormone deficiency were assessed using the Depression Self-Rating Scale for Children. A score of 16 or more indicated a depressive tendency. The first assessment was carried out before growth hormone treatment, and the second one was carried out at 6 months or longer after the beginning of growth hormone treatment.
Results:   The Depression Self-Rating Scale for Children improved significantly from 9.7 ± 6.1 points before treatment to 6.9 ± 4.6 points after treatment ( P = 0.0013). A depressive tendency was observed in six patients (15%) before growth hormone treatment, and in two patients (5%) after treatment. No significant relationship was observed between the decrease in the score and the length of the treatment. A significant improvement was observed for 6 of the 18 items in the Depression Self-Rating Scale for Children.
Conclusion:   A depressive tendency was relatively common in children with growth hormone deficiency, and the Depression Self-Rating Scale for Children was decreased after growth hormone treatment. These results suggest that growth hormone treatment may have positive effects on the psychosocial aspects in children with growth hormone deficiency.     

A case of familial thyroxine binding globulin excess associated with growth hormone deficiency

A 7 years 3 months old Japanese boy with familial thyroxine binding globulin (TBG) excess associated with growth hormone (GH) deficiency is reported. The patients height was 106.4 cm (- 2.86 s.d.) and his bone age was 5 years and 3 months. He had no goiter and his developmental milestones were normal. The serum thyroid stimulating hormone (TSH) was 2.8 μU/mL, triiodothyronine (T₃) 3.1 ng/mL, thyroxine (T₄) 23.4 μg/dL and free T₄ 1.8 ng/dL. The serum TBG level was beyond 80.0 μg/mL, with normal TSH response to the thyrotropin-releasing hormone (TRH) test. Familial study revealed that his grandmother, mother, uncle, younger sister and younger brother had high TBG and T₃ levels, thus an X-linked co-dominant transmission was suggested. The peak GH responses to insulin and clonidine hydrochloride were 5.8 and 8.2 ng/mL, respectively. The mean nocturnal GH concentration was 2.5 ng/mL. His growth velocity increased from 4.8 to 8.4 cm/year and his serum TBG levels decreased gradually after human growth hormone (hGH) treatment.     

Recombinant human growth hormone treatment in children with thalassemia major

BACKGROUND: To evaluate the growth hormone reserve and the growth hormone response to recombinant human growth hormone (GH) in prepubertal thalassemic children with growth retardation. METHODS: Twenty thalassemic patients with short stature and delayed bone age were studied. Patients were randomized into GH-treated (n = 10) and non-GH treated (control; n = 10) groups. The GH-treated group received recombinant human (rh)-GH (Genotropin) at the dose of 0.7 IU/kg per week for 12 months. RESULTS: There was a significant discordance between GH response to pharmacologic stimuli and physiological secretion of GH/GHRH testing. Following the administration of rhGH, growth velocity increased from 2.47 +/- 0.48 cm/year to 6.27 +/- 0.76 cm/year (P = 0.005), whereas there was not a similar change in the non-GH-treated group. The height velocities of the two groups during the 1 year follow-up period were significantly different (6.27 +/- 0.76 vs 3.99 +/- 0.34 cm/year; P = 0.025). There were significant differences between the height velocity improvements and height velocity standard deviation scores of the two groups as well. CONCLUSION: The present study has demonstrated that rhGH is a safe and efficacious mode of treatment in thalassemic children.     

Occurrence of acute megakaryoblastic leukemia in a patient with idiopathic growth hormone deficiency

We describe a case of a 15 year old boy who developed acute megakaryoblastic leukemia (AMKL) while receiving treatment with human growth hormone (hGH) for idiopathic growth hormone deficiency (GHD). He was diagnosed as having idiopathic GHD and given hGH from December 1991. The examination of his peripheral blood showed mild pancytopenia 2 months before the start of the hGH therapy. Since January 1992, paleness of the skin, general fatigue and fervescence progressed gradually. In February 1992, because of the occurrence of acute leukemia, administration of hGH was discontinued. Judging from the results of surface marker analysis of the blast cells, the patient was diagnosed as having AMKL. He was treated with chemotherapy for acute non-lymphoblastic leukemia from March 1992. A complete remission was obtained after 4 weeks of treatment. The chemotherapy was completed in July 1993. He remains in complete remission 26 months after diagnosis. This case suggests the importance of hematological examination and, when there is any abnormality which is not caused by GHD, such as pancytopenia, more detailed medical examinations (for example bone marrow examination) are necessary.     

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)     

Follow-up of antibodies to growth hormone in 210 growth hormone-deficient children treated with different commercial preparations

The aim of the study was to evaluate the immunogenicity of different commercial recombinant-growth hormone preparations. The presence of antibodies to growth hormone was tested in 210 growth hormone-deficient children at 6-month intervals during treatment for 6-66 months. The patients were treated with three preparations (groups A, B and C of 70 cases each) having the authentic growth hormone sequence. Groups A and B received hormone synthesized by the recombinant DNA technique in E. coli, while the group C preparation was produced in a mammalian cell line. The preparations showed poor immunogenicity and antibodies were found as follows: 1.4% in patients of group A (1 case: binding capacity 0.2mg/l and Ka 3.5 10⁷ 1 M^-1), 2.8% in patients of group B (2 cases; case 1 binding capacity 0.7mg/l and Ka 1.5 10⁷1M^-1; case 2 binding capacity 0.04mg/1 and Ka of 1.8 10⁸ and 6.5 10⁶ 1 M^-1), and 8.5% in group C (6 cases; binding capacity from 0.4 to less than 0.02 mg/ 1, Ka from 1.6 10⁷ to 3.8 10⁸ 1 M^-1). Only two patients of group C presented the antibodies in two subsequent examinations; in the other patients the positivity was found once. In all patients positive samples were found at intervals of 6-24 months after the start of therapy. In all antibody-positive patients growth velocity presented no decrease at the time of antibody detection and was never different to that of negative patients. We conclude that the three commercial preparations examined showed poor immunogenicity without clinical relevance.     

Growth hormone secretion in children and adolescents with familial tall stature

Sixty-five patients (22 boys and 43 girls) presenting with familial tall stature were investigated with regard to growth hormone (GH) secretion, both physiological and after stimulation with thyrotropin releasing hormone (TRH) and growth hormone relasing hormone (GHRH). Plasma insulin-like growth factor-I (IGF-I) was also measured. Two groups of patients were distinguished according to their physiological secretion of GH: a high secretory group (n=49) with a mean 24 h integrated concentration of GH (IC-GH) of 5.4±2.3 g/l per minute and a large number of peaks (5.1±1.6 in 24 h), and a low secretory group (n=16) with a mean 24 h IC-GH of 2.1±0.5 g/l per minute and few peaks (3.3±1.3 in 24h). Plasma IGF-I levels and GH peak values after the TRH test were significantly higher in the high secretory group. These results indicate that familial tall stature is the consequence either of hypersecretion of GH or of hypersensivity to this hormone (IGF-I levels being normal in spite of low GH levels).     

Growth-stimulating effects of human growth hormone therapy in patients with Turner syndrome

We determined the effect of pituitary human growth hormone treatment on the growth rate of 52 children with Turner syndrome. The pretreatment growth rate was 3.2 +/- 0.8 cm/yr. Growth hormone treatment (0.2 IU/kg three times per week) resulted in enhancement of the growth rate to 5.9 +/- 1.4 cm/yr for the first year of therapy. The bone age advanced approximately 1 year during the year of therapy. The growth hormone therapy was discontinued at 12 months, and the mean growth rate decreased to pretreatment levels, 3.1 +/- 1.9 cm/yr; 26 of 41 patients actually had post-treatment growth rates that were less than the pretreatment rate. Glucose tolerance tests at 6-month intervals did not indicate an effect of hGH treatment on glucose intolerance. Several patients had glucose intolerance that preceded hGH treatment, but this remained stable during treatment; glucose intolerance likely was related to obesity in this group of patients. Basal and hGH-stimulated somatomedin C levels (32 patients) correlated with age of the patient but not with growth rate during therapy. We conclude that hGH therapy can accelerate the growth rate of patients with Turner syndrome. The growth rate increased to "normal" levels and was dependent on continued treatment with hGH. If the response continues, long-term treatment of Turner syndrome may result in increased adult height.