Psychosomal dwarfism with reversible growth hormone deficiency (author's transl)]

The diagnosis of psychosocial dwarfism in a 9 year-old boy with severe growth retardation (-6 1/2 standard deviations) was deduced from the typical history. The bone age was severely retarded and in the first days after admission a deficiency of growth hormone and other pituitary hormones was established. The change in environment per se led to a spontaneous reversal of the growth hormone deficiency within a short time. A rapid catch up growth was observed over the subsequent 2 1/2 years, as well as a normalisation of the psychological retardation.     

Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism

In addition to its classical effects on growth, growth hormone (GH) has been shown to have a number of other actions, all of which are initiated by an interaction with specific high affinity receptors present in a variety of tissues. Purification of a rabbit liver protein via its ability to bind GH has allowed the isolation of a cDNA encoding a putative human growth hormone receptor that belongs to a new class of transmembrane receptors. We have previously shown that this putative growth hormone receptor gene is genetically linked to Laron dwarfism, a rare autosomal recessive syndrome caused by target resistance to GH. Nevertheless, the inability to express the corresponding full-length coding sequence and the lack of a test for growth-promoting function have hampered a direct confirmation of its role in growth. We have now identified three nonsense mutations within this growth hormone receptor gene, lying at positions corresponding to the amino terminal extremity and causing a truncation of the molecule, thereby deleting a large portion of both the GH binding domain and the full transmembrane and intracellular domains. Three independent patients with Laron dwarfism born of consanguineous parents were homozygous for these defects. Two defects were identical and consisted of a CG to TG transition. Not only do these results confirm the growth-promoting activity of this receptor but they also suggest that CpG doublets may represent hot spots for mutations in the growth hormone receptor gene that are responsible for hereditary dwarfism.     

Cross-reactivity of monomeric and dimeric biosynthetic human growth hormone in commercial immunoassays

Commercial kits give different measurements for concentrations of growth hormone (GH, somatotropin) in serum. Most notably, a two-site monoclonal-antibody-based immunoradiometric assay (IRMA) from Hybritech routinely yields lower values than do conventional RIAs in which polyclonal antibodies are used. We used purified dimeric biosynthetic human GH as a model compound to investigate the specificity of five commercial immunoassays for size variants of GH. In all five assays, biosynthetic monomeric GH was significantly more potent than pituitary-derived standard GH supplied with the kits. Dimeric GH was significantly less potent than monomer in four of the five assays, and cross-reactivities varied more than fivefold, from 15% to 84%. Using three commercial kits selected for their specificity for dimeric GH, we measured GH in serum samples from 18 normal adults. The mean GH concentrations in serum--0.7 (Hybritech, IRMA), 1.8 (Diagnostic Products, RIA), and 3.1 (Cambridge, RIA) micrograms/L--differed significantly, but in the same rank order as that obtained in the experiments on dimer cross-reactivity.     

生长激素激发试验在矮小症儿童诊断中的价值及可能影响因素

目的探讨生长激素(GH)激发试验对矮小症儿童的诊断价值及可能影响因素。方法对642例矮小症儿童进行精氨酸和左旋多巴联合GH激发试验,测定激发后30、60、90、120、150、180min GH水平。将患儿分为GH缺乏症(GHD)组(GH峰值小于10ng/mL)和非GHD组(GH峰值大于或等于10ng/mL),比较两组患儿体格及实验室检测指标。结果共检出GHD患儿441例(68.69%),非GHD患儿201例(31.31%),两组患儿所占比例比较差异有统计学意义(χ~2=6.19,P0.05)。GH峰值出现时间以30、150min相对较多,分别占22.42%和34.27%,峰值有延后现象。GHD组与非GHD组患儿年龄、身高标准差、体质量指数、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、胰岛素样生长因子1和25-羟维生素D水平比较差异有统计学意义(P0.05)。结论精氨酸和左旋多巴联合激发试验可作为矮小症儿童GH缺乏的诊断试验;GH水平与多种体格和实验室检测指标有关,诊断GHD需综合考虑相关影响因素。     

Lack of hormone binding in COS-7 cells expressing a mutated growth hormone receptor found in Laron dwarfism.

A single point mutation in the growth hormone (GH) receptor gene generating a Phe-->Ser substitution in the extracellular binding domain of the receptor has been identified in one family with Laron type dwarfism. The mutation was introduced by site-directed mutagenesis into cDNAs encoding the full-length rabbit GH receptor and the extracellular domain or binding protein (BP) of the human and rabbit GH receptor, and also in cDNAs encoding the full length and the extracellular domain of the related rabbit prolactin (PRL) receptor. All constructs were transiently expressed in COS-7 cells. Both wild type and mutant full-length rabbit GH and PRL receptors, as well as GH and prolactin BPs (wild type and mutant), were detected by Western blot in cell membranes and concentrated culture media, respectively. Immunofluorescence studies showed that wild type and mutant full-length GH receptors had the same cell surface and intracellular distribution and were expressed with comparable intensities. In contrast, all mutant forms (full-length receptors or BPs), completely lost their modify the synthesis ligand. These results clearly demonstrate that this point mutation (patients with Laron syndrome) does not modify the synthesis or the intracellular pathway of receptor proteins, but rather abolishes ability of the receptor or BP to bind GH and is thus responsible for the extreme GH resistance in these patients.     

Immunologic hormone detection in hypophyseal adenomas: correlation of serum hormone findings with immunocytochemical hormone levels in tumor tissue

Forty-four out of 82 patients with neurosurgically removed pituitary adenomas showed preoperatively elevated plasma hormone levels of prolactin (PRL; 22 patients), of human growth hormone (hGH; 15 patients), and of adrenocorticotropic hormone (ACTH; 7 patients). Immunocytochemical detection of the hypersecreted hormone in paraffin sections of tumour tissue, was possible in all 7 patients (100%) with Cushing's disease, in 20 patients (90%) with hyperprolactinaemia, and in 10 patients (66%) with acromegaly. In a further 3 cases beta-TSH, in one case beta-LH, and in 8 cases alpha-HCG were demonstrated in sections of tumour tissue. No clinical evidence of endocrine disturbance was found in any of these latter cases. More than one anterior pituitary hormone was detected in sections of tumour tissue in 7 cases. An overall qualitative correlation of 85% was found between the elevated plasma hormone level and immunocytochemical hormone detection in tumour tissue sections. Since there is no correlation between conventional histological staining modalities (acidophilic, basophilic, chromophobic) on the one hand, and the level of plasma hormones or immunological hormone detection in tumour tissue on the other hand, modern histological diagnosis of a pituitary adenoma should include assessment of the functional state as found by immunocytochemical hormone determination.     

生长激素缺乏性侏儒症基因治疗前瞻性研究:重组人生长激素非病毒载体基因治疗体内实验安全性观察

目的:研究携带重组人生长激素(hGH)基因非病毒载体pNMG3骨骼肌注射方法的急性期安全性。方法:实验于2001/2002在哈尔滨医科大学神经外科研究所和哈尔滨兽医研究所生物技术国家重点实验室进行。用纯化裸露质粒pNMG3向幼鼠胫前肌不同剂量单次注射,两周内不同时间RT-PCR检测转录,RI-A检测血清hGH蛋白表达,局部注射部位组织病检,测定血清中谷草转氨酶(GOT)和肌酐检测肝功、肾功。结果:30～480μgpNMG3剂量组肌肉注射两周后RT-PCR,RIA检测结果阳性;7.5～480.0μg剂量组两周后少数见脾组织细胞轻度至中度增多;各组GOT、肌酐无明显变化。120μg剂量组病理检查4h可见肌注部位明显白细胞浸润、脾组织细胞增生,3d时心肌炎性细胞浸润,以上变化随时间延长而减轻,两周后仅少数见脾组织细胞轻度至中度增多。结论:7.5～480.0μg剂量组肌肉注射是安全的;超急性期纯化裸露质粒肌肉注射局部肌肉、心肌、脾受累明显,但是可逆的。     

Enhancement of human granulopoiesis in vitro by biosynthetic insulin-like growth factor I/somatomedin C and human growth hormone.

The effect of biosynthetic recombinant insulin-like growth factor I/somatomedin C (IGF-I/Sm-C) and human growth hormone (hGH) on the in vitro growth and maturation of human marrow myeloid progenitors was investigated. Myeloid colony formation was maximally enhanced by 60 ng/ml IGF-I/Sm-C and by 250 ng/ml hGH, resulting in an increase in colony numbers of 41 +/- 7 and 38 +/- 4%, respectively (P less than 0.001). Both peptides induced a 1.5-2.5-fold increase in the frequency of colonies composed of granulocytes alone, but did not alter the numbers of monocyte/macrophage or mixed granulocyte/macrophage colonies. IGF-I/Sm-C and hGH were also found to enhance myeloid maturation towards mature granulocytes in suspension cultures of human marrow cells. The effect of both peptides on human marrow granulopoiesis was similarly demonstrable in serum-free cultures stimulated with human recombinant granulocyte/macrophage colony-stimulating factor. Enhancement of human marrow granulopoiesis in vitro by hGH required the presence of marrow adherent cells and was abrogated by specific monoclonal antibodies directed against IGF-I/Sm-C receptors. The effect of hGH on marrow myeloid progenitors thus appears to be mediated by paracrine IGF-I/Sm-C.     

Treatment with growth hormone-releasing hormone (GHRH) 1–44 in children with idiopathic growth hormone deficiency: a randomized double-blind dose-effect study

One hundred and eleven pre-pubertal children (70 boys, 41 girls, aged 2.5 to 14.3 years) with growth failure (height 2 SD below the mean for chronological age (CA) and height velocity (HV) below the 10th percentile for bone age) due to idiopathic growth hormone deficiency (peak plasma GH < 20 mUI/1 to two standard provocative tests) were treated with GHRH 1-44 NH2. Patient stratification in two classes was performed according to body weight; in each class, patients were randomly allocated to one of seven GHRH doses, from 30 to 300 micrograms/day. GHRH was injected subcutaneously, every evening, for six months in a double-blind fashion. No relationship was found between the absolute or incremental HV during treatment and the dose (range from 1.3-23.1 micrograms/kg/day) of GHRH. However, HV (cm/year) increased from 3.8 +/- 0.1 (mean +/- SEM) before treatment to 6 +/- 0.2 during six months treatment and 47 patients (42%) increased their HV up to at least the mean normal HV for bone age (catch-up growth). Low titer antibodies to GHRH were found in 19 patients (17.1%) at six months; no adverse effect was observed. Our results suggest that patients showing catch-up growth were older, had a height closer to the mean for chronological age and a slower pre-treatment height velocity. Failure to demonstrate a relationship between GHRH dose and changes in growth velocity might be explained by the combination of a placebo effect, insufficient frequency of GHRH administration and heterogeneity of the population.     

重组人生长激素治疗儿童生长激素缺乏症的临床价值

目的探讨应用重组人生长激素 (γ-h GH)治疗儿童生长激素缺乏症 (GHD)的临床疗效、安全性及其临床价值。方法分别选择GHD儿童 66例 ,正常对照组儿童 3 5例。 GHD组给予γ-h GH 0 .1U/(kg· d) ,疗程 3个月。观察用药后生长速率、血清胰岛素样生长因子 -1(IGF-1)、血清胰岛素样生长因子结合蛋白 3 (IGFBP-3 )等指标的变化。结果治疗后 3个月时 GHD组生长速率由 (2 .8± 0 .7)cm/a增至 (13 .6± 3 .5 ) cm/a(P<0 .0 1) ;该药对患儿无明显副作用。 GHD组血清 IGF-1、IGFBP-3及骨转换指标均明显低于正常对照组 (P<0 .0 1) ,治疗后血清生长因子及骨转换生化指标均有明显提高 ,与治疗前比较有显著性差异 (P<0 .0 1)。结论 1γ-h GH治疗GHD近期疗效显著 ,且安全可靠 ;2检测血清 IGF -1和 IGFBP-3将有助于儿童 GHD的正确诊断 ;3血清骨转换生化指标对早期预测r-h GH疗效具有明显优势     

The effects of growth hormone therapy on heart rate variability in adults with growth hormone deficiency

Background: Growth hormone (GH) deficiency is associated with increased cardiovascular morbidity and mortality. Abnormalities in heart rate variability (HRV) (such as decreased cardiac sympathetic activity), which is a marker of cardiac autonomic tone, have been found in patients with GH deficiency.Objective: The purpose of this study was to investigate the effects of GH therapy on HRV in adults with GH deficiency.Methods: Adult patients with GH deficiency were eligible. HRV measurements were obtained by 24-hour measurements from Holter electrocardiography before and after 6 months of GH therapy in adult patients with GH deficiency. The following time domain parameters of HRV were calculated: the SD of the normal-to-normal (NN) interval (SDNN), the SD of the average NN interval (SDANN), the square root of the mean squared differences (RMSSD), and the proportion derived by dividing the number of interval differences of successive NN intervals >50 ms (NN50) by the total number of NN intervals (PNN50).Results: A total of 21 patients (7 men, 14 women; mean age, 46.0 ± 11.2 years) were enrolled. Thirteen patients had panhypopituitarism and 8 had normal adrenocorticotropic hormone secretion. At the end of 6 months of GH therapy, the mean values of the sympathetically influenced parameters SDNN (before GH treatment, 134.5 ± 6.0 ms; after GH treatment, 118.5 ± 8.0 ms) and SDANN (before GH treatment, 121.2 ± 6.0 ms; after GH treatment, 96.2 ± 9.1 ms) decreased significantly (P < 0.05), but the parasympathetically influenced parameters RMSSD and PNN50 did not differ significantly from baseline. The mean heart rate and ventricular premature beats were not significantly different from baseline after GH therapy.Conclusions: In this patient population, cardiac sympathetic tone was increased, without an obvious arrhythmogenic effect, after 6 months of GH therapy.     

Enhancement of epidermal regeneration by biosynthetic epidermal growth factor

Epidermal regeneration depends on mitosis and migration of keratinocytes. Epidermal growth factor is known to stimulate growth of keratinocytes in vitro, thus it might be expected to promote wound healing. The results of this study show that topical application of biosynthetic human epidermal growth factor accelerates epidermal regeneration in split-thickness wounds and partial-thickness burns. The significant enhancement of epidermal regeneration suggests the potential for clinical use of epidermal growth factor for accelerating healing of burns, wounds from trauma, diabetic ulcers, skin graft donor sites, and others.