Growth and growth hormone in children after bone marrow transplantation

Growth and growth hormone (GH) were investigated every year in 24 children after allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA) or leukemia. Conditioning included total body irradiation (TBI) in all cases of leukemia. The young leukemic children grew poorly. At 4 years after BMT, the mean standard deviation score for attained height had decreased from 0 to -1.73. GH deficiency was diagnosed with provocation tests. Three years after BMT, 10/18 children had a subnormal response. Ten children were further investigated with 24-hour GH profiles. Children with SAA had normal growth and GH levels. TBI seemed to be the major factor responsible for impaired growth.     

Growth hormone concentration following various factors stimulating its release]

Growth hormone concentration has been assayed in 105 children (45 girls and 60 boys) during starvation and following its stimulation with clonidine and insulin and during the sleep. A significant difference between growth hormone concentration during fasting and after stimulation has been noted. No statistically significant difference between growth hormone concentrations during the sleep and following insulin has been found. The most intensive growth hormone release has been observed during the sleep. Test with clonidine is technically simple and may be performed also in the out-patient clinics.     

Changes in the levels of growth hormones, insulin, cortisol, thyroxine and somatomedin-C/IGF-1, with increasing gestational age in the fetal pig, and the effect of thyroidectomy in utero

1. Blood samples were taken from 30 chronically catheterized pig fetuses in utero. Levels of growth hormone, insulin, cortisol, thyroxine and somatomedin-C/IGF-1 were measured in the plasma of intact fetuses and the plasma of thyroidectomized fetuses at various gestational ages during the latter part of pregnancy. 2. Growth hormone levels were high (mean +/- SEM: 83 +/- 9 ng/ml and remained constant throughout this period. 3. Insulin levels were also constant and ranged between 4 and 14 mU/l. 4. Cortisol levels showed a general increase from 400 nmol/l at 97 days to 1200 nmol/l at term and this increase was not affected by thyroidectomy. 5. IGF-1 levels were lower than in the sows (48.0 +/- 3.0 ng/ml) and did not change throughout this period. 6. Thyroxine levels were also unchanged at about 92 +/- 4 nmol/l. 7. Thyroidectomy resulted in lower (P less than 0.001) thyroxine levels (28 +/- 3 nmol/l) but had no effect on the levels of any other hormone.     

Effects of human growth hormone on immune functions: in vitro studies on cells of normal and growth hormone-deficient children

We have studied the in vitro effects of human growth hormone on cell surface markers and mitogenic responses of peripheral blood lymphocytes (PBL) of normal and growth hormone-deficient children before, during and after treatment with growth hormone. Growth hormone resulted in a decrease in B cell expression but it did not affect expression of T cell subsets. Growth hormone depressed the proliferation of PBL of normal and untreated growth hormone-deficient children. The proliferative responses to phytohemagglutinin (PHA) versus PHA with growth hormone were not statistically different, though the responses of most normal and on treatment children were diminished by the addition of growth hormone. PBL derived from growth hormone-deficient children during treatment with human growth hormone exhibited significantly greater spontaneous proliferation then the PBL of normal children. Growth hormone further significantly enhanced their proliferation. PHA and PHA with growth hormone resulted in significantly greater proliferation of these patients' PBL when compared to those of normal children. We demonstrated that human growth hormone had substantial in vitro effects on immune functions. These effects, some of which depend on the treatment status of the children, may need to be considered in the clinical use of human growth hormone.     

血清生长激素水平与儿童单纯性肥胖伴身高略矮的关系

目的:探讨血清生长激素(growth hormone,GH)水平与儿童单纯性肥胖伴身高略矮的关系。方法:选择2013年1月~2013年11月27例在我院儿童保健科门诊就诊的被诊断为单纯性肥胖症的儿童,且其身高均小于同龄儿童平均身高5 cm以上,采用放射免疫法检测其血清生长激素水平,分析其生长激素水平的变化及其意义。结果:27例患儿化验结果显示生长激素完全缺乏者22例,部分缺乏5例。结论:生长激素缺乏可能是肥胖伴身高略矮儿童患肥胖症的重要原因,测定血清生长激素水平有助于了解肥胖伴身高略矮儿童体内生长激素水平从而应用于肥胖症的病因治疗。     

重组人生长激素治疗生长激素缺乏症的疗效观察

目的：正确评价重组人生长激素（rhGH）治疗儿童生长激素缺乏症（GHD）的疗效。方法：GHD患儿47例,给予rhGH0．1U／（kg．d）,疗程3个月,并对其疗效进行观察。结果：身高（height）由（122±17．67）cm增至（125．32±17．50）cm,生长速率（growthrate）由〈4cm／年增加到（10．40±3．74）cm／年。血清碱性磷酸酶（AKP）由（207±48．11）IU／L增至（261±45．29）IU／L。I型前胶原羧基端伸展肽（PICP）由（97．80±14．94）ng／ml增至（119．50±24．10）ng／ml值。肌酐（Cr）由（40．20±8．28）umol／L变为（36．50±8．33）umol／L值。结论：rhGH是治疗GHD有效的药物。     

Comparison of spontaneous growth hormone secretion during daytime and sleep in children with short stature

The authors compared diurnal growth hormone (GH) secretion with GH secretion during sleep in 24 children with delayed growth. In group I (children with normal response to provocative tests), the level of daytime secretion was lower than that of nocturnal secretion. In 3 of 9 cases, daytime secretion was abnormal, whereas nocturnal secretion was normal. In 2 cases, both diurnal and nocturnal secretion were abnormal, but response to provocative stimuli was normal. In group II (children with a false partial GH deficiency, i.e. with inadequate response to provocative tests, GH peak less than 11 ng/ml and normal nocturnal secretion), the results were comparable with those of group I, with extremely low diurnal secretion in 6 of 9 cases. In group III (children presenting true partial GH deficiency, i.e. GH less than 11 ng/ml in response to provocative tests together with abnormal nocturnal secretion), both diurnal and nocturnal GH secretion were insufficient, with nonexistent diurnal secretion in 5 of 6 cases. Diurnal secretion does not seem to be a reliable indicator of 24-hour spontaneous secretion.     

Serum thyrotropin response to thyrotropin-releasing hormone and free thyroid hormone indices in patients with familial thyroxine-binding globulin deficiency.

The response in serum thyrotropin (TSH) to synthetic thyrotropin-releasing hormone (TRH) as well as serum free thyroxine index (FT4I) and free triiodothyronine index (FT3I) was investigated in six patients with familial thyroxine-binding-globulin (TBG) deficiency. The total serum thyroxine (T4) and triiodothyronine (T3) concentrations were significantly decreased, compared with those of normal subjects (3.4 +/- 0.9 microgram/dl, mean +/- SD. vs. 9.0 +/- 1.5 microgram/dl, p less than 0.01 and 87 +/- 27 ng/dl vs. 153 +/- 37 ng/dl, p less than 0.01, respectively). FT4I was lower than the normal range in all but one (5.3 +/- 1.5 vs. 8.9 +/- 1.6, p less than 0.01), whereas FT3I was all in the normal range and of no significant difference from the normal control (132 +/- 22 vs. 148 +/- 25). Serum TSH concentrations in TBG deficiency were all in the normal range (1.0-4.2 muU/ml) and the maximum TSH increments following TRH 500 microgram iv were 8.9 +/- 2.0 muU/ml and of no significant difference from the normal control (10.2 +/- 4.5 muU/ml). These results indicate that the euthyroid state in familial TBG deficiency is more clearly defined by TRH-test and the normal response to TRH in familial TBG deficiency is presumably under the control of the serum free T3 level rather than the serum free T4 level.     

Euthyroid hypothyrotropinemia in children of short stature

Unique association of hypothyrotropinemia with euthyroidism was described in 2 children of short stature. Both had a history of intrauterine growth retardation (IUGR), but showed an appropriate growth rate after infancy (5 cm/y). Growth hormone secretion after provocation tests was normal, whereas TSH response to TRH was absent. With a highly sensitive TSH radioimmunoassay (RIA) and a specific RIA for TSH-alpha-subunit, both responded to a high dose of TRH stimulation. Serum thyroid hormones were within the normal range, while prolactin response to TRH was exaggerated. Exogenous thyroxine (T4) supplement in case 1 did not improve his growth rate, indicating absence of hypothyroidism. Case 2 was treated with stanozolol, which accelerated his growth velocity to 8 cm/y. During the treatment, serum T4 gradually decreased to 50% of the initial level, but blunted TSH response to TRH remained unchanged. These results indicate that their thyrotrophs are resistant to TRH stimulation and the pituitary setpoint of TSH release is unusually high. The exact mechanism involved in maintaining euthyroidism despite hypothyrotropinemia remains to be elucidated, but a common history of IUGR appears to play a role in producing this pituitary-thyroid state.     

Plasma growth hormone response to synthetic GH-RH1-44 in 52 children and adults with growth hormone deficiency of various etiologies

52 patients (42 children and 10 adults) with growth hormone deficiency (GHD), grouped into four diagnostic categories, and 6 children with constitutional short stature who served as controls were tested for plasma GH response to synthetic GH-RH1-44 given in an intravenous bolus. The response was classified into three degrees according to the magnitude of the maximal rise: Good, greater than 9 ng/ml; Partial, 3.1-9.0 ng/ml; None, less than or equal to 3 ng/ml. Among the GHD patients the highest response was observed in patients with partial growth hormone deficiency (PGHD), and 60% of the children with isolated GH deficiency (IGHD) showed an increase in plasma GH levels. Nevertheless, the response of the GHD patients was lower than that in the control group. In the children and adolescents with PGHD and IGHD the response was not age related. Among those with multiple pituitary hormone deficiencies-idiopathic (MPHD-ID) there was no response in the adolescents although a hypothalamic disorder had been documented by other tests. Among those with MPHD-organic (MPHD-ORG) the GH-RH stimulated GH secretion in the patients with glioma, who had received only irradiation treatment, and in the youngest of the patients with craniopharyngioma. Of the 10 young adults tested none showed a good response. It is concluded that GH-RH is useful in differentiating between GH deficiency of hypothalamic origin and that of pituitary origin, and in selecting those patients who might benefit from long-term treatment with GH-RH in the future.     

Growth hormone responses to sleep, insulin hypoglycaemia and arginine infusion

This study compares the peak serum growth hormone (GH) concentration during slow wave sleep with the serum GH responses to insulin-induced hypoglycaemia and intravenous arginine infusion in 23 children referred because of short stature (20) or precocious puberty (3). Peak serum GH concentration during sleep correlated significantly with peak GH response to insulin hypoglycaemia (r = 0.64, p less than 0.01) and arginine infusion (r = 0.57, p less than 0.01). 3 children had subnormal (less than 15 mU/l) peak serum GH concentrations during sleep but normal responses to either insulin-induced hypoglycaemia or intravenous arginine infusion. 1 child had a normal peak serum GH response to sleep but subnormal responses to insulin and arginine. Sleep studies of GH secretion may be indicated when the GH responses to pharmacological stimuli are inconsistent with the observed growth pattern.     

Effect of corticoid therapy on growth hormone secretion

Exogenous corticoids are known to be potent inhibitors of linear growth in children. We investigated the mechanisms underlying growth failure by evaluating growth hormone (GH) release during short-term high-dose prednisone treatment (40 mg/m2/day given orally in 3 divided doses) and 7 days after steroid withdrawal in 7 prepubertal children (4 males, 3 females, age range 3-12 years), affected by acute lymphoblastic leukemia. Patients also received weekly administrations of vincristine (1.5 mg/m2 i.v.), daunomycin (20 mg/m2 i.v.) and L-asparaginase (6,000 IU/m2 i.m.). Corticoid therapy suppressed GH secretion during deep sleep as well as in response to arginine, insulin and GH-releasing hormone (GHRH) administration. A significant recovery of GH responsiveness after drug discontinuation was observed during deep sleep (14.03 +/- 3.47 vs. 1.49 +/- 0.43 ng/ml, p less than 0.025) as well as in response to arginine (13.63 +/- 2.73 vs. 4.95 +/- 1.54 ng/ml, p less than 0.025) and GHRH (32.62 +/- 4.59 vs. 7.27 +/- 3.52 ng/ml, p less than 0.005) but not to insulin (7.12 +/- 0.88 vs. 4.47 +/- 0.96 ng/ml, p = NS). Insulin-like growth factor 1 levels during deep sleep (0.61 +/- 0.13 IU/ml/min) were found to be low in the course of steroid therapy and did not increase after drug withdrawal (0.41 +/- 0.07 IU/ml/min). Our preliminary data suggest that recovery of adrenergic response to insulin does not immediately follow corticosteroid discontinuation.     

Insulin hypoglycemia test and releasing hormone (corticotropin-releasing hormone and growth hormone-releasing hormone) stimulation in patients with pituitary failure of different origin

To investigate the efficacy of endocrine evaluation in diagnosing and localizing the cause of anterior pituitary failure, 17 patients with suprasellar space-occupying lesions, 4 patients with intrasellar tumors, 8 patients with no detectable anatomical lesion, 1 patient with posttraumatic failure and 1 patient with septooptical dysplasia were investigated. Endocrine evaluation consisted of measuring adrenocorticotropic hormone (ACTH), cortisol, and growth hormone (GH) levels during insulin hypoglycemia test (IHT) and after administration of corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GRH). In addition, basal prolactin levels, gonadal and thyroid function were evaluated. The results showed that 4 of 17 patients with suprasellar tumors had normal ACTH and GH responses during IHT and after releasing hormone (RH) administration. Five of these patients had a normal ACTH or cortisol rise but no GH response during IHT. All 5 had a normal ACTH and 3 had normal GH rise after RH. Seven patients with suprasellar tumors had no ACTH or GH response during IHT, but all had an ACTH response to CRH. Only 3 of this group had a GH response to GRH. There was one exception of a patient who showed a GH and ACTH rise during IHT but only a blunted ACTH and no GH rise after RH administration. Four patients with pituitary failure and no demonstrable lesion had an ACTH rise after CRH but no GH rise after GRH, whereas in 3 patients with isolated ACTH deficiency no ACTH rise after CRH was seen. In 4 patients with nonsecreting pituitary tumors normal ACTH responses to IHT and CRH were seen, whereas GH rose during IHT only in 1 patient.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acromegaly with 'normal' serum growth hormone levels. Clinical features, diagnosis and results of transsphenoidal microsurgery.

Among 216 consecutive patients with growth hormone secreting pituitary adenomas who underwent primary neurosurgical treatment at the University of Erlangen-Nürnberg, 8 cases of acromegaly with 'normal' basal growth hormone levels (less than or equal to 5 ng/ml) were seen. They all had the typical clinical features of acromegaly, exhibited an abnormal growth hormone secretion following an oral glucose load, and had markedly elevated somatomedin C levels. The GRH- and TRH/GnRH-tests were not found helpful in establishing the diagnosis. Neuroradiology could demonstrate a pituitary adenoma in all of the patients. Following transsphenoidal microsurgical resection of the tumours, growth hormone secretion during oral glucose tolerance testing was normalised in 7 of the 8 patients. Immunohistology and explant culture studies documented growth hormone secreting pituitary adenomas in all cases. The authors conclude that even the finding of repetitive 'normal' (less than or equal to 5 ng/ml) serum GH levels does not exclude active acromegaly and when the clinical diagnosis of acromegaly is suspected, dynamic endocrine testing may reveal abnormal secretion patterns of GH in these cases. Transsphenoidal microsurgical resection of a pituitary adenoma offers a good chance of clinical and endocrinological remission in these cases.     

Comparison of growth hormone sleep release and responses to pharmacological tests

The spontaneous release of growth hormone (GH) during nocturnal sleep was studied at age 5-19 years in 44 male and 15 female patients with severe growth retardation (-2.1 to -6.5 SD) among whom 43 were prepubertal and 16 pubertal. Comparison with the results of classical stimulation tests with ornithine, arginine and/or insulin showed good agreement in cases of classical hypopituitarism (n = 14) as in patients who seemed to be endocrinologically normal (n = 27). In 18 patients (31%) there was a discrepancy between sleep release and responses of GH to stimulation test: treatment with hGH was available in only 4 of these children and enhanced sharply their growth rate. It is suggested that a large span of intermediary situations exists between normal GH secretion and complete GH deficiency, deserving a controlled therapeutic trial with hGH.     

Possible change in noradrenergic receptor sensitivity following methylphenidate treatment: Growth hormone and MHPG response to clonidine challenge in children with attention deficit disorder and hyperactivity

Growth hormone (GH) and 3-methoxy-4-hydroxyphenelethylene glycol (MHPG) response was measured hourly for 4 hours in 8 children with Attention Deficit Disorder with Hyperactivity (ADD+H) following an acute single-dose of clonidine. The clonidine challenge was repeated before, during, and one day after 12 weeks of treatment with methylphenidate (MPH). Before MPH treatment, the plasma growth hormone (GH) rose to 31.3 ± 4.6 (Mean ± SE) ng/ml; during MPH treatment, the GH peak was only 14.8 ± 3.2 ng/ml; one day after discontinuation of MPH, GH rose to only 20.8 ± 3.9 ng/ml. MHPG release was inhibited by clonidine in all treatment conditions but tended to be more decreased during MPH treatment. Some children with ADD+H may have hypersensitivity of the post-synaptic alpha-1 noradrenergic receptor which is diminished by MPH treatment. The extent to which these effects are pharmacological or represent a change in receptor sensitivity requires further study.     

Zip1, Zip2, and Zip8 mRNA Expressions Were Associated with Growth Hormone Level During the Growth Hormone Provocation Test in Children with Short Stature

Short stature of children is affected by multiple factors. One of them is growth hormone (GH) deficiency. Growth hormone therapy can increase the final height of children with growth hormone deficiency. Zinc is found to induce dimerization and to enhance the bioactivity of human GH. Two gene families have been identified involved in zinc homeostasis. Previous studies in our laboratory have shown that Zip1, Zip2, Zip6, and ZnT1 mRNA were associated with zinc level in established human breast cancer in nude mice model; Zip8 was significantly lower in zinc-deficient Wistar rats in kidney. In this study, five zinc transporters: Zip1, Zip2, Zip6, Zip8, and ZnT1 were chosen. We aimed to investigate the mRNA expression of zinc transporters and to explore the relationship between zinc transporters and growth hormone in short stature children. Growth hormone provocation test is used to confirm the diagnosis of growth hormone deficiency. Six short children for the test were enrolled. At the same time, 15 sex- and age-matched normal children were enrolled as control. The expression levels of zinc transporters in peripheral blood mononuclear cells were determined by quantitative real-time PCR. Zip1 and Zip2 mRNA expression positively correlated with growth hormone level (r?=?0.5133, P?=?0.0371; r?=?0.6719, P?=?0.0032); Zip8 mRNA expression negatively correlated with growth hormone level (r?=??0.5264, P?=?0.0285) during the test in short stature children. The average expression level of Zip2 was significantly higher and Zip6, Zip8 mRNA levels were significantly lower in short stature children than in health controls at 0 min (P?<?0.05, P?<?0.05).     

Somatomedin in growth disorders and chronic renal insufficiency in children.

Somatomedin activity was measured using an embryonic chick cartilage assay in 33 normal and short normal children, 23 children with pituitary growth hormone (GH) deficiency, 14 children with sexual precocity, and 13 children with chronic renal insufficiency. In normal children somatomedin activity correlated well with chronological age: low valles in early childhood rose to higher than adult levels at puberty. Children with GH deficiency had significantly lower activities and those with sexual precocity significantly higher activities than normal children. In all three groups somatomedin activity correlated well with bone age. In children with chornic renal insufficiency there was a significant correlation between decreasing somatomedin activity and both a reduced growth velocity and a falling glomerular filtration rate. Somatomedin activity and growth velocity were within normal limits in children with glomerular filtration rates above 30 ml/min/1-73 m2.