THE EFFECT OF GALANIN ON BASELINE AND GHRH-INDUCED GROWTH HORMONE SECRETION IN OBESE CHILDREN

We have evaluated the effect of the administration of galanin (Gal), a newly identified hypothalamic peptide, on baseline and GHRH-induced GH rise in five obese children and in seven controls. The GH response to GHRH (hpGRF(1-29), 1 microgram/kg i.v.), and to Gal (15 micrograms/kg/h for 1 h), evaluated both as the maximum GH peak and as integrated area under the curve (AUC), was significantly lower in the obese children than in the controls. Simultaneous administration of Gal plus GHRH significantly increased the GH response to GHRH in all the obese subjects, so that their mean peak GH levels and AUC after Gal plus GHRH were similar to those of the control children after GHRH. Also, in control children Gal caused a significant augmentation of the GH response to GHRH. Mean peak GH levels and mean AUC after Gal plus GHRH were significantly higher in the controls than in the obese children given the same treatment. Our data indicate that obese children have a blunted GH response to Gal, which, however, is able to enhance the GH response to GHRH. This observation strengthens the view that the mechanism of action of Gal involves modulation of endogenous somatostatin (SRIH) release. In addition, similarity between the effects of Gal and pyridostigmine on baseline and GHRH-stimulated GH release in obese children may indicate the existence of a cholinergic link in the action of Gal.     

THE EFFECT OF METHANDROSTENOLONE ON PITUITARY GROWTH HORMONE SECRETION IN PREPUBERTAL CHILDREN

The effect of methandrostenolone on plasma growth hormone levels was studied in twenty-two apparently healthy prepubertal children (nineteen males and three females) with idiopathic growth retardation, following insulin hypoglycaemia (eight children) or arginine infusion (fourteen children). The tests were performed before and after 5 days or 34 months of peroral administration of methandrostenolone (0.1 54.33 or 0.03-0.05 mg/kg/day, respectively).     

THE EFFECT OF CALCITONIN ON GROWTH HORMONE SECRETION IN MAN

To determine whether human calcitonin inhibits GH secretion in man, as has been described for salmon calcitonin, the effect of an i.v. bolus of human calcitonin or saline on GH release after either insulin-induced hypoglycaemia or the administration of GH-releasing hormone (GHRH) or saline was studied. After the injection of calcitonin, no spontaneous GH surges were seen; the GH response to hypoglycaemia was diminished and the response to GHRH almost completely suppressed. Administration of calcitonin also caused a small and transient rise in plasma PRL and TSH but not LH levels, and no change in the integrated PRL or TSH response. Calcium and magnesium levels did not change. It is concluded that human calcitonin suppresses GH secretion in man, but not by suppressing GHRH and probably not by increasing somatostatin release. In addition, calcitonin has limited PRL and TSH-releasing activity.     

THE EFFECT OF CALCITONIN ON GROWTH HORMONE SECRETION IN ACROMEGALY

To determine whether human calcitonin inhibits GH secretion in acromegaly, as previously described for healthy subjects, the effect of an i.v. bolus injection of calcitonin or saline on GH levels in patients with active acromegaly was studied and compared to that of an i.v. bolus injection of the synthetic somatostatin analogue, octreotide. After the injection of calcitonin, GH levels decreased by 46% of initial values, whereas octreotide reduced GH levels by 87% and saline had no significant effect. Administration of calcitonin to acromegalics did not cause the transient rise in plasma PRL and TSH levels seen in normal subjects. Octreotide induced a decrease in plasma PRL in three out of seven patients. It is concluded that human calcitonin suppresses GH secretion in acromegaly, but not to normal levels; moreover the effect is less than that found for octreotide. In addition, acromegalic patients did not exhibit the PRL and TSH-releasing activity of calcitonin found in normal subjects, while octreotide inhibited PRL secretion in some acromegalic patients.     

COMPARISON OF THE EFFECT OF APOMORPHINE AND l-DOPA ON SERUM GROWTH HORMONE LEVELS IN NORMAL MEN

Apomorphine hydrochloride (0.75 mg s.c.) has been compared with L-dopa (500 mg p.o.) in their effects on growth hormone secretion in a double blind cross-over study involving nine healthy men. Apomorphine increased serum GH levels above 10 ng/ml in all nine subjects 30-60 min after injection. In contrast, only six of these subjects showed a similar elevation with L-DOPA and in only three had the level increased above 6 ng/ml by 60 min. One subject failed to respond to L-dopa and in two others the peak was less than 6 ng/ml. GH levels were significantly higher at 30, 45 and 60 min following apomorphine than following L-dopa. Apomorphine-induced GH release was not related to changes in serum cortisol or blood sugar. Benztropine mesylate (1 mg i.m.) had no effect on apomorphine-induced GH release. These results suggest: (a) apomorphine may have advantages over L-dopa as a provocative agent to assess GH secretory capacity; (b) a dopaminergic mechanism subserves GH secretion; (c) cholinergic mechanisms do not antagonize dopaminergic-related GH release.     

THE EFFECT OF OXANDROLONE ON THE GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING HORMONE IN CHILDREN WITH CONSTITUTIONAL GROWTH DELAY

The effect of treatment with oxandrolone, an anabolic steroid, on GH response to GH-releasing hormone (GHRH) has been evaluated in children with constitutional growth delay. Five subjects, four males and one female, aged 11.0-17.1 years were given oxandrolone 0.1 mg/kg p.o. daily for 2 months, and underwent acute administration of GHRH (GRF 1-40, 1 microgram/kg i.v.) before and after withdrawal of oxandrolone therapy. GHRH administration induced a much greater GH response, evaluated either as a peak plasma GH levels or plasma GH integrated area, after than it did before oxandrolone treatment. These findings indicate that in children with constitutional growth delay oxandrolone increases the sensitivity of somatotrophs to exogenous GHRH and, likely, to the endogenously-released neurohormone.     

LACK OF EFFECT OF OESTROGENS ON ADRENAL ANDROGEN SECRETION IN CHILDREN AND ADOLESCENTS WITH A COMMENT ON OESTROGENS AND PUBIC HAIR GROWTH

To study the effect of oestrogen on adrenarche and adrenal androgen secretion we measured plasma concentrations of dehydroepiandrosterone-sulphate (DHEA-S), androstenedione (Δ⁴A) and oestradiol (E₂) in the following groups: children with premature adrenarche; agonadal patients before and after initiation of oestrogen replacement therapy; and, children exposed to increased concentrations of endogenous oestrogen at a precocious age. Fourteen of fifteen patients with premature adrenarche had plasma E₂ levels in the normal prepubertal range (> 10 pg/ml), despite a mean DHEA-S concentration that was significantly elevated for age (6–8 years: 72·5 ± 12·6 μg/dl v. 11·4 ± 2·9 μg/dl, P 0·002). DHEA-S and Δ⁴ A concentrations in fifteen patients with gonadal dysgenesis before and 2–14 months after initiation of oestrogen replacement therapy were not significantly different despite the appearance of oestrogen-induced secondary sex characteristics. Six of fifteen patients developed increased pubic hair during oestrogen therapy but had no increase in the concentrations of plasma DHEA-S. Two patients (aged 1 year 4 months and 4 years 10 months) with oestradrol secreting ovarian follicular cysts (plasma E₂ 11–796 pg/ml) and one patient (aged 6 years 10 months) who had had a granulosa cell tumour of the ovary maintained preadrenarchal DHEA-S levels (> 6·2 μg/dl) despite exposure to concentrations of circulating oestrogen that were high for their chronological age. We interpret the results as follows: (1) Initiation of premature adrenarche occurs without an increase into the early pubertal range of E₂ levels. (2) Administration of replacement doses of oestrogen does not increase adrenal androgen concentrations in adolescent patients with gonadal dysgenesis. (3) Elevated plasma concentrations of endogenous ovarian oestrogens at a precocious age did not increase adrenal androgen secretion in childhood. Thus, it appears that circulating oestrogens are either required for the activation or maintenance of adrenarche nor do they significantly affect the plasma concentrations of adrenal androgens in children and adolescents. (4) The pubic hair growth associated with the institution of oestrogen replacement in adolescent patients with gonadal dysgenesis is not mediated by an increase in adrenal androgen secretion and may result from a specific effect of oestrogen on androgen action at the target tissue (pubic skin).     

GROWTH HORMONE SECRETION AND PLASMA SOMATOMEDIN-C IN PRIMARY HYPOTHYROIDISM

The effect of thyroid hormone deficiency on plasma immunoreactive somatomedin-C concentrations, growth hormone (GH) secretion in response to provocative stimuli, and the plasma somatomedin-C response to exogenous GH was studied in patients with primary hypothyroidism. Plasma Somatomedin-C concentrations were below the 95% confidence interval in 11 of 12 hypothyroid patients (mean +/- SD = 0.27 +/- 0.14 U/ml). With thyroid hormone therapy the mean plasma somatomedin-C level increased four-fold (1.00 +/- 0.43 U/ml). The capacity to secrete GH in response to pharmacological agents was impaired in 3 of the 6 hypothyroid patients tested and normal in the remainder. When the same 6 patients were given a single intramuscular injection of GH (0.1 U/kg) plasma somatomedin-C concentrations increased four-fold by 28 h after the injection. The magnitude of the somatomedin-C response was equal to or greater than that reported for euthyroid GH deficient subjects treated similarly. This study shows that plasma somatomedin-C concentrations are diminished by hypothyroidism. The decreased somatomedin-C levels do not appear to result from resistance to the stimulatory effect of GH, but may be either a result of diminished GH secretion or may be due to direct effects of hypothyroidism upon somatomedin production.     

THE EFFECT OF SHORT- AND LONG-TERM CORTICOSTEROID TREATMENT ON SLEEP-ASSOCIATED GROWTH HORMONE SECRETION

Eight healthy medical studients and four renal transplant patients had blood sampled two or three times hourly throughout EEG monitored nocturnal sleep. This was carried out on the healthy subjects for a total of 12 nights without medication (control nights asleep), a total of 12 nights following 40 mg of flucortolone the previous morning, and a total of 6 nights with similar blood sampling when sleep was prevented (control nights awake). Four renal transplant patients who were receiving long-term therapy with prednisolone were similarly studied (total of 7 nights asleep). Circulating corticosteroid and growth hormone (GH) levels were determined. A peak of GH was seen during the first 2 h of sleep on the control nights when slow-wave sleep predominated. The GH peak was absent on the control nights awake. The pattern of plasma corticosteroid levels was identical during control nights asleep and awake. Both single-dose and chronic corticosteroid administration inhibited the GH peak associated with slow-wave sleep. Chronic corticosteroid therapy, but no single-dose administration in the morning, suppressed the circadian rise of plasma corticosteroids which normally occurs late in sleep.     

NYCTOHEMERAL SECRETION OF GROWTH HORMONE IN NORMAL CHILDREN OF SHORT STATURE AND IN CHILDREN WITH HYPOPITUITARISM AND INTRAUTERINE GROWTH RETARDATION

A continuous blood sampling technique has been used to monitor human growth hormone (GH) during sleep in fourteen normal short children (age range 6.5-15.0 years), twelve hypopituitary children (2.8-17.3 years), three children with psychosocial GH deficiency (4.0-13.0 years), and three children with intrauterine growth retardation (9.5-11.3 years). The mean GH level of a 5 h sleep period (22.30-03.30 hours) was used to represent the GH response to sleep. The GH response to insulin induced hypoglycaemia (IST) was also determined. In normal short children there was a significant relationship between 5 h mean GH levels and chronological age. The curve defining this relationship was similar to the third centile linear growth velocity curve. The 5 h mean GH levels of the hypopituitary and psychosocial GH deficiency children were more than 2 SD below the age related mean established for normal short children. The children with intrauterine growth retardation demonstrated values which were more than 2 SD above the age related mean.     

EFFECT OF SOMATOSTATIN ON ABNORMAL GROWTH HORMONE AND PROLACTIN SECRETION IN PATIENTS WITH THE CARCINOID SYNDROME

Growth hormone (GH) secretion has been studied in two patients with the carcinoid syndrome during glucose loading and growth hormone-release inhibiting hormone (GHRIH, somatostatin) infusion. Both patients had elevated fasting GH levels which were not suppressed by glucose; GH levels fell rapidly during GHRIH infusion. One patient also had hyperprolactinaemia with galactorrhoea and the prolactin (PRL) levels were unaltered by GHRIH. The association between carcinoid tumours and abnormalities of GH and PRL secretion is discussed.     

THE INTERACTION BETWEEN CLONIDINE AND GROWTH HORMONE RELEASING HORMONE IN THE STIMULATION OF GROWTH HORMONE SECRETION IN MAN

Six normal adult males were given clonidine and GHRH either separately, or in combination, in random order. The peak serum GH concentrations elicited by clonidine or GHRH were variable but one factor influencing the GH response to GHRH was the GH secretory status in the hour prior to the administration of the GHRH. Peak serum GH concentrations attained were significantly greater when serum GH concentrations were rising (mean 52.9 mU/l, SD 17.2) than if they were falling (mean 27.5 mU/l, SD 13.3) or unchanged/undetectable (mean 20.6 mU/l, SD 9.8) (one-way ANOVA, F = 8.77; P = 0.004). The GH response to clonidine was not influenced by the secretory status in the hour prior to administration of clonidine. Pretreatment with clonidine did not augment the peak serum GH response to GHRH but the direction of response was more predictable than when GHRH was administered separately or repeatedly. Prior treatment with GHRH(1-29)-NH2 led to a marked attenuation of the peak serum GH response to clonidine. These results suggest that the alpha-2 adrenergic agonists probably stimulate GH secretion through pathways other than just GHRH.     

EFFECT OF ORAL THYROTROPHIN-RELEASING HORMONE ON SERUM THYROXINE IN GROWTH HORMONE DEFICIENT AND NORMAL CHILDREN

Oral administration of synthetic TRH in a dose of 80 mg/1-73 m-2 at 0 and 12 h to normal and constitutionally small children caused a significant increase of total serum thyroxine (T4) within 6-24 h. The mean maximal T4 increment was +3-7 plus or minus 1-1 and +3-8 plus or minus 1-2 mug/dl (mean plus or minus 1 SD) respectively in the two groups. Of seventeen euthyroid GH deficient children, fifteen showed a normal and two patients a slightly subnormal response. Of fifteen hypothyroid GH deficient children nine had a prompt and normal increase of serum T4 indicating primary TRH deficiency. Two had a delayed T4 response and four had no response, even after prolonged stimulation. The localization of the primary defect in these latter subjects with severe hypothyroidism can not be made by measuring T4 only, since the thyroid gland may become unresponsive to TSH after longstanding TSH deficiency. TSH measurements are necessary in these circumstances for a clear localization of the primary defect. One GH deficient patient with hypothalamic TRH deficiency was treated with high oral TRH doses for 7 months and showed no side effects.     

THE EFFECT OF PLASMA GLUCOSE ON THE GROWTH HORMONE RESPONSE TO HUMAN PANCREATIC GROWTH HORMONE RELEASING FACTOR IN NORMAL SUBJECTS

Pituitary responsiveness to 44 amino acid human pancreatic growth hormone releasing factor was tested under conditions of euglycaemia and hyperglycaemia in six normal subjects. A 100 μg dose of growth hormone releasing factor was given at a fasting blood glucose of 5.1 ± 0.4 mmols/1 (mean ± S.D.), and at a blood glucose level of 10.9 ± 1.5. Under conditions of hyperglycaemia, the GH response to releasing factor was significantly depressed when compared to results obtained at fasting blood glucose ( n = 6, t = 3.902, P = 0.0114). This is in keeping with the hypothesis that hyperglycaemia, mediated by the hypothalamus, causes decreased pituitary sensitivity to natural growth hormone releasing hormone.     

生长介素对肢端肥大症患者垂体瘤生长激素分泌影响的体外研究

作者在8例肢端肥大症体外培养的垂体GH瘤细胞上探讨IGF-1对GH分泌的反馈调节作用。10~(-7)mol IGF-1使3例垂体GH瘤细胞GH基础分泌抑制到对照的44.6％～52.4％(P<0.05),1例GH分泌增加134.9％(P<0.05),4例GH基础分泌没有明显改变,表明体外培养的垂体GH瘤有一半以上对IGF-1 3小的·的急性作用失去正常的GH分泌抑制反应。3例对IGF-1失去GH分泌抑制反应的垂体GH瘤细胞同时伴有GH对GHRH_(1-44)及(或)生长抑素激动剂SMS_(201-995)反应消失,提示部分垂体GH瘤细胞的IGF-1和某些下丘脑激素受体或受体后有异常。     

GONADOTROPHIN, GROWTH HORMONE AND PROLACTIN SECRETION IN CHILDREN WITH PRIMARY HYPOTHYROIDISM

We have studied eight children with primary hypothyroidism (6F, 2M) aged 6.7 to 14.2 years. The girls were prepubertal and the boys had early normal pubertal development. Overnight secretion of LH, FSH, TSH, PRL and GH, and ovarian ultrasound morphology were assessed before and up to 9 months after commencing thyroxine treatment. Serum FSH concentrations in all the girls were increased above LH levels and severe hypothyroidism was associated with reduced GH secretion. These abnormalities reversed with thyroxine treatment. The boys had less severe hypothyroidism and did not demonstrate abnormal gonadotropin or GH secretion. We conclude that primary hypothyroidism in childhood is associated with widespread disturbance of pituitary function, including increased FSH secretion often without signs of early sexual maturation.     

生物工程合成生长激素对生长激素缺乏性侏儒症血浆脂肪酸的急性作用

采用生物工程合成的第二代人生长激素(hGH)治疗GH缺乏性侏儒症20例随访一年的过程中,观察hGH对GH缺乏性侏儒症的血浆脂肪酸的急性影响。实验结果表明:hGH首剂应用后4小时血浆总脂肪酸明显升高,与应用前比较,二者差异非常显著(P<0.001),其中油酸、亚油酸、花生四烯酸变化最为显著。应用hGH治疗3、12个月及单纯禁食4小时,同样条件下观察hGH注射前后脂肪酸含量均无显著变化。并对酸性肽与GH关系进行讨论。     

GROWTH HORMONE SECRETION IN CHILDREN DETERMINED BY TIME SERIES ANALYSIS

Mid childhood growth has been studied in 26 short children (18M;8F) aged between 5.2 and 11.9 years growing with height velocity standard deviation score (SDS) between 0 and -0.8 and 24 short children (17M;7F) growing with height velocity SDS less than 0.8. Twenty-four hour GH profiles were analysed by an iterative method of pulse detection and subjected to time series analysis to determine dominant periodicity within the data arrays. Children aged less than 7 years displayed no dominant periodicity but after this age a periodicity of 200 min emerged. In the whole sample, differences between growth rate could be explained entirely by pulse amplitude. Nevertheless, the normal decline in height velocity over this age period occurred despite a significant shift in periodicity and an increase in GH pulse amplitude. This modulation of childhood growth by GH pulse amplitude persisted into puberty and the pubertal growth spurt of 14 tall girls was shown to be amplitude modulated with the periodicity unchanged. We conclude that mid childhood and pubertal growth is GH pulse amplitude modulated with a periodicity of approximately 200 min.