Plasma somatomedin activity and urinary hydroxyproline excretion during administration of human growth hormone in children with short stature. Long-term effects and relation with short-term changes

Growth velocity, somatomedin activity (SM-act) and total urinary hydroxyproline excretion (THP) were studied in 9 prepubertal short children on long-term human growth hormone (hGH) therapy, and compared to the short-term responses to hGH, described in the accompanying paper. Positive correlations were found between the short-term increases of either SM-act or THP and growth acceleration, but these were too weak to be used as a predictor. On a schedule of biweekly injections, pre-injection SM-act values were only slightly higher than pre-treatment values, but post-injection values were considerably higher and similar to the values obtained with comparable hGH doses in the short-term study. There was an excellent relationship of the increment of SM-act during chronic therapy over untreated values and the increases of growth velocity. During the first year on hGH therapy the mean SM-act, mean THP and growth acceleration showed strong correlations.     

Effect of chronic clonidine treatment on urinary growth hormone excretion and linear growth in children with short stature

Eleven prepubertal children with short stature were treated with clonidine (0.15 mg/m2 daily) for a period of 1 year. The effect of this drug was evaluated on both clinical (growth velocity, height standard deviation scores for chronological age and bone age) and hormonal (urinary growth hormone excretion and insulin-like growth factor I) parameters. Our study shows that long-term clonidine administration in children with short stature did not result in significant differences in growth velocity, height standard deviation scores for chronological age and bone age, insulin-like growth factor I or in urinary growth hormone excretion.     

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.     

Physiological growth hormone secretion in children with short stature and intra-uterine growth retardation

31 prepubertal children with short stature [mean height standard deviation score (SDS) -2.84] and low birth weight (mean -2.82 SDS) were studied. Mean age was 6.0 years and mean height velocity SDS was -0.76. Patients were classified as having either the clinical characteristics of Russell-Silver syndrome (RSS) (4 F, 13 M) or not (4 F, 10 M). All children had an overnight profile of spontaneous growth hormone (GH) secretion. 4 children achieved a maximum GH concentration of less than 20 mU/l. 9 children with RSS secreted only one large GH peak during the night. Most of the non-RSS group had normal GH pulse frequency but 3 boys had a fast-frequency pattern. Abnormal GH secretion may contribute towards growth failure in children with low birth weight/RSS.     

Growth response of Egyptian children with idiopathic short stature during four years of growth hormone therapy

BACKGROUND:

Multiple factors affect the growth response to recombinant human growth hormone (rhGH) in children with idiopathic short stature (ISS).

AIM:

To evaluate the growth responses of children with ISS treated with rhGH, aiming to identify the predictors of growth response.

MATERIALS AND METHODS:

We studied 120 cases, 90 males (75%), with a mean age of 13.8±2.7 years and 30 females (25%), with a mean age of 12.3±2.5 years. All patients received rhGH with a standard dose of 20 IU/m²/week. The calculated dose per week was divided into six days and given subcutaneous at night.

RESULTS:

A significant positive trend was detected in the delta changes of all anthropometric data. For the first year, the growth response was positively correlated to CA and BA delay and negatively correlated to height, weight and IGF-1 SDSs. For the second year, the growth response was correlated positively to first year growth velocity, BA, triceps skin fold thickness SDS and deviation from target height, and negatively correlated to weight, IGFBP3 SDS and target height SDS. For the third year, the growth response was positively correlated to five variables namely target height, 2^nd year growth velocity, IGF-1 SDS, weight SDS and triceps skin fold thickness SDS. For the fourth year, growth response was positively correlated to 2^nd and 3^rd year growth velocity, BA, deviation from target height and weight/ height SDS.

CONCLUSION:

Our study showed multiplicity of predictors that is responsible for response in ISS children treated with rhGH, and BA was an important predictor.     

Spontaneous growth hormone secretion and plasma somatomedin-C in children of short stature

We studied 17 short prepubertal children, aged 7.5 to 17.0 years (mean +/- SD: 11.7 +/- 2.4) more than 2.0 SD below the mean height for their age and of delayed bone age (M +/- SD: 8.1 +/- 2.3), to clarify their physiological GH secretory status. The mean concentration of GH (MCGH) was calculated and was compared with the subjects' GH responses to insulin and arginine tolerance tests (IATT) and plasma somatomedin-C (SM-C). The mean 24-h MCGH value was 3.2 +/- 1.3 ng/ml (range 1.6-5.5). The mean peak GH response to the IATT was 13.0 +/- 7.5 ng/ml (range 2.4-33.9). In addition to the two patients with abnormally low GH responses to the IATT, seven with normal responses showed low 24-h MCGH values, a small number of GH pulses and low mean GH amplitude. The mean plasma SM-C in all patients was 0.60 +/- 0.20 U/ml. This was significantly lower than that of age-matched children of normal height (p less than 0.001). The 24-h MCGH was significantly correlated with plasma SM-C levels (r = 0.51, p less than 0.05) and with that of the first three hours of sleep at night (r = 0.84, p less than 0.01). These results indicate that: 1) some short children with normal GH response to pharmacological tests secrete a low amount of GH physiologically and 2) blood sampling during the first three hours of sleep as well as 24-hour sampling is suitable in evaluating the physiological secretion of GH.     

Plasma growth hormone (GH) response to GH-releasing factor (SM-8144) in children of short stature and patients with GH deficiency

Synthetic human GRF (hGRF (1-44) NH2; SM-8144) was administered as an iv bolus to 141 normal children of short stature (NSC), 73 patients with severe idiopathic GH deficiency (IGD; group A), 30 patients with mild idiopathic GH deficiency (IGD; group B), 29 patients with secondary GH deficiency, 3 patients with primary hypothyroidism, 21 patients with Turner's syndrome and 25 patients with various other disease. Their height was below normal for their age and sex, and they were all below 25 years old without obesity. The maximal GH responses (M+SEM) were 39.5 +/- 2.2, 7.2 +/- 0.9, 27.2 +/- 3.7, 5.2 +/- 0.8, 9.7 +/- 4.4, 25.1 +/- 2.8 and 32.3 +/- 4.8 ng/ml, respectively (significance from the NSC, ; p less than 0.05, ; p less than 0.001). The GH responses to hGRF were greater than those elicited by standard pharmacological tests. There was a negative correlation between bone age and peak plasma GH response to hGRF in patients with idiopathic GH deficiency (IGD) but not in normal children (NSC). In twenty-two percent of the patients with IGD in group A the response was above 10 ng/ml and in 57% of the patients with IGD in group B the response was above 20 ng/ml, suggesting that a large percentage of patients with idiopathic GH deficiency lack hypothalamic GRF. The side effect of flushing was observed in 15.2% of all subjects. These results indicate the potential usefulness of hGRF (1-44) NH2 (SM-8144) in inducing GH release from the pituitary.     

Effect of growth hormone-releasing factor on plasma growth hormone, prolactin and somatomedin C in hypopituitary and short normal children

We studied the effect of a single intravenous bolus of 0.5 microgram/kg of growth hormone-releasing factor (GRF) on plasma GH, prolactin (PRL) and somatomedin C (SMC) in 12 short normal children and 24 patients with severe GH deficiency (GHD), i.e. GH less than 5 ng/ml after insulin and glucagon tolerance tests. GRF elicited an increase in plasma GH in both short normal and GHD children. The mean GH peak was lower in the GHD than in the short normal children (8.2 +/- 2.5 vs. 39.2 +/- 5.1 ng/ml, p less than 0.001). In the GHD patients (but not in the short normals) there was a negative correlation between bone age and peak GH after GRF (r = -0.58, p less than 0.005); GH peaks within the normal range were seen in 5 out of 8 GHD children with a bone age less than 5 years. In the short normal children, GRF had no effect on plasma PRL, which decreased continuously between 8.30 and 11 a.m. (from 206 +/- 22 to 86 +/- 10 microU/ml, p less than 0.005), a reflection of its circadian rhythm. In the majority of the GHD patients, PRL levels were higher than in the short normal children but had the same circadian rhythm, except that a slight increase in PRL was observed 15 min after GRF; this increase in PRL was seen both in children with isolated GHD and in those with multiple hormone deficiencies; it did occur in some GHD patients who had no GH response to GRF. Serum SMC did not change 24 h after GRF in the short normal children. We conclude that: (1) in short normal children: (a) the mean GH response to a single intravenous bolus of 0.5 microgram/kg of GRF is similar to that reported in young adults and (b) GRF has no effect on PRL secretion; (2) in GHD patients: (a) normal GH responses to GRF are seen in patients with a bone age less than 5 years and establish the integrity of the somatotrophs in those cases; (b) the GH responsiveness to GRF decreases with age, which probably reflects the duration of endogenous GRF deficiency, and (c) although the PRL response to GRF is heterogeneous, it does in some patients provide additional evidence of responsive pituitary tissue.     

Morphological changes in the central sulcus of children with isolated growth hormone deficiency versus idiopathic short stature

In this study, the morphological changes in the central sulcus between children with isolated growth hormone deficiency (IGHD) and those with idiopathic short stature (ISS) were analyzed. Thirty children with IGHD (peak growth hormone < 5 µg/L) and 30 children with ISS (peak growth hormone > 10.0 µg/L) were included. Morphological measurements of the central sulcus were obtained from T1‐weighted MRIs using BrainVISA, including the average sulcal width, maximum depth, average depth, top length, bottom length, and depth position‐based profiles (DPPs). The bilateral average width of the central sulci was significantly wider, while the left maximum depth and right average depth of the central sulcus were significantly smaller, in children with IGHD than in children with ISS. There were no significant differences in the right maximum depth, left average depth, or bilateral top length and bottom length of the central sulcus between groups. The DPPs of the middle part of both central sulci (corresponding to the hand motor activation area) and the inferior part of the right central sulcus (corresponding to the oral movement area) near the Sylvian fissure were significantly smaller in children with IGHD than in controls before false discovery rate (FDR) correction. However, all the above significant DPP sites disappeared after FDR correction. There were significant morphological changes in the three‐dimensional structure of the central sulcus in children with IGHD, which were the outcome of other more essential cortical or subcortical changes, resulting in their relatively slower development in motor, cognitive, and linguistic functional performance.     

Psychosocial functioning of adolescents with idiopathic short stature or persistent short stature born small for gestational age during three years of combined growth hormone and gonadotropin-releasing hormone agonist treatment

AIM: To examine psychosocial functioning of medically referred adolescents with idiopathic short stature (ISS) or persistent short stature born small for gestational age (SGA) during 3 years of combined growth hormone (GH) and gonadotropin-releasing hormone agonist (GnRHa) treatment. METHODS: Thirty-eight adolescents participated in a controlled trial with GH/GnRHa treatment or no intervention. Each year the adolescents and their parents completed questionnaires and structured interviews. Multilevel analysis was used to analyze data. RESULTS: The adolescents of the treatment group showed a worse outcome than the adolescents of the control group on 3 of 16 variables: perceived competence of scholastic (p < 0.01) and athletic ability (p < 0.05) and trait anxiety (p < 0.05). Adolescents in both the treatment and control groups perceived improved current height (p < 0.001) and self-appraisal of physical appearance (p < 0.05). The parents did not report changes in their children during treatment. CONCLUSION: The observation of some adverse psychological consequences as experienced by the adolescents indicates that it is useful to monitor psychosocial functioning during a combined GH/GnRHa treatment in adolescents with ISS or SGA. It is uncertain whether the hypothesized positive effects of the expected gain in final height by adulthood can sufficiently counterbalance possible short-term negative effects.     

Relationship of urinary kallikrein excretion to urinary potassium excretion during furosemide administration with and without amiloride

The relationship of urinary kallikrein excretion to urine volume, and to urinary sodium and potassium excretions was studied in normal rats during furosemide diuresis and superimposed injection of amiloride, a K+-sparing diuretic. Continuous infusion of furosemide increased urinary kallikrein, sodium and potassium excretions and the urine volume. Amiloride injection during furosemide diuresis caused further increase in diuresis and natriuresis, but a prompt decrease in urinary kallikrein excretion to basal level, and potassium excretion to below the basal level. The significant correlation of urinary kallikrein excretion to urinary potassium excretion, but not to urine volume and urinary sodium excretion after amiloride injection suggests that the major determinant of urinary kallikrein excretion is renal potassium secretion through a mechanism that is affected by amiloride.     

Short-term secretory regulation of ghrelin during growth hormone provocative tests in prepubertal children with various growth hormone secretory capacities

BACKGROUND AND OBJECTIVE: Ghrelin is a novel gastric peptide which stimulates GH secretion and has been demonstrated to have orexigenic and adipogenic properties. Insulin is a physiological and dynamic modulator of plasma ghrelin, and insulinemia possibly mediates the effect of the nutritional state on the plasma concentrations of ghrelin in adults. No data on the regulation of GH secretion by ghrelin have so far been reported, nor has the possible influence of hypoglycemia on the plasma ghrelin levels in children been reported. METHODS: Provocative studies were performed using a variety of stimuli, including insulin-induced hypoglycemia, and glucagon, arginine and L-dopa loading. We studied a group of 27 children with short stature being investigated for GH deficiency (10 F, 17 M; age 4-14 years; height SDS -0.92 to -3.27); the subjects were instructed to fast overnight, and the following morning, the relationships among the plasma ghrelin, GH and glucose levels were investigated by determining the plasma ghrelin profiles during those provocative tests. Using a new method for determining the two types of ghrelin, samples were obtained for determination of the plasma ghrelin, serum glucose and serum GH levels after the administration of the aforementioned stimulating agents. RESULTS: All the four stimuli caused a significant decrease in the circulating C- and N-ghrelin levels with a nadir at +30 min, with the exception of the N-ghrelin level following the L-dopa loading. During the same period, the plasma GH level increased following insulin, arginine and L-dopa loading, and the plasma glucose level increased significantly following glucagon loading. In the arginine and L-dopa load connected, a significant correlation was observed between the 30-min change in the serum GH level and the 30-min change in the plasma C-ghrelin level. In the multiple regression analysis to explain the 30-min change in the plasma level of C-ghrelin, the baseline plasma level of C-ghrelin (basal), height and % overweight were the only three significant parameters, accounting for 85.2% of the variance. CONCLUSION: This study demonstrated that the inverse relation between the circulating GH and ghrelin levels may indicate the existence of a feedback loop, and also lends support to the assumption of a GH-independent relationship between plasma ghrelin and glucose levels. These observations constitute further evidence to suggest that peripheral ghrelin is a direct growth-promoting hormone.     

Spontaneous growth hormone secretion in healthy prepubertal children of normal stature.

To evaluate the dynamics of growth hormone (GH) secretion in healthy prepubertal children of normal stature, we determined spontaneous GH secretion by measuring GH every 30 min in 21 Japanese subjects, age: 5.4 +/- 2.3 (1.6-10.6) years; height: -1.4 +/- 1.1 (-1.98-1.77) SD. The 24-h mean GH concentration was 4.8 +/- 1.5 ng/ml. The 24-h mean GH was similar in boys and girls (mean +/- SD: 4.8 +/- 1.7 vs 4.7 +/- 1.1 ng/ml). No correlation was found between chronological age and the 24-h mean GH. The 24-h mean GH was closely correlated with GH pulse amplitude (r = 0.94; P less than 0.001), but not with the number of GH pulses. The 24-h mean GH was also highly correlated with 3-h mean GH after sleep and 3-h peak GH after sleep (r = 0.86; P less than 0.001 and r = 0.72; P less than 0.001, respectively). Our data suggest that in healthy prepubertal children of normal stature, (1) spontaneous GH secretion is independent of sex and age, (2) the amount of spontaneous GH secretion is controlled by pulse amplitude, not by number of pulses. (3) 3-h mean GH and 3-h peak GH after sleep might represent 24-h total spontaneous GH secretion.