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.     

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.     

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.     

Subcutaneous treatment with growth hormone-releasing hormone for short stature

In the present study we report the effects of therapy with growth hormone-releasing factor (1-29)NH2 (GRF) on growth rate, plasma levels of insulin growth factor I (IGF-I) and growth hormone (GH) secretion in 11 children who were selected solely on the basis of their short stature and normal GH secretion on standard provocative tests. All children received GRF for 6 months (5 micrograms/kg body weight subcutaneously) each evening. The 24-hour GH secretory profile was studied before and after 6 months of treatment. Simultaneously, GH secretory responses to single intravenous bolus GRF (1.5 micrograms/kg body weight) were also studied before, during, and 6 months off therapy with GRF(1-29)NH2. Plasma levels of IGF-I were measured before, during (1, 2 and 6 months), and after 6 months off therapy with GRF. Statural growth was measured at 3-month intervals. The peak plasma GH level in response to GRF was 56.04 +/- (SD) 24.46 ng/ml before treatment, and similar results were found after therapy. The 24-hour GH secretory profile did not show differences before, during, and after treatment. Comparably, no differences were found in GH pulse frequency, pulse amplitude, pulse height, pulse increment, pulse area and total area before, and 6 months off therapy with GRF. The increments in serum IGF-I achieved were not significantly different at all intervals studied. All patients increased growth velocities (mean +/- SD, cm/year) in response to GRF therapy. Our results demonstrate that GRF administration was effective in accelerating growth velocity in 11 children without GH deficiency.     

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.     

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

15 prepubertal children with short stature and varying peak growth hormone (GH) levels were given daily injections of increasing doses of human growth hormone (hGH) for consecutive periods of 7 days. Somatomedin activity (SM-act) and total urinary hydroxyproline excretion (THP) were determined in each period. In patients with a varying degree of GH deficiency, but without non-pituitary dependent abnormalities, there was a high correlation between basal SM-act and height velocity. Patients with catch-up growth had an unproportionally low SM-act and the Prader-Willi and transient Cushing patients had an unproportionally high one. All patients showed increases of SM-act and THP on hGH administration, but there was considerable variation of the shape of the curve and of the amplitude of the response. 3 1/2 days after the last injection, SM-act was back to basal level. There was a good correlation between weight-for-height and SM-act during the first two hGH doses, which fits the hypothesis of GH and insulin synergism on SM generation.     

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.     

Adrenal androgens in children with short stature

Recent data suggest that adolescent individuals with growth hormone (GH) deficiency have subnormal levels of adrenal androgens (AA). In order to determine the developmental pattern of AA in GH deficiency and to assess whether AA levels can help identify children with GH deficiency, we measured plasma concentrations of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), delta 4-androstenedione (delta 4A), and cortisol in the basal state and during prolonged adrenocorticotropin (ACTH) infusion (8 h) in a group of 34 individuals, 26 males and 8 females, with short stature. Their chronological ages (CA) ranged from 1.75 to 17.5 years (median 10.35 years). The subjects were grouped into two categories according to the results of pituitary testing: group 1 = short, non-GH-deficient (n = 16), and group 2 = GH-deficient, ACTH-sufficient (n = 18). Patients in groups 1 and 2 had similar bone ages (BA: 7.2 +/- 0.7 vs. 7.5 +/- 1.0 years) and Z scores for height (-3.0 +/- 0.2 vs. -3.2 +/- 0.3 units) and height velocity (-2.5 +/- 0.4 vs. -2.6 +/- 0.2 units). For both groups there were significant increases from basal to peak levels for DHEA, DHEA-S, delta 4A and cortisol following prolonged ACTH infusion. Although both basal and peak levels of DHEA-S overlapped in groups 1 and 2 for all CA and BA, levels in group 2 tended to be lower, especially for BA greater than 10 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Growth hormone secretion during sleep. II. Interrelationships between growth hormone secretion, insulin-like growth factor I and sex steroids

The serum levels of insulin-like growth factor I (IGF I), dehydroepiandrosterone sulfate (DHAS), testosterone (T) and estradiol (E2) have been measured in 78 prepubertal and 57 early pubertal patients referred for short stature, at the same time when their secretion of GH was evaluated both during nocturnal sleep and by two conventional stimulation tests. According to the results of GH measurements they were considered as having a normal secretion of GH (group I), a complete GH deficiency (group II), a partial GH deficiency (group III), low responses to stimuli with normal secretion during sleep (group IV) or a nocturnal neurosecretory dysfunction (group V). Though widely scattered, the IGF I levels showed the following characteristics: a significant increase at puberty from 0.77 to 1.29 U/ml (p less than 0.001) in the so-called endocrinologically normal patients of group I, not in the other groups; in the prepubertal patients of group I, a correlation of IGF I with chronological age (r = 0.47, p less than 0.005) and bone age (r = 0.52, p less than 0.002); significantly reduced IGF I levels in patients of group II having complete GH deficiency (p less than 0.001); no significant differences between prepubertal patients with partial or atypical GH deficiency from groups III, IV, V and prepubertal patients from group I; lower pubertal levels in groups III, IV, V than in pubertal patients from group I (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Nocturnal profile of growth hormone secretion during sleep induced by zolpidem: a double-blind study in young adults and children

Overnight blood sampling for repeated growth hormone (GH) assays, regarded as the most physiological assessment of GH status, may induce some disturbances in patients' sleep and then in the evaluation of GH secretion. We studied the influence of a hypnotic drug, zolpidem (10 mg), on nocturnal GH profiles (GH peak, time to first and maximum GH peak, area under the curve, mean integrated concentration) over two nights at a 7-day interval, in a double-blind cross-over design in a group of 12 young adult volunteers (27.9 +/- 4.3 years), and in a group of 12 children (10.8 +/- 2.3 years) with short stature, in a parallel double-blind study. Mean GH profiles showed no difference between zolpidem-treated subjects and placebo-treated controls, either in adults or in children. Although in these experimental conditions, sleep onset latency was significantly reduced with zolpidem in the adult volunteers, the mean time to first GH peak remained unchanged. Furthermore, GH profile did not relate with sleep duration, sleep onset latency or number of awakenings. A hypnotic drug, such as zolpidem, given at bedtime, is therefore devoided of effect on nocturnal GH profile and may be used in young children for overnight blood sampling when needed.     

Final height in patients with idiopathic short stature and high growth hormone responses to stimulation tests

Children with idiopathic short stature (ISS) may have normal or increased growth hormone (GH) responses to provocation tests and achieve a final height (FH) below -2.0 standard deviation score (SDS) if untreated. FH of subjects with high stimulated GH levels has not been studied in detail. AIM: It was the aim of this study to analyse FH in ISS patients with high GH peak responses to the provocation test. PATIENTS AND METHODS: We studied 16 patients (9 pre-pubertal) with ISS and a GH peak >or=40 mU/l to insulin-induced hypoglycaemia. The patients were recalled at age 19.7 +/- 2.5 years for measurement of FH when blood samples were obtained for serum insulin-like growth factor (IGF)-I, IGF binding protein 3, acid-labile subunit and GH binding protein measurements. GH bioactivity was determined using the Nb2 bioassay. RESULTS: FH was -3.1 +/- 1.0 SDS, being significantly lower than target height (TH). At FH, IGF-I levels were within -1.5 and +1.5 SDS for age and sex in 10 patients and higher than +1.5 SDS in 6 patients. IGF binding protein 3, acid-labile subunit, GH binding protein levels and GH bioactivity values were normal. SUMMARY: These data suggest that patients with ISS and high GH levels during a GH stimulation test may have a more compromised FH. The association of severe ISS with a peak GH >40 mU/l might suggest a degree of insensitivity for the GH-IGF-I axis.     

A proteomic approach identified growth hormone-dependent nutrition markers in children with idiopathic short stature

Background  

The broad range in growth observed in short prepubertal children receiving the same growth hormone (GH) dose is due to individual variation in GH responsiveness. This study used a pharmaco-proteomic approach in order to identify novel biomarkers that discriminate between short non-GH-deficient (GHD) children who show a good or poor growth response to GH treatment.     

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.     

Growth hormone (GH) peak after falling asleep reflects spontaneous nocturnal GH secretion, however is not corresponding to the results of GH stimulating tests in children with short stature

OBJECTIVE: Growth hormone (GH) secretion is characterized by a pulsatile, circadian rhythm, with the highest concentrations at night hours. Evaluation of nocturnal GH secretion may be truncated to 6 hours. Growth hormone stimulating tests are the standard method of assessment of GH secretion. In Poland, the assessment of GH peak during 2 hours after falling asleep was introduced as a screening procedure in children, suspected for GH deficiency. The aim of current study was to compare the results of a screening test with GH secretion during 6-hour nocturnal profile and with the results of GH stimulating tests, as well as with IGF-I secretion in children with short stature. Methods: In 72 short children, GH concentrations were measured every 30 minutes during first 6 hours after falling asleep and in two GH stimulating tests (the cut-off level of GH peak for all the tests was 10.0 ng/ml). Also, IGF-I concentrations were measured and expressed as IGF-I SDS for age and sex. Results: The screening test results correlated significantly with both GH peak in 6-hour profile and mean GH concentration, and the area under the curve (AUC) in 6 hour profile (r= 0.94, r=0.90 and r=0.89, respectively, p<0.05) but not with GH peak in stimulating tests (r=0.07, NS). There was no correlation between IGF-I secretion and any of the analyzed parameters of spontaneous and stimulated GH secretion. Conclusions: The results of screening test seem to reflect overnight GH secretion in short children, remaining, however, discordant with the results of GH stimulating tests and with IGF-I secretion.     

Normal progression of testicular size in boys with idiopathic short stature and isolated growth hormone deficiency treated with growth hormone: experience from the KIGS

BACKGROUND: The aim of this retrospective analysis was to evaluate the effects of growth hormone (GH) treatment on testicular development in boys with idiopathic short stature (ISS) and isolated GH deficiency (IGHD) followed in the KIGS (Pharmacia International Growth Database). METHODS: For inclusion in the study, the patients had to have received more than 1 year of prepubertal GH treatment, at least 4 consecutive years of GH treatment in total, and to have attained their final height, defined as a height velocity of less than 2 cm/year. Data on 107 boys in the KIGS database have been analyzed. RESULTS: No significant differences in duration of GH treatment and testicular volume at the start of treatment or at final height were found between the boys with ISS and those with IGHD. The progression of testicular volume in boys with ISS or IGHD during GH treatment did not differ from the reference population. CONCLUSIONS: This analysis shows that GH treatment does not alter testicular growth in boys with ISS or IGHD. However, prospective controlled studies are needed to rule out moderate attenuating or stimulating effects.