Nocturnal Growth Hormone Concentration Research Articles

Relationship between Nocturnal Growth Hormone Concentrations, Serum IGF-I/IGFBP-3 Levels, Insulin Sensitivity and GH Receptor Allelic Variant in Small for Gestational Age Children

Growth hormone may help to increase final height in patients with short stature, but its efficacy is variable. It has been recently reported that the isoform of the GH receptor (GHR) that lacks exon 3 (d3-GHR) is associated with a greater growth response to GH therapy. We hypothesized that nocturnal growth hormone concentrations, basal IGF-I and IGFBP-3 levels, and insulin sensitivity might show variations among individuals depending on their GHR allelic variant. To test this hypothesis, we studied 38 prepubertal LBW children with nocturnal GH concentrations, IGF-I and IGFBP-3 levels and insulin sensitivity during OGTT and Insulin test. The GHR allelic variant was analyzed through multiplex PCR analysis in DNA from peripheral leukocytes. Characteristics of the overnight GH secretion [(mean GH: 6.8 ± 0.6 vs. 6.2 ± 0.5 ng/ml), (AUC: 3,227 ± 280 vs. 2,908 ± 212 ng/ml·min), (peak number: 4.4 ± 0.3 vs. 4.4 ± 0.2), (amplitude: 12 ± 1.1 vs. 10.8 ± 1.1 ng/ml)] did not differ between groups (f1/f1 vs. f1/d3 plus d3/d3). In addition, we did not observe any significant differences in serum IGF-I SDS (–0.49 ± 0.26 vs. –0.40 ± 0.35) or IGFBP-3 SDS (–1.21 ± 0.24 vs. –0.89 ± 0.21) nor in insulin sensitivity (WIBSI: 12 ± 1.2 vs. 10.8 ± 1.1) in LBW children with full length GHR compared to children carrying at least one GHRd3 allele. The distribution of the f1/f1 allelic variant and fi/d3 or d3/d3 was similar in the LBW children with or without catch-up growth. These results suggest that the GHR allelic variant does not play a significant role in the regulation of GH-IGF-I/BP3 axis or in insulin sensitivity in prepubertal LBW children.

Effects of sleep deprivation on ghrelin, ACTH, GH and cortisol secretion in normal controls

Ghrelin is an endogenous ligand of the growth hormone (GH) secretagogue (GHS) receptor. Besides GH-releasing hormone (GHRH) and somatostatin it is thought to be a regulating factor of GH release. Ghrelin appears to be involved in sleep regulation. We showed recently that ghrelin promotes slow wave sleep and the nocturnal release of GH, cortisol and prolactin in humans. Similarly promotion of non-REM-sleep was reported in mice after systemic ghrelin. There are no data available about the pattern of ghrelin secretion during the recovery night after total sleep deprivation (TSD). Nocturnal ghrelin, GH, ACTH and cortisol plasma concentrations were determined by radioimmunoassay and simultaneously sleep EEG was recorded (23:00–07:00) during sleep before and after one night of TSD in 8 healthy subjects (3 females and 5 males, mean age 26.3yrs, SD 4.4). We observed a trend suggesting higher ghrelin secretion during the first half of the night after TSD (before TSD mean 466ng/ml, SD 113ng/ml, after TSD mean 545ng/ml, SD 176, p=0.093). In the night before TSD the maximum time of ghrelin secretion occured at 03:40 (SD 117min.) and after TSD this time point was 00:42 (SD 76min.), indicating an earlier ghrelin secretion after TSD (p<0.05). GH secretion during the first half of the night and total night after TSD were elevated. ACTH and cortisol were also elevated, which was most pronounced during the second half of the night (ACTH: AUC before TSD, mean 5278, SD 1814, after TSD mean 10817, SD 3314, p<0.05).

Spontaneous and provoked growth hormone (GH) secretion and insulin-like growth factor I (IGF-I) concentration in patients with beta thalassaemia and delayed growth.

Growth retardation in children with thalassaemia major is multifactorial. We studied the growth hormone (GH) response to provocation by clonidine and glucagon, measured the circulating concentrations of insulin, insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP3), and ferritin, and evaluated the spontaneous nocturnal (12 h) GH secretion in prepubertal patients with thalassaemia and age-matched children with constitutional short stature (CSS) (height SDS < -2, but normal GH response to provocation). The anatomy of the hypothalamic pituitary area was studied in patients with abnormal GH secretion using MRI scanning. Children with thalassaemia had significantly lower peak GH response to provocation by clonidine and glucagon (8.8 +/- 2.3 micrograms/l and 8.2 +/- 3.1 micrograms/l respectively) than did controls (17.6 +/- 2.7 micrograms/l and 15.7 +/- 3.7 micrograms/l respectively). They had significantly decreased circulating concentrations of IGF-I and IGFBP3 (68.5 +/- 19 ng/ml and 1.22 +/- 0.27 mg/l respectively) compared to controls (153 +/- 42 ng/ml and 2.16 +/- 0.37 mg/l respectively). Seven of the thalassaemic children had a GH peak response of < 7 micrograms/l after provocation. Those with a normal GH response after provocation also had significantly lower IGF-I and IGFBP3 concentrations than controls. Analysis of their spontaneous nocturnal GH secretion revealed lower mean (2.9 +/- 1.77 micrograms/l) and integrated (2.53 +/- 1.6 micrograms/l) concentrations compared to controls (4.9 +/- 0.29 micrograms/l and 5.6 +/- 0.52 micrograms/l respectively). Five of them had mean nocturnal GH concentration < 2 micrograms/l and four had maximum nocturnal peak below 10 micrograms/l. These data denoted defective spontaneous GH secretion in some of these patients. MRI studies revealed complete empty sella (n = 2), marked diminution of the pituitary size (n = 4), thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2), and evidence of iron deposition in the pituitary gland and midbrain (n = 7) in those patients with defective GH secretion (n = 9). Serum ferritin concentration was correlated significantly with the circulating IGF-I (r = -0.47, p < 0.01) and IGFBP3 (r = -0.43, p < 0.01) concentrations. These data prove a high prevalence of defective GH secretion in thalassaemic children associated with structural abnormality of their pituitary gland.

The impact of gender, puberty and body mass on reference values for urinary growth hormone (GH) excretion in normally growing non-obese and obese children.

There is a lack of normal reference data on urinary GH (u-GH) excretion in children. We have investigated the impact of age, gender, pubertal development and body mass on reference values for u-GH excretion in normally growing non-obese and obese children. u-GH levels were evaluated in 1153 healthy normal children (aged 5-14) and in 684 obese children (body mass index, BMI: > 75th). u-GH levels (ng/8 h) were determined by ELISA as the mean value of three consecutive first morning voidings. Reference values (5-95th centile) for u-GH excretion in obese and non-obese children of both sexes are reported. In normal prepubertal children median u-GH levels were relatively stable and superimposable in the two sexes; subsequently, u-GH levels increased, reaching a peak value at 13 years in both sexes. Significant increments (P < 0.0001) in u-GH levels were shown at B2 for females and at G3 for males. A slight decline was evident at 14 years. In obese children, median u-GH concentrations were significantly lower than those recorded in normal children of prepubertal age and at all stages of puberty (except in females at B2), in spite of their comparable normal height. u-GH levels significantly increased at puberty also in obese children, although the pubertal rise was significantly (P < 0.001) lower (1.7-fold in both sexes) than that observed in normal children (2.5-fold in boys and 2.3-fold in girls). A multiple regression analysis showed that both chronological age (beta: 0.20), BMI (beta: - 0.11), gender (beta: - 0.04) and pubertal stage (beta: 0.25) contributed significantly to the physiological variation in u-GH levels (multiple R: 0.44, P < 0.00001). This study provides reference values for u-GH in normally growing non-obese and obese children, analysing the impact of gender, puberty and body mass on this parameter. In agreement with previous studies, which demonstrate blunted GH-responses to provocative stimuli and reduced nocturnal GH concentration, obese children have significantly lower u-GH levels than age-matched normal weight children, both before and during puberty.

Reduced spontaneous growth hormone secretion in patients with Turner's syndrome

Pirazzoli P, Mazzanti L, Bergamaschi R, Perri A, Scarano E, Nanni S, Zucchini S, Gualandi S, Cicognani A, Cacciari E. Reduced spontaneous growth hormone secretion in patients with Turner's syndrome. Acta Pædiatr 1999; 88: 610‐3. Stockholm. ISSN 0803‐5253We evaluated growth hormone (GH) secretion in 81 patients with Turner's syndrome (TS) (mean age 10.7 ± 3.6 y) with respect to karyotype, auxological characteristics and growth response to GH treatment (1 IU/kg/wk). None of the patients had spontaneous puberty or had started replacement therapy with estrogens. Thirty‐nine patients (48%) had monosomia 45X, 29 (36%) structural abnormalities of the X chromosome and 13 (16%) X mosaicism. Before the start of GH therapy, each patient underwent an evaluation of mean nocturnal GH concentration (MGHC) and 75 patients also underwent 2 pharmacological tests. MGHC of the TS patients did not differ from that of 29 prepubertal GH‐deficient girls (GH peaks &lt; 8 μg/l after pharmacological tests) and both groups were lower (p &lt; 0.0001 and p &lt; 0.0005, respectively) than MGHCs of 27 short normal girls (GH peak &gt; 8 μg/l). MGHC of the patients with TS was negatively correlated (p &lt; 0.001) with bodyweight excess (BWE) at multiple regression analysis. MGHC of the TS patients with BWE &lt; 20% was significantly higher (p &lt; 0.02) than that of the TS patients with BWE &gt; 20%, but again did not differ from that of the GH‐deficient patients and was lower (p &lt; 0.001) than that of the short normal girls. MGHC did not significantly differ between the 3 groups subdivided according to karyotype. Forty‐four percent of the TS patients showed GH responses to pharmacological tests &lt; 8 μg/l. Height velocity SDS at first and second year of therapy was not influenced by MGHC levels, chronological or bone age, target height or BWE. In conclusion, spontaneous secretion in our patients with TS was lower than that of the short normal prepubertal girls and did not differ from that of GH‐deficient subjects, even if we excluded overweight patients. The level of GH secretion was unable to predict GH response to treatment. □Bodyweight excess, growth hormone secretion, growth hormone therapy, Turner's syndrome

Reduced spontaneous growth hormone secretion in patients with Turner's syndrome.

We evaluated growth hormone (GH) secretion in 81 patients with Turner's syndrome (TS) (mean age 10.7+/-3.6 y) with respect to karyotype, auxological characteristics and growth response to GH treatment (1 IU/kg/wk). None of the patients had spontaneous puberty or had started replacement therapy with estrogens. Thirty-nine patients (48%) had monosomia 45X, 29 (36%) structural abnormalities of the X chromosome and 13 (16%) X mosaicism. Before the start of GH therapy, each patient underwent an evaluation of mean nocturnal GH concentration (MGHC) and 75 patients also underwent 2 pharmacological tests. MGHC of the TS patients did not differ from that of 29 prepubertal GH-deficient girls (GH peaks < 8 microg/l after pharmacological tests) and both groups were lower (p < 0.0001 and p < 0.0005, respectively) than MGHCs of 27 short normal girls (GH peak > 8 microg/l). MGHC of the patients with TS was negatively correlated (p < 0.001) with bodyweight excess (BWE) at multiple regression analysis. MGHC of the TS patients with BWE < 20% was significantly higher (p < 0.02) than that of the TS patients with BWE > 20%, but again did not differ from that of the GH-deficient patients and was lower (p < 0.001) than that of the short normal girls. MGHC did not significantly differ between the 3 groups subdivided according to karyotype. Forty-four percent of the TS patients showed GH responses to pharmacological tests < 8 microg/l. Height velocity SDS at first and second year of therapy was not influenced by MGHC levels, chronological or bone age, target height or BWE. In conclusion, spontaneous secretion in our patients with TS was lower than that of the short normal prepubertal girls and did not differ from that of GH-deficient subjects, even if we excluded overweight patients. The level of GH secretion was unable to predict GH response to treatment.

Recombinant human insulin-like growth factor-I (rhIGF-I) therapy in adults with type 1 diabetes mellitus: effects on IGFs, IGF-binding proteins, glucose levels and insulin treatment.

Insulin-like growth factor-I (IGF-I) has both insulin-like and anabolic actions but unlike insulin, IGF-I circulates bound to a number of specific binding proteins that regulate its availability and activity. Patients with type 1 diabetes mellitus have low levels of circulating IGF-I despite increased growth hormone (GH) secretion, and are a group that may benefit from rhIGF-I therapy. Understanding the relationship between IGF-I and its binding proteins is necessary to appreciate the actions of exogenously administered rhIGF-I. Therefore, we examined the effects of 19 days' subcutaneous administration of rhIGF-I (50 micrograms/kg BID) on the levels of IGF-I, IGF-II and the IGF-binding proteins (IGFBPs), as well as the daily dose of insulin necessary to maintain glycaemic control in patients with type 1 diabetes mellitus. This was an open study, and the patients were studied initially while resident (days 1-5) in the hospital and thereafter (days 6-24) as outpatients. Serum was collected at baseline and at intervals throughout the study for the measurement of total IGF-I, IGF-II, IGFBP-1, -2, -3, free insulin and growth hormone (GH). Daily insulin doses and glucometer readings were recorded throughout the study. The changes in each of these variables were examined. The subjects were six adults (35.3 +/- 4.0 years, mean +/- SE), with type 1 diabetes, and all had reasonable glycaemic control (HbA1c 7.2 +/- 0.5%). rhIGF-I administration increased circulating total IGF-I over two-fold (15.3 +/- 1.9 vs. 33.7 +/- 5.4 nmol/l, mean +/- SEM, P < 0.01, day 1 vs. day 20) and decreased plasma IGF-II concentration (85.0 +/- 4.7 vs. 50.6 +/- 4.7 nmol/l, P < 0.01, day 1 vs. day 20). The dose of insulin required for adequate glycaemic control decreased significantly during rhIGF-I therapy (46 +/- 7 vs. 31 +/- 8 U/day, P < 0.05, day -1 vs. day 19), as did the fasting free insulin concentration (8.4 +/- 1.5 vs. 5.0 +/- 0.8 mU/l, P < 0.05, baseline vs. day 5). IGFBP-2 concentration increased (388 +/- 115 vs. 758 +/- 219 micrograms/l, P < 0.05, day 1 vs. day 20), but IGFBP-1 and IGFBP-3 were unchanged during rhIGF-I treatment. Mean nocturnal GH concentration decreased (12.7 +/- 3.3 vs. 3.8 +/- 0.9 mU/l, P = 0.05) after 4 days' rhIGF-I therapy. Twice daily rhIGF-I therapy in adults with type 1 diabetes resulted in an increase in circulating IGF-I with a reciprocal decrease in IGF-II, and a marked elevation of IGFBP-2 concentration. The levels of IGFBP-1 and -3 were not dramatically changed despite a reduction in the concentration of serum free insulin, and a large decrease in the requirement for insulin. The mechanisms behind these changes remains unclear but alterations in circulating levels of of IGFBPs may alter IGF-I bioactivity. If rhIGF-I is to have an application in the management of adults with type 1 diabetes, further work is necessary to determine the metabolic consequences of the alterations seen in the IGFs and their binding proteins following rhIGF-I administration.

Failure of nocturnal changes in growth hormone to alter carbohydrate tolerance the following morning.

To determine whether the increases in growth hormone that occur during sleep alter carbohydrate tolerance the following morning, two groups of volunteers were studied on two occasions. In one group saline alone was injected and infused (i.e. no octreotide) on one occasion and on the other octreotide was injected at 23.00 hours to inhibit endogenous growth hormone secretion followed by saline infusion to create a state of relative nocturnal growth hormone deficiency. In the other group the octreotide injection was followed on one occasion by a constant growth hormone infusion designed to maintain growth hormone concentrations at "basal" levels throughout the night whereas on the other it was followed by a constant infusion plus two supplemental growth hormone infusions given at midnight and 02.30 hours to mimic the normal nocturnal rise in growth hormone. The next morning, subjects were fed a radiolabelled mixed meal. The differences in the nocturnal growth hormone concentrations had no effect on the glucose, insulin, C-peptide and glucagon concentrations following breakfast ingestion nor did they alter postprandial rates of glucose production, disappearance or substrate oxidation. Thus, the normal nocturnal rise in growth hormone does not appear to be an important regulator of carbohydrate tolerance the following morning.

RELATIONSHIP BETWEEN NOCTURNAL GROWTH HORMONE RELEASE AND BODY COMPOSITION IS MATURATION DEPENDENT 64

We examined the relationship between gender, percent body fat (% fat) and 12-hour growth hormone (GH) release in healthy children and adolescents. The sample included 25 boys and 23 girls in Tanner genital stages (G) 1 through 4. The sample was divided as follows: boys G1+G2=19, G3+G4=6; girls G1+G2=8, G3+G4=15. Body composition was measured by underwater weighing using age-related density corrections. Blood samples were withdrawn every 10 min from 1800 h to 0600 h to determine the mean nocturnal serum GH concentration. The data (mean ± SE) are: Table. Two-way ANOVA showed no gender by maturation interactions. As expected, the boys and girls in G3+G4 were older, taller, and heavier than in G1+G2. As a group, the girls had a higher% fat than the boys. Significant inverse relationships existed between mean GH concentration and% fat for the G1+G2 boys (r = -0.49, p<0.05) and G1+G2 girls (r = -0.73, p < 0.05), but not for the G3 + G4 boys (r = -0.07) and G3+G4 girls (r = 0.05). Conclusion: Pre- and early-pubertally adiposity and GH release are inversely related and the relationship appears to be stronger in females than males. During mid- and late-puberty the relationship is much weaker. Gender and maturational differences in GH release may be due to changes/differences in intra-abdominal visceral fat, insulin resistance, and an over-riding effect of gonadal steroids during puberty.

A case of familial thyroxine binding globulin excess associated with growth hormone deficiency

A 7 years 3 months old Japanese boy with familial thyroxine binding globulin (TBG) excess associated with growth hormone (GH) deficiency is reported. The patients height was 106.4 cm (-2.86 s.d.) and his bone age was 5 years and 3 months. He had no goiter and his developmental milestones were normal. The serum thyroid stimulating hormone (TSH) was 2.8 microU/mL, triiodothyronine (T3) 3.1 ng/mL, thyroxine (T4) 23.4 micrograms/dL and free T4 1.8 ng/dL. The serum TBG level was beyond 80.0 micrograms/mL, with normal TSH response to the thyrotropin-releasing hormone (TRH) test. Familial study revealed that his grandmother, mother, uncle, younger sister and younger brother had high TBG and T3 levels, thus an X-linked co-dominant transmission was suggested. The peak GH responses to insulin and clonidine hydrochloride were 5.8 and 8.2 ng/mL, respectively. The mean nocturnal GH concentration was 2.5 ng/mL. His growth velocity increased from 4.8 to 8.4 cm/year and his serum TBG levels decreased gradually after human growth hormone (hGH) treatment.

Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist. Direct evidence for involvement of endogenous GHRH in the generation of GH pulses.

To study the potential involvement of growth hormone-releasing hormone (GHRH) in the generation of growth hormone (GH) pulses in humans we have used a competitive antagonist to the GHRH receptor, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2(GHRH-Ant). Six healthy young men were given a bolus injection of GHRH-Ant 400 micrograms/kg body wt or vehicle at 2200 h and nocturnal GH concentrations were assessed by every 10-min blood sampling until 0800 h. Integrated total and pulsatile GH secretion were suppressed during GHRH-Ant treatment by 40 +/- 6 (SE) % and 75 +/- 5%, respectively. GHRH-Ant suppressed maximum (7.6 +/- 2.2 vs 1.8 +/- 0.5 micrograms/liter; P < 0.001) and mean (3.3 +/- 1.0 vs 1.1 +/- 0.2 micrograms/liter; P = 0.02) GH pulse amplitudes. There was no change in integrated nonpulsatile GH levels, pulse frequency, or interpulse GH concentration. GHRH-Ant 400 micrograms/kg also suppressed the GH responses to intravenous boluses of GHRH 0.33 micrograms/kg given 1, 6, 12, and 24 h later by 95, 81, 59, and 4%, respectively. In five healthy men, the responses to 10-fold larger GHRH boluses (3.3 micrograms/kg) were suppressed by 82 and 0%, 1 and 6 h after GHRH-Ant 400 micrograms/kg, respectively. These studies provide the first direct evidence that endogenous GHRH participates in the generation of spontaneous GH pulses in humans.

Magnetic resonance imaging of the pituitary area in children treated for acute lymphoblastic leukemia with low-dose (18-Gy) cranial irradiation. Relationships to growth and growth hormone secretion.

To determine the effects of 18-Gy cranial irradiation on growth, growth hormone (GH) secretion, and pituitary magnetic resonance imaging in children who underwent previous irradiation for treatment of acute lymphoblastic leukemia. Clinical survey. Department of Pediatrics of the University of Bologna (Italy). Ten boys and 18 girls who were treated for acute lymphoblastic leukemia; median age at diagnosis was 3.1 years and at the end of follow-up was 11.5 years. Height was periodically measured from diagnosis until the end of follow-up, when GH secretion study and magnetic resonance imaging were performed. The mean height SD score was significantly lower than at diagnosis only at the end of treatment. Nocturnal mean GH concentration and GH response to pharmacological tests (arginine and levodopa [L-dopa]) were pathological in 22 cases (81.5%) and 18 cases (64.3%), respectively. Sixteen cases (59.2%) had a blunted GH release to the three tests. Mean pituitary anterior lobe height was reduced and seven subjects (25%) showed an empty sella. Cranial irradiation with 18 Gy does not seem to influence the growth pattern of most children who are treated for acute lymphoblastic leukemia, despite severe impairment of GH secretion and morphological abnormalities of the sellar area. However, a follow-up until final height is necessary.

Neuroendocrine aspects of primary endogenous depression X: Serum growth hormone measures in patients and matched control subjects

To determine the extent of dysregulation of growth hormone (GH) secretion in endogenous depression, we measured nocturnal serum GH concentrations and GH responses to thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (LHRH), and dexamethasone administration in 40 Research Diagnostic Criteria primary, definite endogenous depressives and 40 individually matched normal control subjects. Compared with their controls, the patients showed no difference in basal nocturnal GH concentrations or in GH responses to TRH or LHRH. The GH measures were not significantly related to the other endocrine measures reported previously, including dexamethasone suppression test status. None of the diagnostic schemes for endogenous/melancholic depression which we studied was significantly related to the GH measures in the patients. Of the other subject and symptom variables, the mood depression factor of the Hamilton depression scale and the performance difficulty factor of the Beck depression inventory were moderately negatively correlated with the nocturnal GH measures. These findings suggest that, in contrast to the previously reported hypothalamopituitary-adrenal cortical and thyroid axis abnormalities in our patients, GH secretion was relatively normal. Patients with more severe depressed mood and greater difficulty accomplishing tasks did have moderately lower nocturnal GH values.

Atenolol Enhances Nocturnal Growth Hormone (GH) Release in GH-Deficient Children during Long Term GH-Releasing Hormone Therapy*

The effect of the selective beta 1-adrenergic blocking agent atenolol (50 or 100 mg, orally) on spontaneous and GH-releasing hormone (GHRH)-stimulated GH release was evaluated in six GH-deficient children during long term therapy with GHRH. Nocturnal GH concentrations were determined every 20 min for 12 h under the following four conditions: 1) control, 2) atenolol administration only, 3) sc GHRH administration only, and 4) combined GHRH and atenolol administration. The mean 12-h nocturnal GH concentrations after administration of atenolol alone [2.4 +/- 0.6 microgram/L (mean +/- SEM)] or GHRH alone (2.7 +/- 1.0 micrograms/L) were indistinguishable from baseline values (2.0 +/- 0.5 microgram/L; P greater than 0.05). In contrast, the addition of atenolol to ongoing GHRH therapy caused a clear augmentation of 12-h overnight GH release compared to that during all other study periods (5.0 +/- 1.3 micrograms/L; P less than 0.05). In a subset of three subjects for whom GH pulse characteristics were determined, the primary mode of the enhanced GH release was through an increase in the amplitude of serum GH pulses. These results are consistent with the hypothesis that beta-adrenergic blocking compounds enhance the responsivity of the pituitary gland to agents that permit GH release by inhibiting hypothalamic somatostatin secretion or action. They suggest that atenolol may have potential as an adjunctive therapy in some children with abnormalities of GH secretion when GHRH is the primary therapeutic agent.

Criteria for recognition of the growth-inefficient child who may respond to treatment with growth hormone.

In this study three groups of short children composed of 104 subjects (61 boys, 43 girls) were evaluated for spontaneous secretion of growth hormone (GH). Group 1 consisted of 10 subjects (6 boys, 4 girls) with "classic" GH deficiency. Group 2 consisted of 31 subjects (17 boys, 14 girls) with "nonclassic" GH deficiency. Group 3 consisted of 63 subjects (38 boys, 25 girls) with short normal stature. Blood samples were drawn every 20 minutes over 24 hours, and the mean GH concentration, nocturnal GH concentration, diurnal GH concentration, pulse amplitude, and number of pulses with a GH peak above 5 micrograms/L were determined. The values for mean height, height velocity, bone age to chronological age ratio, somatomedin C concentration, GH concentration, nocturnal GH concentration, diurnal GH concentration, pulse amplitude, and number of pulses with a GH peak over 5 micrograms/L were significantly greater in group 3 than in group 2, and these same values, except for the mean diurnal GH concentration, were greater in group 2 than in group 1. The mean GH concentration correlated with the mean nocturnal GH concentration. Subjects in groups 1 and 2 were treated with GH for 1.23 +/- 0.53 years (mean +/- SD). All the group 1 subjects and 27 (87%) of the group 2 subjects responded with an increase in height velocity greater than 2 SDs per year of therapy. In conclusion, 87% of subjects with a normal GH response to provocative stimuli testing who had a mean height velocity of less than 4 cm/y, mean height lower than the third percentile, mean bone age to chronological age ratio of less than 0.8, and mean GH concentration less than 3 micrograms/L responded to GH therapy.

GROWRH HORMONE THERAPHY IN NON GH-DEFICIENT SHORT CHILDREN

The growth response during Growth Hormone (GH) treatment was evaluated in a heterogeneous group of 1? prepubertal non GH-deficient short children. Diagnosis were: familial short stature (3), constitutional delay of growth associated with familial short stature (3), intrauterine growth retardation (3), sporadic primary microcephaly (3), and idiophatic short stature (5). Mean height (±SEM) was -2.98±0.08 SD, mean bone age was -2.84±0.27 years, end growth rate was 3.45±0.15cm/year. All children showed a normal GH response to standard pharmacologic stimulation tests. Biosynthetic GH was administered for 6-12 months at o dose of 7-14 IU/m2 b.s./week, 3 or 6 times weekly, i.m. or s.c. Mean growth rate increase was 2.50±0.31 cm/year, 12 children showing an increase >2 cm/year. Growth rate increase was not correlated with height, bone age or GH dose and was weekly correlated with pretreatment height velocity (r=-0.58, p<0.05); a lack of correlation was also demonstrated with mean nocturnal spontaneous GH concentration (arithmetical mean of GH levels in blood samples drawn every 30 min. from 8 p.m. to 8 a.m.) and SmC levels. As suggested by several Authors, a diagnostic-therapeutic trial of GH therapy, with auxological monitoring may be the only means of identifying the non GH-deficient short children who will benefit from treatment.

Nocturnal rhythm of growth hormone in Duchenne patients: effect of different doses of mazindol and/or cyproheptadine.

Human growth hormone (hGH) inhibition may be beneficial for Duchenne muscular dystrophy (DMD) patients and slow the rate of progression of the disease. The purpose of the present investigation was 1) to assess, before any therapeutic trial, the natural growth hormone (GH) rhythm during physiological sleep in DMD patients and in normal control boys of comparable age; 2) to evaluate the effect of different doses of two potential GH inhibitors on nocturnal GH secretion in DMD patients receiving mazindol (1-4 mg), cyproheptadine (4-8 mg), or both drugs. The results from the present investigation showed 1) wide variability in nocturnal GH secretion before medication; 2) no correlation between nocturnal GH concentration and height, age, bone age, L-dopa provocative test, or Tanner staging; and 3) no consistent effect on GH release after mazindol, cyproheptadine therapy, or combined therapy.

Attenuation of spontaneous, nocturnal growth hormone secretion in children with hypothyroidism and its correlation with plasma insulin-like growth factor I concentrations

To define further the alterations in growth hormone (GH) secretion that occur in childhood hypothyroidism, we quantified spontaneous nocturnal secretion in seven patients with primary hypothyroidism. We examined the relationship between plasma insulin-like growth factor I (IGF-I) and GH secretory profile in each patient before and during therapy with L-thyroxine. In contrast to the results of previous studies that used pharmacologic tests of GH release, spontaneous GH secretion was consistently attenuated in the hypothyroid state. Mean nocturnal GH levels were reduced by 58% (1.48 +/- 0.38 ng/ml, mean +/- SEM) in comparison with values obtained during L-thyroxine therapy (3.54 +/- 0.71 ng/ml, p less than 0.01). Coincident with the reduced levels of GH, plasma IGF-I concentrations were lower in patients before therapy (0.46 +/- 0.20 U/ml) compared with concentrations during therapy (1.50 +/- 0.34 U/ml, p less than 0.01). In treated, euthyroid patients, GH and IGF-I levels were equivalent to those of normal children. The excellent correlation (r = 0.77) between plasma IGF-I and mean nocturnal GH concentrations indicates that reduced plasma IGF-I levels in hypothyroidism probably result from suppressed GH secretion.

99 TREATMENT OF SHORT NORMAL PREPUBERTAL CHILDREN WITH GRWOTH HORMONE

The growth reponse to growth hormone (GH) was studied in 9 short normal prepubertal children (6 boys, 3 girls) with a low height velocity. Their average age was 8.2yr (range 4.7-12.1), height standard deviation score (SDS) for chronological age (CA) was -2.6 (-2.0 to -3.7). All had normal maximum plasma GH responses above 10ng/mL to stimulation with clonidine and/or insulin induced hypoglycemia. Assessment of overnight GH secretion by measurement of GH in 20min intervals for 12h yielded low peak levels of 8.7±3.0(SD)ng/mL and low mean pool values of 1.9±1.0. With informed consent treatment with somatrem (Protropin) 0.11±0.01mg/kg three times weekly s.c. was then begun and continued for one year. No major side effects were noted. After 6 months of GH therapy, height velocity SDS for CA increased significantly (p<0.001) from a pretreatment mean of -1.7 (-0.6 to -3.0) to +3.4 (-1.0 to +5.7), representing a change from 4.7cm/yr (3.5-6.0) to 9.3 (5.7-12.5). Height velocity during GH treatment (SDS for CA and cm/yr) inversely correlated with endogenous nocturnal peak GH concentration (r=-0.76, and r=-0.78; both p<0.05). We conclude that some short normal children with low height velocity and low endogenous GH secretion may profit from GH therapy. A major goal should be the proper identification of these patients and careful long-term follow-up to final height. Supported by Genentech, Inc., South San Francisco, California.