Blunted Growth Hormone Secretion Research Articles

Diagnosis of Growth Hormone Deficiency is Affected by Calibrators Used in GH Immunoassays

Growth hormone (GH) values vary among immunoassays depending on different factors, such as the assay method used, specificity of antibodies, matrix difference between standards and samples, and interference with endogenous GH binding proteins (GHBPs). We evaluated whether the use of different calibrators for GH measurement may affect GH values and, consequently, the formulation of GH deficiency (GHD) diagnosis in children. Twenty-three short children (5 F, 18 M; age 11.4±3.1 years), with the clinical characteristics of GHD (height: -2.3±0.5 SDS; height velocity -2.3±1.5 SDS; IGF-I -1.2±0.9 SDS), underwent GH stimulation tests to confirm the clinical diagnosis of GHD. Serum GH values were measured with Immulite 2000, using 2 different calibrators, IS 98/574, a recombinant 22 kDa molecule of more than 95% purity, and IS 80/505, of pituitary origin and resembling a variety of GH isoforms. We found blunted GH secretion in 20 subjects with the Immulite assay using the IS 98/574 GH as a calibrator, confirming the diagnosis of GHD. Subsequently, using IS 80/505 GH as a calibrator, in the same samples only 14 children showed reduced GH levels. The total cost for the first year of GH therapy of patients diagnosed with IS 98/574 as a calibrator was higher than that for patients diagnosed with IS 80/505 as a calibrator. These data confirm that GH values may depend on different calibrators used in the GH assay, affecting the formulation of GHD diagnosis and the consequent decision to start GH treatment.

Modulation of circulating IGF-I and IGFBP-3 levels by hormonal regulators of energy homeostasis in obese children

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are key factors in the control of somatic growth. Recent work revealed a critical role for the transcription factor STAT5b in GH stimulated IGF-I gene expression. In obesity, the normal regulation of the GH/IGF-I axis is disturbed, with normal levels of circulating IGF-I despite blunted GH secretion. We hypothesized that leptin or other hormonal regulators of energy homeostasis, which can activate Stat5b-regulated gene expression or exert an effect on GH secretion, might be able to substitute for GH in terms of IGF-I synthesis. Thus, the aim of this study was to identify potential regulators of IGF-I serum levels in obesity with a particular focus on the interaction of leptin and IGF-I. In a cross-sectional study, we measured hormonal and auxiological parameters in 99 obese children who were referred to our obesity outpatient clinic and analysed correlations between unadjusted hormone levels and between hormone concentrations expressed as SDS values, adjusted for sex, age, and/or puberty and BMI. Serum concentrations of IGF-I correlated highly significant with IGFBP-3, leptin, fasting ghrelin and insulin (p<0.001). However, when expressing hormone levels as SDS values, only leptin SDS and IGFBP-3 SDS correlated significantly with IGF-I SDS (p<0.01). This correlation between leptin SDS and IGF-I SDS was more pronounced in prepubertal and in male subjects, with increasing IGF-I SDS values paralleling an increase in leptin SDS tertiles in prepubertal subjects. In linear regression analyses, leptin SDS, IGFBP-3 SDS and BMI SDS contributed significantly to the variation of IGF-I SDS values, and explained 53.3% of the variability of IGF-I SDS levels in male subjects. In summary, we demonstrated a strong correlation of age and sex-adjusted standard deviation scores (SDS) for IGF-I and leptin in obese children, which is modulated by sex, pubertal stage and body weight. Whether this association results from a direct induction of hepatic IGF-I gene expression by leptin or reflects a more complex interrelationship between IGF-I and obesity-related factors should be subject of future research.

The GH/IGF-1 Axis in Obesity: Physiological and Pathological Aspects

The cluster of cardiovascular risk factors-abdominal obesity, dyslipidaemia, insulin resistance and hypertension-has been recognized as the core of the metabolic syndrome. Adults with severe growth hormone (GH) deficiency have, to a large extent, features of the metabolic syndrome, and there is a strong inverse association between visceral fat accumulation and blunted GH secretion in adults. Hyposomatotropism in abdominal obesity has therefore been suggested to be of importance for its metabolic consequences. However, the underlying pathophysiological mechanisms are poorly understood. Prevalence of the metabolic syndrome is steadily increasing worldwide. Overnutrition and sedentary habits are the stigmata of modern society that predispose genetically susceptible individuals to develop central obesity and other features of the metabolic syndrome including glucose intolerance, hypertension and dyslipidemia. Although there are still no unified definitions of the syndrome, it is clear that this condition is associated with an increased risk for development of cardiovascular disease (CVD) and diabetes mellitus (DM). In this review, we discuss current evidence regarding alterations in the GH-IGF- 1 axis in abdominal obesity and its possible impact on other features of the metabolic syndrome.

Biological studies in depressed children and adolescents

The objective was to review the literature on the biological correlates of major depressive disorder (MDD) in children and adolescents. A computerized search for articles published during the last 20 years was done and selected studies presented. To date, examination of growth hormone (GH), prolactin, and cortisol levels after pharmacological stimulation have shown abnormalities in the secretion of these hormones (e.g. blunted GH secretion after the administration of growth hormone releasing hormone). Identical results have been found in never-depressed children at high risk to develop MDD due to high family loading for MDD suggesting that alteration in certain hormonal systems may be trait markers for MDD. Other biological studies (e.g. the hypothalamic--pituitary axis, sleep electroencephalogram) have yielded more inconsistent results with subjects with melancholic symptoms, severe depressions, and older age showing some abnormalities similar to the ones reported in adults with MDD. Factors such age, sex, maturation, psychiatric family history and exposure to stress need to be considered since they also affect the same biological systems associated with the aetiology of MDD. Considerable biological research has been done in youth with MDD. Further research is needed to investigate whether these markers predict the development of new episodes of MDD, recurrences, and treatment response. Also, these and other studies using more sophisticated methods (e.g. functional MRI) aimed at elucidating the interrelationship between biological and other risk factors are needed.

Regulation of somatotroph cell function by the adipose tissue.

Obese subjects exhibit a marked decrease in plasma growth hormone (GH) levels. However, the mechanisms by which increased adiposity leads to an impairment of GH secretion are poorly understood. Recent evidence suggests that the adipose tissue can markedly influence GH secretion via two different signals, namely free fatty acids (FFA) and leptin. FFA appear to inhibit GH secretion mainly by acting directly at pituitary level. Interestingly, reduction in circulating FFA levels in obese subjects led to a marked increase in GH responses to different GH secretagogues. This indicates that FFA exert a tonic inhibitory effect that contributes to blunted GH secretion in obese subjects. Recent data have shown that leptin is a metabolic signal that regulates GH secretion, since the administration of leptin antiserum to adult rats led to a marked decrease in spontaneous GH secretion. However, leptin prevents,the inhibitory effect exerted by fasting on plasma GH levels. The effect of leptin in adult rats appears to be exerted at hypothalamic level by regulating growth hormone releasing hormone (GHRH), somatostatin and neuropeptide Y (NPY)-producing neurones. In addition, during fetal life or following the development of pituitary tumors, leptin can also act directly at the anterior pituitary.

Effect of aging on growth hormone-induced insulin-like growth factor-I secretion from cultured rat chondrocytes

The physiological roles of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in adult other than their effects on tissue growth is to maintain the integrity of the organism. It has been proposed that reduced availability of both hormones in late adulthood may contribute to the initiation of the major alterations and senescent changes in body composition that characterize normal human aging. Since accumulated evidence points to a direct interplay of GH with chondrocytes in cartilage, we determined in the present study the effect of aging on both basal and GH-stimulated IGF-I production from rat cultured chondrocytes. Namely, we investigated the effect of 0, 10 and 100 ng/ml of growth hormone on IGF-I levels during 1, 2, 4 and 8 days in monolayer cultured costal chondrocytes from 2-, 6-, 14- and 18-month-old rats. Measurement of IGF-I levels was done by a radioimmunoassay following a validated formic acid-heating-acetone extraction procedure. In 6- and 14-month-old rat chondrocytes, basal IGF-I secretion was higher than that of the 2-month-old control rats. In 18-month-old rat chondrocytes, basal IGF-I secretion was lower than in any other age group. Whereas in 2-, 6- and 14-month-old rat chondrocytes, GH induced a dose-related IGF-I response which was highly significant on day 8, the 18-month-old rat chondrocytes no longer responded to GH treatments. Our results suggest that the decrease in IGF-I production from cultured rat chondrocytes could be related to the blunted GH secretion in the course of aging. Therefore, GH availability in the course of aging appears to be a determinant factor in tissue responsiveness and underscores the hypothesis that GH replacement could present a therapeutic potential against the aging senescent changes.

Growth hormone secretion during sleep in male depressed patients

1. 1. Growth hormone (GH) secretion during sleep was studied in ten male patients with major depression according to DSM III and eight normal controls. 2. 2. Samples were collected through a continuous blood withdrawal pump while sleep was recorded in the laboratory. 3. 3. The results showed a marked decrease in the GH secretion mainly during the first three hours of sleep in depressed patients as compared to normal controls. DST and TRH tests were also administered to the same patients but no correlation was observed between a positive test and a blunted GH secretion, suggesting that the various neuroendocrinological disturbances do not coexist in all depressed patients. 4. 4. This disturbance in GH secretion during sleep, along with reduced slow wave sleep (SWS), gives support to the theory that GHRH is the common stimulus of SWS and GH release and that the ratio of GHRH and its counterpart CRH plays a major role in the pathophysiology of disturbed endocrine activity during sleep in depression.

Growth Velocity After Growth Hormone (GH) Therapy in Children with Isolated GH Deficiency (IGHD) and Prader-Willi syndrome (PWS) † 397

Short stature, obesity, decreased lean mass, cryptorchidism, and hypogonadism are characteristic features of PWS. The growth pattern in PWS suggest an abnormality in GH secretion or action. Body composition changes in PWS including increased adipose and decreased muscle mass are similar to those children with IGHD. In GH deficiency, GH secretion is negligible and IGF levels are low, leading to decreased linear growth. In exogenous obesity the GH are low but the IGF levels however are normal or high. Contrary to exogenous obesity PWS children have decreased growth velocity, sexual development, muscle mass, and IGF levels. Other investigators and ourselves have shown blunted GH secretion in both obese and non-obese PWS children and the benefits of GH therapy (J of Ped End & Metab. 9,943-400, 1996.). We now compare the growth velocity in 96 PWS children and 6965 children with IGHD from the National Cooperative Growth Study (NCGS) after 4 years of GH therapy. The linear growth was similar in both groups. Although is unlikely that GHD is the only cause of short stature, decreased growth velocity and increased adiposity in PWS children, suggest that GHD is a common feature and significant contributory factor in expression of PWS phenotype. Figure

Two-Month Treatment of Obese Subjects with the Oral Growth Hormone (GH) Secretagogue MK-677 Increases GH Secretion, Fat-Free Mass, and Energy Expenditure1

Obesity is associated with blunted GH secretion, unfavorable body composition, and increased cardiovascular mortality. The objective of this study was to investigate the effects of oral treatment with the GH secretagogue MK-677 on GH secretion and body composition in otherwise healthy obese males. The study was randomized, double blind, parallel, and placebo controlled. Twenty-four obese males, aged 18-50 yr, with body mass indexes greater than 30 kg/m2 and waist/hip ratios greater than 0.95, were treated with MK-677 25 mg (n = 12) or placebo (n = 12) daily for 8 weeks. Serum insulin-like growth factor I (IGF-I) increased approximately 40% with MK-677 treatment (P < 0.001 vs. placebo). Serum IGF-binding protein-3 was also significantly increased (P < or = 0.001 vs. placebo). GH and PRL (peak and area under the curve values) were significantly increased after the initial dose of MK-677. Significant increases, with the exception of peak PRL, persisted at 2 and 8 weeks of treatment. The increases in GH and PRL after the initial dose were significantly greater than the increase seen after multiple doses. Serum and urinary concentrations of cortisol were not increased at 2 and 8 weeks (P = NS, vs. placebo). Fat-free mass increased significantly in the MK-677 treatment group when determined with dual energy x-ray absorptiometry (P < 0.01) or using a four-compartment model (P < 0.05). Total and visceral fat were not significantly changed with active therapy. The basal metabolic rate was significantly increased at 2 weeks of MK-677 treatment (P = 0.01) but not at 8 weeks (P = 0.1). Fasting concentrations of glucose and insulin were unchanged, whereas an oral glucose tolerance test showed impairment of glucose homeostasis at 2 and 8 weeks. We conclude that 2-month treatment with MK-677 in healthy obese males caused a sustained increase in serum levels of GH, IGF-I, and IGF-binding protein-3. The effects on cortisol secretion were transient. Changes in body composition and energy expenditure were of an anabolic nature, with a sustained increase in fat-free mass and a transient increase in basal metabolic rate. Further studies are needed to evaluate whether a higher dose of MK-677 or a more prolonged treatment period can promote a reduction in body fat.

Enhanced growth hormone (GH) responsiveness to GH-releasing hormone after dietary restriction in patients with Cushing's syndrome.

In patients with Cushing's syndrome, decreased growth hormone (GH) secretion is observed although the basic mechanism is not yet understood. A short-term hypocaloric diet is known to increase both spontaneous and GHRH-stimulated GH secretion in normal subjects. In order to gain further insight into the altered GH secretion in patients with Cushing's syndrome, we assessed the effect of a short-term hypocaloric diet on GH responses to GHRH in these patients. Two GHRH tests (1 microgram/kg i.v.) were performed, the first under basal conditions (normocaloric diet) and the second after a 3-day hypocaloric diet (650 cal/day). Six female patients with untreated Cushing's disease. Plasma GH levels were measured by immunoradiometric assay. GHRH-induced GH release was impaired in patients with Cushing's disease on a normal diet (mean peak 12.4 +/- 6.4 mU/l, area under the curve (AUC) 744 +/- 332 mU/l/120 min). Following a hypocaloric diet, GH responses to GHRH were markedly enhanced in the same group of patients (mean peak 46.2 +/- 14.8 mU/l, AUC 3142 +/- 1032 mU/l/120 min, P < 0.05). This study demonstrates that in patients with Cushing's disease the somatotroph hyporesponsiveness to growth hormone releasing home is improved after a short-term hypocaloric diet. Therefore, blunted growth-hormone secretion in chronic hypercortisolism is a potentially reversible state and the secretory capacity of the somatotroph appears not to be severely compromised in patients with Cushing's disease.

Is obesity-related insulin status the cause of blunted growth hormone secretion in turner's syndrome?

Growth hormone (GH) secretion is reduced in girls with Turner's syndrome (TS) at pubertal age. We have recently proposed that the impairment of GH release in TS girls might be secondary to obesity. In the present study, we assessed the influence of overweight-related insulin status on spontaneous GH secretion in a group of 15 TS girls. Eighteen age-matched short normal subjects and six short obese prepubertal children were chosen as controls. Anthropometry, spontaneous GH secretion, insulin-like growth factor-I (IGF-I) serum levels, basal fasting insulin, and glucose concentrations were determined. The percentage of ideal body weight (IBW) was used as an index of nutritional status. Baseline fasting glucose (milligrams per deciliter) to insulin (milliunits per liter) ratio (G/I) was chosen as an index of insulin resistance. GH secretion was significantly lower in TS girls than in non-obese children ( P < .005), whereas no significant difference was seen between TS and obese subjects. IGF-I levels were not statistically different in all groups. GH secretion was confirmed to be related to the degree of overweight ( r = −.52, P < .05 in TS girls and r = −.74, P < .0001 in control group). G/I was closely related to both the percentage of IBW ( r = −.59, P = .02) and GH level ( r = .57, P = .03) in TS patients. These results confirm that the blunted GH secretion in TS patients is dependent on nutritional status, and suggest that insulin resistance secondary to overweight might represent the pathophysiologic link between the obesity-related metabolic status and impaired GH secretion.

Arginine potentiates but does not restore the blunted growth hormone response to growth hormone-releasing hormone in obesity

A blunted growth hormone (GH) response to several stimuli, including growth hormone-releasing hormone (GHRH), has been shown in obesity. Arginine (ARG) has been demonstrated to potentiate the GHRH-induced GH increase in normal subjects, likely acting via inhibition of hypothalamic somatostatin release. To shed further light onto the mechanisms underlying the blunted GH secretion in obesity, we studied the effect of ARG (0.5 g/kg infused intravenously [IV] over 30 minutes) on both basal and GHRH (1 μm/kg iv)-stimulated GH secretion. Eight obese subjects (aged 26.4 ± 3.9 years; body mass index, 39.0 ± 1.9 kg/m 2) and eight normal control volunteers (aged 27.0 ± 1.7 years; body mass index, 22.3 ± 0.5 kg/m 2) were studied. In obese subjects, the GH response to both GHRH and ARG was lower ( P < .01 and P < .002, respectively) than in controls. ARG potentiated the GH response to GHRH in obese patients ( P < .0003). However, in these patients, the GH secretion elicited by GHRH, even when coadministered with ARG, persisted at reduced levels ( P < .005) when compared with controls. Basal insulin-like growth factor-1 (IGF-1) levels did not significantly differ in obese subjects and in normal subjects (161.1 ± 37.0 v 181.0 ± 12.8 μg/L). In conclusion, ARG enhances the blunted GHRH-induced GH increase in obese patients, but the GH responses to ARG alone and to ARG + GHRH persist at lower levels than in normals. Thus, our results suggest the existence of a reduced pituitary GH pool in obesity.

Corticosteroid‐induced growth hormone secretion in normal and obese subjects

In normal subjects, corticosteroids stimulate growth hormone (GH) secretion at 3 hours. Obesity is associated with blunted GH secretion. In order to clarify both the deranged mechanism of GH secretion in obesity and the corticosteroid mechanism of action we have assessed in normal and obese subjects the effects of dexamethasone, pyridostigmine (a drug capable of suppressing somatostatin release) and GHRH. We also compared in normal subjects the stimulatory effect of three different corticosteroids on plasma GH levels. In both normal and obese subjects the following tests were carried out: placebo; dexamethasone alone (4 mg i.v. at 0 minutes); and dexamethasone plus pyridostigmine (120 mg p.o. at 60 minutes). In normal subjects we also studied the effects of hydrocortisone (100 mg i.v. at 0 minutes) and deflazacort (a corticosteroid that does not cross the blood-brain barrier) (60 mg i.v. at 0 minutes). In obese subjects we also assessed the effect of dexamethasone plus GHRH (100 micrograms i.v. at 150 minutes) on plasma GH levels. Ten normal subjects and 22 obese subjects were studied. Normal controls were within 10% of their ideal body weight. Obese subjects had a body mass index of 37.1 +/- 1.1 (mean +/- SEM). Plasma GH levels were measured by radioimmunoassay. Dexamethasone-induced GH secretion in normal subjects (28.6 +/- 7.8 millimicron/l, P less than 0.05). Corticosteroids did not alter GH levels in obese subjects. Pretreatment with pyridostigmine increased dexamethasone-induced GH release in normal subjects (40.8 +/- 6.8 millimicron/l) but this did not achieve statistical significance. Dexamethasone plus pyridostigmine did not alter GH levels in obese subjects (8.0 +/- 1.6 mU/l). In some subjects, dexamethasone pretreatment potentiated GHRH-stimulated GH secretion, while in half the subjects the basal GH levels were not altered. In control subjects, hydrocortisone and deflazacort caused GH release similar to dexamethasone. Corticosteroids are a new and selective stimulus of GH secretion. They do not cause GH release in obese subjects. Their relative independence from cholinergic control suggest that they act by reducing somatostatin secretion.

Alteration of somatostatin but not growth hormone-releasing factor pituitary binding sites in obese Zucker rats

The present study was designed to determine whether the diminution of growth hormone (GH) secretion that occurs in obese Zucker rats is related to alterations of GH-releasing factor (GRF) or somatostatin (SRIF) pituitary binding sites. Cold saturation studies were performed in pituitary homogenates of 4-month-old lean and obese rats, using [ 125I-Tyr 10]hGRF(1–44)NH 2 as radioligand and [ 127I-Tyr 10]hGRF-(1–44)NH 2 as competitor, and in pituitary membrane preparations, using [ 125I-Tyr 0, d-Trp 8]SRIF14 as radioligand and [ 127I-Tyr 0, d-Trp 8]SRIF14 as competitor. In lean rats, analysis of the curves by the Ligand program revealed the presence of two distinct classes of GRF binding sites, the first being of high affinity ( 0.74 ± 0.11 nM ) and low capacity ( 118 ± 31 fmol/mg protein ), the second being of lower affinity ( 880 ± 240 nM ) and higher capacity ( 140 ± 35 pmol/mg protein ), and of a single class of SRIF binding sites (affinity: 0.40 ± 0.12 nM ; capacity: 24 ± 6 fmol/mg protein ). In obese rats, no difference was observed in GRF binding parameters for both classes of sites, but the concentration of somatostatin binding sites was reduced by 67% when compared to their lean littermates. These findings suggest that the SRIF pituitary receptors are down-regulated in obese Zucker rats and indicate that no alteration of GRF pituitary binding sites contribute to the blunted GH secretion observed in this model of obesity.

Acute Effects of Clonidine and Growth-Hormone-Releasing Hormone on Growth Hormone Secretion in Patients with Hyperthyroidism

Patients with hyperthyroidism have reduced growth hormone (GH) responses to pharmacological stimuli and reduced spontaneous nocturnal GH secretion. The stimulatory effect of clonidine on GH secretion has been suggested to depend on an enhancement of hypothalamic GH-releasing hormone (GHRH) release. The aim of our study was to evaluate the effects of clonidine and GHRH on GH secretion in patients with hyperthyroidism. Eight hyperthyroid females with recent diagnosis of Graves' disease (age range 20-55 years, body mass index range 19.2-26.2 kg/m2) and 6 healthy female volunteers (age range 22-35 years, body mass index range 19-25 kg/m2) underwent two experimental trials at no less than 7-day intervals: (a) an intravenous infusion of clonidine 150 micrograms in 10 ml of saline, or (b) a bolus intravenous injection of human GHRH (1-29)NH2, 100 micrograms in 1 ml of saline. Hyperthyroid patients showed blunted GH peaks after clonidine (7.1 +/- 1.7 micrograms/l) as compared to normal subjects receiving clonidine (28.5 +/- 4.9 micrograms/l, p less than 0.05). GH peaks after GHRH were also significantly lower in hyperthyroid subjects (8.0 +/- 1.7 micrograms/l) as compared to normal subjects receiving GHRH (27.5 +/- 4.4 micrograms/l, p less than 0.05). No significant differences in the GH values either after clonidine or GHRH were observed in the two groups of subjects examined. Our data demonstrate that the GH responses to clonidine as well as to GHRH in patients with hyperthyroidism are inhibited in a similar fashion with respect to normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Retinopathy and plasma growth hormone levels in idiopathic hemochromatosis with diabetes.

In patients with idiopathic hemochromatosis, retinopathy was investigated by ophthalmoscopy and fluorescein angiography and was present in eight out of 23; this prevalence is similar to that reported in patients with diabetes aged between 30 and 60 years at onset of diabetes and with the same duration of the disease; in these eight patients retinopathy was of mild degree, with no impairment of visual acuity, fewer than 10 microaneurysms in each fundus, and no other retinal abnormatic islets directly. These studies confirm that anticholinergic drugs may be useful adjuvants in treating these patients.