Twenty-four hour growth hormone secretion in a patient with Werner's syndrome

OBJECTIVE: To assess the 24-h endogenous secretory growth hormone (GH) profile and serum insulin-like growth factor-I (IGF-I) response to exogenous recombinant human growth hormone (rhGH) in a patient with Werner's syndrome. DESIGN: Blood sampling every 20 min for 24 h followed by three daily injections of growth hormone. SETTING: General Clinical Research Center. PATIENTS: Single patient with Werner's syndrome. MEASUREMENTS: Serum GH and IGF-I. RESULTS: Growth hormone pulses were absent during the 24-h monitoring period. Likewise, integrated GH concentrations were very low at 0.25 mu min/mL, and no peaks occurred after sleep onset. Following single daily administration of rhGH, serum GH and IGF-I rose. CONCLUSIONS: Our findings support previous but less extensive studies suggesting patients with Werner's syndrome have reduced growth hormone levels. Preliminary investigations using rhGH in patients with Werner's syndrome should be considered.     

Influence of chronic Naltrexone treatment on growth hormone and insulin secretion in obese subjects

OBJECTIVE: Recent studies have demonstrated the restoration of a normal 24 h GH profile induced by a reduction of insulinaemia after weight loss, suggesting a reciprocal relationship between plasma insulin and GH concentrations. We aimed to clarify if an opiate-induced reduction in plasma insulin could affect GH secretion in obesity. DESIGN: We have studied the insulin response to an oral glucose tolerance test (OGTT) and the GH response to GHRH before and after prolonged treatment with Naltrexone (NTX). C-peptide, IGF-I, IGFBP-3 plasma levels and the IGF-I/IGFBP-3 molar ratio were also determined. SUBJECTS: Twelve obese women (aged 25-41 y; Body mass index (BMI): 31-39 kg/m2) and six lean normal women (aged 25-38; BMI: 19.8-23.1 kg/m2). MEASUREMENT: GH was determined by the IRMA method; insulin, C-peptide, IGF-I and IGFBP-3 were assayed by the RIA method. For molar comparison between IGF-I and IGFBP-3 we have considered 30.5 kDa the molar weight of IGFBP-3. Results are expressed as mean +/- s.e.m. RESULTS: We observed a significant decrease in basal concentration of both insulin (230.1 +/- 34.9 vs 133.2 +/- 16.9 pmol/L; P < 0.005) and C-peptide (3.7 +/- 0.3 vs 2.4 +/- 0.1 micrograms/L; P < 0.02). No modifications in the insulin secretory response to the OGTT were observed. A significant increase of the GHRH-induced GH peak response (7.7 +/- 1.4 vs 19.7 +/- 3.1 micrograms/L; P < 0.01) and GH-AUC (533 +/- 151 vs 1415 +/- 339 micrograms/L/120 min; P < 0.01) was found after NTX treatment. A negative correlation was found between basal insulin and GH peak values, both before (r = -0.641, P = 0.027) and after NTX (r = -0.714, P = 0.013). No modifications were found in IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio. Moreover, NTX affected neither the insulin response to OGTT or IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio in a group of six lean controls. Conversely, NTX significantly reduced the GH response to GHRH, when expressed as both peak and AUC values. CONCLUSIONS: The opiate antagonist significantly reduced basal insulin concentrations and augmented the GH response to GHRH in obese subjects. In the absence of modifications in IGF-I and IGFBP-3 plasma levels and their molar ratio, we propose that insulin may exert a negative feedback on GH secretion.     

Effects of sumatriptan on growth hormone releasing hormone-stimulated growth hormone secretion in acromegaly

Specific inhibition of mammalian genes is possible through the use of antisense oligonucleotides (AS ODNs) or ribozymes. These strategies have led to a better understanding of several cellular and molecular mechanisms, among which cancer development. Recently, these strategies have been applied also for therapeutical purposes in diseases such as AIDS and cancer. In some of these therapeutical trials the antisense strategy is combined with gene transfer technology: the AS ODN or the ribozyme are expressed within the cell by the use of adenoviral or retroviral vectors. However, many difficulties have still to be overcome before ODNs and ribozymes can be used routinely in the clinic.     

Treatment with growth hormone suppresses cortisol production in man

The effect of biosynthetic human growth hormone (GH) on the cortisol production rate was determined in healthy men (N=8) using the stable isotope dilution technique and mass spectrometry. 1alpha,2alpha-D-Cortisol was infused at a dose of 110+/-9 microg/h for 10 hours (8 AM to 6 PM). Blood samples obtained at 20-minute intervals from 2 PM to 6 PM were pooled during two 2-hour periods. Subsequently, each subject received a daily dose of biosynthetic human GH (4 IU/d subcutaneously [SC]) for 7 days. This resulted in an increase of plasma somatomedin C from a basal level of 0.65+/-0.13 U/mL to 1.18+/-1.2 U/mL on day 7 (P < .0001). Plasma concentrations of corticotropin (ACTH) and cortisol-binding globulin (CBG) were similar before and after administration of GH. Determination of the cortisol production rate was repeated on day 7 of treatment with GH. Due to its physiological diurnal rhythmicity, endogenous production of cortisol during basal conditions was higher (P < .05) between 2 and 4 PM (0.70+/-0.30 mg/h) versus 4 to 6 PM (0.55+/-0.28 mg/h). Following treatment with GH, the values were 0.40+/-0.11 mg/h (2 to 4 PM, P < .01 v day 1) and 0.31+/-0.11 mg/h (4 to 6 PM, P < .01 v day 1). Thus, in healthy men, treatment with SC, GH induces a decrease in endogenous cortisol production rates.     

Normal growth hormone secretion in growth hormone insufficient children retested after completion of linear growth

Tuberculosis of the cervical spine is rare, comprising 3-5% of cases of tuberculosis of the spine. Eight patients with tuberculosis of the cervical spine seen during 1989-1992 were reviewed. They all presented with neck pain. The 4 children presented with a kyphotic deformity. In all the children the disease was extensive, with a large prevertebral abscess formation, while in the adults it was localised to one or two motion segments. Cord compression was present in 4 of the 8 patients. All the patients were treated with antituberculosis drugs and 6 underwent surgery. There was full neurological recovery in all patients. The kyphosis was improved though not fully corrected. There was a problem in stabilisation of severe involvement of the body and dens of C2. Surgery seems to play a major role in the treatment of tuberculosis of the cervical spine.     

Levodopa-stimulated growth hormone secretion and diabetic retinopathy

Since growth hormone has been implicated as a possible etiologic factor in the development of diabetic retinopathy, we examined growth hormone levels in two groups of growth-onset diabetics matched for age and duration of disease. The experimental group had definite proliferative diabetic retinopathy; the control group of growth-onset diabetics had no significant retinopathy. Basal and levodopa-stimulated levels of growth hormone were determined for each group. Growth hormone response could not be correlated with the presence or absence of diabetic retinopathy (P less than .05).     

Differential effect of insulin-like growth factor-1 and growth hormone on hypothalamic regulation of growth hormone secretion in the rat

Pharmacological administration of either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) were reported to inhibit endogenous GH release in humans and in the laboratory animal. We have evaluated the short-term differential mechanisms whereby the two hormones affect hypothalamic regulation of GH secretion. Wistar male rats (90 days old) were injected i.p. with either GH (recombinant GH NIAMDD, Baltimore, MD, USA), rIGF-1 (Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan) or saline. Animals were sacrificed at 15, 30, 60 and 120 minutes following injection. Hypothalami were dissected and extracted immediately and the levels of growth hormone-releasing hormone (GHRH) and somatostatin were determined using specific antisera. Trunk blood was collected for GH and IGF-1 determination by RIA. Administration of IGF-1 or GH markedly decreased hypothalamic somatostatin stores by 77% and 54% respectively, within 15 minutes. Concomitantly, the wide range of GH levels found in the control group was reduced in the IGF-1 treated group suggesting that the pulsatile pattern of GH secretion was suppressed. Growth hormone administration induced an increase in hypothalamic GHRH stores (60% at 120 minutes). During this period serum IGF-1 levels were not altered. It is suggested that short term modulation of hypothalamic neurohormones by GH and IGF-1 is mediated by rapid stimulation of somatostatin release by both hormones, and inhibition of GHRH release is induced only by GH.     

Impairment of growth hormone responsiveness to growth hormone releasing hormone and pyridostigmine in patients affected by Prader-Labhardt-Willi syndrome

In order to evaluate the impairment of GH response in patients affected by Prader-Labhardt-Willi (PLW) syndrome, in 18 patients we studied GH response to clonidine and to GHRH + pyridostigmine, a cholinergic drug which enhances GHRH induced GH responsiveness in obese patients. After clonidine GH response was abnormal in 14/18 subjects (mean GH peak: 4.1 +/- 1.3 micrograms/l; area under curve: 208.1 +/- 74.2 micrograms/l.h) while all but 5 patients showed an inadequate GH response to GHRH + pyridostigmine (mean GH peak: 13.4 +/- 2.5 micrograms/l; area under curve: 903.4 +/- 171.0 micrograms/l.h). However, in the three patients with low adiposity index, GH response to GHRH + pyridostigmine was significantly higher than that observed in fatter subjects. In addition, GH response to GHRH + pyridostigmine was negatively correlated to age and adiposity index. In conclusion, our data are consistent with the hypothesis of the existence of a complex derangement of GH neuroendocrine regulation in these subjects.     

Control of prolactin and growth hormone secretion in mice by obesity

Prolactin (PRL) and growth hormone (GH) secretions in mice rendered obese by the administration of gold thioglucose (GTG) are abnormal. The objective of the present experiments was to determine whether the effects were related to the drug or to the resultant obesity. Perphenazine-induced PRL release in normal mice and in GTG-injected non-obese mice was compared to that of GTG-injected obese mice after the initial development of obesity, after body weight reduction by diet control and after the resumption of obesity by ad lib. feeding. The GTG-injected mice which did not become obese had greater (50%) than normal levels of serum PRL following perphenazine stimulation in 2 of 3 experiments. This suggested that the injection of GTG directly affected the control mechanism for PRL secretion, but that the abnormal PRL secretion was probably not the cause of obesity that develops after GTG treatment. Perphenazine-induced PRL levels in mice rendered obese with GTG were much greater (2-3 times higher than normal). However, the unusually high levels of PRL were totally abolished when the body weights of these mice were brought down to normal by dietary restriction. Conversely, when obesity was permitted to recur by giving the mice free access to food, PRL levels reverted back to the original obese pattern. The concentrations of GH were usually lower than normal in GTG-obese mice, and these levels were also more often associated with the development of obesity than with the injection of GTG. The data show a marked influence of obesity on the control of PRL and GH secretions in the mouse.     

Erythroid differentiation and growth inhibition of K562 cells by 2',5'-dideoxyadenosine: synergism with interferon-alpha

We found that 2',5'-dideoxyadenosine (DDA), a P-site specific adenylate cyclase inhibitor, inhibited the growth of K562 cells and caused them to become benzidine positive. The continuous exposure of cells to DDA was needed to recruit cells for growth inhibition and differentiation. Fetal calf or human sera were also necessary for DDA to induce differentiation. DDA at a concentration of 1.5 mM with serum induced 98% of the cells to produce hemoglobin and inhibited their growth to 15% of that of the control. An increase of epsilon-globin mRNA and a decrease of c-myc and c-myb mRNA occurred only during differentiation in the presence of fetal calf serum (FCS). An incubation with DDA and interferon-alpha (IFN-alpha) or hemin synergistically induced more benzidine-positive cells than in the presence of DDA alone, although IFN-alpha did not trigger differentiation by itself. The erythroid differentiation and growth inhibition were, however, not related to a decreased intracellular cyclic AMP (cAMP) concentration induced by DDA. The simultaneous incubation with dibutyryl cyclic AMP (dbc-AMP) and DDA enhanced the effects of DDA. Adenine, a possible metabolite of DDA digestion by purine nucleoside phosphorylase (PNP), also induced erythroid differentiation in K562 cells. However, it did not act synergistically with IFN-alpha.     

The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes

The type 1 copper in Pseudomonas aeruginosa azurin was studied by electron paramagnetic resonance (EPR) spectroscopy at low microwave frequencies. Partially resolved ligand hyperfine structure was observed in the perpendicular region of the spectra at both S-band (2.4 GHz) and L-band (1.1 GHz). A trial and error method, requiring several hundred simulations, has been used to simulate the low frequency EPR data and yield an optimum value of 30 MHz for ACUx, more than one half that previously reported. The fit between the simulated and experimental data is sensitive to changes in the Euler angles and, in particular, to the angle alpha which rotates the Cu A-tensor about the z-axis. Thus, the A- and g-tensors for copper in P. aeruginosa azurin do not appear to be coincident. A value for the Euler angle beta of at least 10 degrees does not disturb the fit between the simulated and experimental data. These studies demonstrate the advantage of evaluating EPR parameters from simulations at more than one frequency, especially at low frequencies where ligand superhyperfine structure may be resolved for type 1 copper.     

Cytokine-induced inhibition of lipid synthesis and hormone secretion by isolated human islets

Interleukin-1, tumor necrosis factor, and interleukin-6 inhibit insulin release and may be cytotoxic to isolated pancreatic islets. These cytokines have been postulated to play an important role in the beta cell destruction characteristic of type 1 diabetes. The present study was designed to investigate the effect of the above cytokines on insulin, glucagon, somatostatin, and thyrotropin-releasing hormone secretion by isolated human islets. In addition, we have investigated if cytokine-induced modifications in hormone secretion are accompanied by modifications in the ab initio synthesis of any specific lipidic fraction. All three cytokines studied, although not modifying insulin and somatostatin release to glucose 5 mmol/L, inhibited the response of both hormones to glucose 20 mmol/L. On the other hand, the cytokines almost completely blocked islet basal glucagon release, without affecting thyrotropin-releasing hormone secretion. The added cytokines also suppressed 20 mmol/L [U-14C]glucose incorporation into both phospholipids and diacylglycerol. Our results demonstrate a beta-, alpha-, and delta-cell, sensitivity to cytokine action. Additionally, they suggest that ab initio lipid synthesis might be implicated in the mechanism of insulin release in human islets.     

Evaluation of growth hormone secretion during sleep and after L-dopa

Control of infectious atrophic rhinitis in swine breeding herds by culturing of 3 series of nasal swab specimens from each animal, with subsequent elimination of Bordetella bronchiseptica culture-positive animals, was evaluated. Thirteen of 17 (77%) B bronchiseptica-infected herds experiencing clinical atrophic rhinitis were feedic rhinitis were freed of clinical signs of the disease by the use of this nasal culturing procedure. In 15 of 23 (65%) B bronchiseptica-infected herds, pigs were cultured negative for this organism at 4 to 10 weeks of age.     

Cholecystokinin (CCK)-induced stimulation of luteinizing hormone (LH) secretion in adult male rhesus monkeys: examination of the role of CCK in nutritional regulation of LH secretion

Studies were performed with the overall goal of testing the hypothesis that cholecystokinin (CCK), a peptide hormone released from the gastrointestinal tract in response to meal consumption, provides a metabolic signal which modulates LH secretion in response to changes in the body's nutritional intake. In an initial study to document the effects of CCK on LH secretion in adult male rhesus monkeys, sulfated CCK-8 (7 and 15 micrograms/kg) was administered to six monkeys, and blood samples were collected from indwelling venous catheters. The 15-micrograms/kg dose of CCK elicited a rapid release of LH, with peak LH levels of 31.29 +/- 7.19 ng/ml occurring within 5-15 min. To determine the CCK receptor type mediating the effect of CCK on LH secretion, specific CCK type-A (L-364,718) and type-B (L-365,260) receptor antagonists (1 mg/kg) were administered to five monkeys 15 min before CCK administration. The CCK-A antagonist completely blocked LH secretion in response to CCK, whereas the CCK-B antagonist had no effect. To assess whether endogenous CCK, released in response to food intake, stimulates LH secretion, six monkeys were fasted for 1 day and then provided with a normal meal of monkey chow (i.e. a refeed meal) the following day, with either no antagonist, CCK-A antagonist, or CCK-B antagonist administered 30 min before the meal. As previously demonstrated, meal consumption after a brief period of fasting caused a rapid stimulation of pulsatile LH secretion. The refeed meal led to a comparable stimulation of LH secretion regardless of whether monkeys received no antagonist (3.7 +/- 0.44 LH pulses/9 h), CCK-A antagonist (3.33 +/- 0.56 LH pulses/9 h), or CCK-B antagonist (4.0 +/- 0.78 LH pulses/9 h). These results indicate that CCK can stimulate LH secretion in adult male rhesus monkeys, acting via type-A CCK receptors. However, endogenous CCK released in response to meal intake does not appear to be responsible for the meal-induced stimulation of LH secretion that occurs when monkeys are fed a normal meal after a brief period of fasting.