The in vitro lipolytic activity of human growth hormone (HGH) has been assayed on fat pads from rats, rabbits and guinea pigs. Results of various experiments suggest that lipolytic activity is an intrinsic property of HGH and that the active sites for the growth-promoting and lipolytic potencies are located in different areas of the HGH molecule.
In order to elucidate whether ectopic ACTH-producing tumours elaborate corticotrophin-releasing factors (CRF)-like materials, the CRF-like activity of tumour extracts was measured by the in vitro pituitary incubation method. Seven out of 12 tumour extracts with suspected ACTH-producing tumours showed CRF-like activity. No correlation was found between ACTH and CRF-like activities in tumour extracts in which both activities were present. The dose-response curve of a tumour extract was almost parallel to that of crude CRF (NIAMDD) and clearly different from those of lysine-8-vasopressin and arginine-vasopressin, both of which showed CRF-like activity by this assay method.
Trypsin digestion considerably lowered the CRF-like activity of a tumour extract. These results suggest that ectopic production of CRF-like substance(s) occurs more frequently than was supposed previously, especially in ACTH-producing tumours.
OBJECTIVE: To evaluate the influence of factors intrinsic to the Japanese population on consequences of growth hormone deficiency (GHD) and effects of GH treatment in adult Japanese hypopituitary patients with GHD. STUDY DESIGN: A 24-week, randomised, placebo-controlled, double-blind study in 64 patients in Japan, with GHD onset during adulthood (AO; n=27) or childhood (CO; n=37). Body composition measured by dual-energy X-ray absorptiometry (DXA) was evaluated centrally. Serum IGF-I, IGF binding protein-3 (IGFBP-3) and lipid levels were determined centrally. RESULTS: In contrast to Caucasian patients, there were no significant differences before treatment between AO and CO patients for body mass index (BMI), lean body mass (LBM) and fat mass (FM). Baseline BMI was >/=25 kg/m(2) for 32.8% of patients. For all patients combined, a significant increase in LBM and decrease in FM (P<0.001 for each) was seen with GH treatment. Serum IGF-I and IGFBP-3 were significantly lower at baseline in CO compared with AO patients, similar to Caucasian patients, and were increased in both onsets following GH treatment. Serum total and low-density lipoprotein (LDL)-cholesterol concentrations did not differ between AO and CO patients at baseline and were elevated compared with normal ranges. GH-induced decreases were significant compared with placebo for both total (P=0.036) and LDL-cholesterol (P=0.040). Glycosylated haemoglobin was increased with GH compared with placebo treatment (P=0.016) but remained within the upper limit of normal for all patients at endpoint. CONCLUSIONS: Adult Japanese hypopituitary patients with GHD demonstrated obesity relative to healthy Japanese subjects but the clinical presentation differed from that of Caucasian patients. GH treatment improved body composition and serum cholesterol profiles of adult Japanese hypopituitary patients with GHD.
Prolactin (PRL) and TSH responses to TRH, chlorpromazine (CPZ) and L-DOPA were studied in 23 children (15 male and 8 female) with human growth hormone (HGH) deficiency. Eight patients (group I) showed normal PRL response to TRH and CPZ but TSH response to TRH was delayed in 4 of this group. Twelve patients (group II) had normal (4 patients) or higher (8 patients) baseline PRL level and showed lower PRL response to CPZ than that to TRH. TSH response to TRH was normal in 3, blunted in 1, and delayed in 8 patients. Three patients (group III) had no PRL response to either TRH or CPZ. TSH response to TRH was normal in 1 but blunted in 2 patients. Of 8 patients with a higher baseline PRL level (group II and III), L-DOPA suppressed PRL secretion to less than 50 % of the initial value in 7 patients, but not in 1 patient, in whom the diagnosis of hypothalamic tumour was established on brain surgery following these examinations. These results suggest that hypothalamic disorders are involved in more than half of 23 children with HGH deficiency.
OBJECTIVE: Although ovarian cysts commonly occur in patients with congenital lipoid adrenal hyperplasia (CLAH), the mechanism of development remains to be determined. To clarify the pathogenesis of the ovarian cysts, endocrinological examinations were performed in patients with CLAH. METHODS: The subjects were three Japanese CLAH patients. Basal body temperature, serum and urinary gonadotropin levels, serum and/or urinary ovarian hormones and mutations of the steroidogenic acute regulatory protein (StAR) gene were examined. RESULTS: The basal body temperature was not biphasic in any patient. Basal LH levels were high in all CLAH patients and markedly responded to LH-releasing hormone in two patients. Urinary gonadotropin analysis revealed repetitive LH surges in the menstrual cycles of the CLAH patients. No increase in the urinary pregnanediol suggested anovulation in all patients, and bilateral ovarian cysts were found in two of the subjects. Examination of the StAR gene revealed a frameshift mutation 840delA at codon 238, a nonsense mutation Q258X at codon 258, a homozygotic mutation at Q258X, and a compound heterozygotic mutation with 251insG and Q258X. CONCLUSIONS: We concluded that the development of ovarian cysts may be derived from continued anovulation in CLAH patients. Elevated LH levels may be explained by increased sensitivity of the anterior pituitary to circulating estrogen.
OBJECTIVE: It has been demonstrated that ghrelin plays a major role in the regulation of GH secretion and food intake. These actions make ghrelin a strong candidate for the treatment of GH deficiency, anorexia and cachexia. However, only preliminary studies have been performed to assess ghrelin administration in humans. In this study, we have conducted a double-blind, randomized, placebo-controlled trial to investigate the pharmacokinetics, safety, and endocrine and appetite effects of ghrelin in young healthy volunteers. DESIGN: Eighteen male volunteers were randomly assigned into three groups of six subjects: low- and high-dose ghrelin groups, who received intravenous injections of 1 and 5 microg/kg ghrelin (acylated form) respectively, and a placebo group who were injected with mannitol instead of ghrelin. RESULTS: Acylated ghrelin disappeared more rapidly from plasma than total ghrelin, with elimination half life (t(1/2)) of 9-13 and 27-31 min respectively. The number of subjects that experienced adverse effects did not significantly differ among the three groups, and all adverse effects were transient and well tolerated. Both the low and high doses of ghrelin strongly stimulated GH release (peak plasma concentration (C(max,0-90 min)): 124.2+/-63.9 and 153.2+/-52.2 ng/ml for 1 and 5 microg/kg ghrelin respectively). Slight alterations of blood glucose and insulin levels after the injection were observed. Although not statistically significant, ghrelin administration tended to increase hunger sensation in a dose-dependent manner. CONCLUSIONS: These results suggest that ghrelin is safe, and that clinical trials may be started to assess the usefulness of ghrelin for the treatment of disorders related to GH secretion and appetite.
OBJECTIVE: To investigate the effect of acute hyperinsulinemia on the plasma levels of adrenomedullin (AM) in patients with type 2 diabetes mellitus. DESIGN: We measured the plasma levels of AM in 18 patients with type 2 diabetes mellitus and in 19 normal subjects before and during a euglycemic hyperinsulinemic clamp study (the goal was for blood sugar levels of 5.24 mmol/l and insulin levels of 1200 pmol/l). Both plasma AM and serum insulin were measured by immunoradiometric assays. RESULTS: Before the glucose clamp study there was no significant difference in the plasma levels of AM between patients with type 2 diabetes mellitus and normal subjects. During the glucose clamp study, the serum levels of insulin significantly increased (from 33.0+/-3.6 to 1344.6+/-67.8 pmol/ml, P<0.001), as did the plasma levels of AM (from 12.8+/-0.7 to 14.2+/-0.9 fmol/ml, P<0.03) only in patients with type 2 diabetes mellitus. There was a significant correlation between the change in circulating levels of insulin and AM (r=0.755, P<0.01). CONCLUSIONS: Acute hyperinsulinemia induced a significant increase in the plasma levels of AM in patients with type 2 diabetes mellitus. Increased insulin may regulate circulating levels of AM in patients with type 2 diabetes mellitus.
OBJECTIVE: It is well known that nitric oxide synthase (NOS) is expressed and that it modulates glucose transport in skeletal muscles. Recent studies have shown that adipose tIssues also express inducible and endothelial nitric oxide synthase (eNOS). In the present study, we investigated whether nitric oxide (NO) induces glucose uptake in adipocytes, and the signaling pathway involved in the NO-stimulated glucose uptake in 3T3-L1 adipocytes. METHODS: First, we determined the expression of eNOS in 3T3-L1 adipocytes, and then these cells were treated with the NO donor sodium nitroprusside (SNP) and/or insulin, and glucose uptake and phosphorylation of insulin receptor substrate (IRS)-1 and Akt were evaluated. Moreover, we examined the effects of a NO scavenger, a guanylate cyclase inhibitor or dexamethasone on SNP-stimulated glucose uptake and GLUT4 translocation. RESULTS: SNP at a concentration of 50 mmol/l increased 2-deoxyglucose uptake (1.8-fold) without phosphorylation of IRS-1 and Akt. Treatment with the NO scavenger or guanylate cyclase inhibitor decreased SNP-stimulated glucose uptake to the basal level. Dexamethasone reduced both insulin- and SNP-stimulated glucose uptake with impairment of GLUT4 translocation. CONCLUSION: NO is capable of stimulating glucose transport through GLUT4 translocation in 3T3-L1 adipocytes, via a mechanism different from the insulin signaling pathway.
