Effects of hormone replacement on growth hormone and prolactin exercise responses in postmenopausal women

Studies were conducted to identify a 64-kD thylakoid membrane protein of unknown function. The protein was extracted from chloroplast thylakoids under low ionic strength conditions and purified to homogeneity by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Four peptides generated from the proteolytic cleavage of the wheat 64-kD protein were sequenced and found to be identical to internal sequences of the chloroplast-coupling factor (CF1) alpha-subunit. Antibodies for the 64-kD protein also recognized the alpha-subunit of CF1. Both the 64-kD protein and the 61-kD CF1 alpha-subunit were present in the monocots barley (Hordeum vulgare), maize (Zea mays), oat (Avena sativa), and wheat (Triticum aestivum); but the dicots pea (Pisum sativum), soybean (Glycine max Merr.), and spinach (Spinacia oleracea) contained only a single polypeptide corresponding to the CF1 alpha-subunit. The 64-kD protein accumulated in response to high irradiance (1000 mumol photons m-2 s-1) and declined in response to low irradiance (80 mumol photons m-2 s-1) treatments. Thus, the 64-kD protein was identified as an irradiance-dependent isoform of the CF1 alpha-subunit found only in monocots. Analysis of purified CF1 complexes showed that the 64-kD protein represented up to 15% of the total CF1 alpha-subunit.     

Short and long-term cardiovascular effects of growth hormone therapy in growth hormone deficient adults

OBJECTIVE: Since GH substitution therapy is now available for adult GH deficient patients, information on the cardiovascular effects of GH substitution has assumed major clinical interest. We have therefore assessed cardiovascular effects of short and long-term growth hormone substitution therapy in these patients. PATIENTS AND MEASUREMENTS: Doppler echocardiography was performed in 21 GH deficient patients after 4 months placebo and 4 months GH therapy, in a double blind cross-over study. In an open design study, 13 patients were reinvestigated following 16 months and 9 patients following 38 months of GH therapy. Twenty-one age and sex-matched normal control subjects were also investigated. RESULTS: Heart rate was increased in placebo treated patients as compared to controls. After 4 months of GH treatment, heart rate showed a further increase (10%, P < 0.01) and seemed to remain elevated after 16 months of GH therapy. Systolic and diastolic blood pressures were significantly lower in placebo treated patients than in controls, and did not change significantly after GH treatment. The left ventricular diastolic diameter was reduced in patients as compared to controls, but increased after 4 months GH therapy (P > 0.05) and seemed to increase further during prolonged GH treatment. Cardiac index was at the same level in controls and in placebo-treated patients, but increased by 20% following GH therapy and remained elevated after 16 and 38 months (P < 0.05) of GH substitution. CONCLUSION: Following GH substitution in GH deficient adult patients, left ventricular diastolic dimensions increased and seemed to normalize, while heart rate and cardiac output were found to be increased to supranormal levels.     

Effect of growth hormone therapy on bone metabolism of growth hormone deficient children

The effects of human growth hormone (hGH) therapy on biochemical markers of bone metabolism were studied in 17 children (10 boys and 7 girls, aged 3.7-13.1 years old) with idiopathic GH deficiency, before and 1 and 6 months after GH therapy (0.5 0.7 IU/kg weekly SC). Serum levels of calcium, phosphate, alkaline phosphatase osteocalcin, parathyroid hormone, 1,25 dihydroxyvitamin D, insulin-like growth factor I (IGF-I) and renal phosphate per 100 ml glomerular filtrate (TPO4/GFR) were assessed. During therapy with hGH a significant decrease of serum calcium levels and increases of phosphate, osteocalcin, parathyroid hormone 1,25 dihydroxyvitamin D and IGF-I were observed. TPO4/GFR was also significantly increased. Growth response (increment in HV) was positively related with changes in alkaline phosphatase and IGF-I levels after 6 months of hGH therapy. There was also a significant positive correlation between increment in HV and increment in TPO4/GFR after 1 month of GH therapy, whereas no correlation between HV and changes in osteocalcin levels was found. CONCLUSION: GH treatment significantly influences mineral metabolism and the measurement of TPO4/ GFR after 1 month of GH therapy may serve as a useful predictor of growth response to hGH therapy in GH-deficient children.     

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.     

Urinary growth hormone following exercise to assess growth hormone production in adults

OBJECTIVE: The insulin stress test (IST) is the most commonly used test to assess the GH reserve in children and adults. It is a time-consuming, expensive and potentially dangerous test. We investigated whether measurement of urinary growth hormone excretion following exercise would prove on reliable method to diagnose adult GH deficiency. DESIGN: Healthy volunteers underwent a standard IST to confirm GH secretion. Using a standardized exercise protocol on a treadmill, the urinary excretion of GH was measured. Three patients confirmed as GH deficient by an IST were exercised during the same exercise protocol and their urinary excretion of GH was measured. PATIENTS: Ten healthy volunteers and three patients with hypopituitarism were evaluated. MEASUREMENTS: A standard IST was performed on both healthy volunteers and patients, with measurements of plasma GH and plasma cortisol. Urinary growth hormone and urinary GH/creatinine (GH/CR) ratios were measured before and after IST. On a separate visit, healthy volunteers and patients were exercised on the treadmill with measurements of plasma GH and cortisol. Urinary GH and GH/CR ratios were measured before and after exercise. RESULTS: There was at least a two-fold increase in urinary GH and GH/CR ratios following exercise in all healthy adults. By contrast, patients with GH deficiency showed no rise in urinary GH or urinary GH/CR ratios following exercise. CONCLUSIONS: Measurements of urinary GH following exercise can distinguish between GH-deficient adults and healthy volunteers. Urinary GH excretion can be measured over a timed interval following exercise or can be expressed as the GH/CR ratio. This can be measured on a single sample following exercise and can be used to diagnose GH deficiency. The exercise test employed for this study is arduous. We are therefore performing further studies with a less strenuous exercise protocol with a view to designing a 'patient-friendly' exercise test for GH deficiency in adults.     

The effects of hormone replacement therapy (HRT) on lipid metabolism in the menopause

Immunohistochemical localizations of carbonic anhydrase isozymes (CA-I, CA-II and CA-III) in bovine male reproductive tracts were studied. In bulls, no immunoreaction was seen after treatment with antibodies to CA-I, -II and CA-III in the testis. Specific staining for CA-III, however, was evident in peritubular cells in interstitial tissue of the testis, epididymis. CA-II activity could be detected in epithelium of the epididymis, ductus deferentis and ampulla ductus deferentis. Especially, a strong reaction for CA-II was seen in apical in epithelium of the epididymis in the initial and middle segment. CA-I activity was only founded in ductus deferentis and ampulla ductus deferentis. No or a weak reaction for CA-I, CA-II and CA-III were seen in the three accessory reproductive glands. Specific immunostaining for CA-II and CA-I could be observed in the organ, suggesting the bicarbonate in bovine semen to derive primarily from the genital tract and not accessory reproductive organs. CA-III-positive peritubular cells in interstitial tissue were also stained for alpha smooth muscle actin, and were very similar to contractile myofibroblast cells (Wrobel et al., 1979).     

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.     

Effects of low-dose recombinant human insulin-like growth factor-I on insulin sensitivity, growth hormone and glucagon levels in young adults with insulin-dependent diabetes mellitus

Despite recent interest in the therapeutic potential of recombinant human insulin-like growth factor-I (rhIGF-I) in the treatment of diabetes mellitus, its mechanism of action is still not defined. We have studied the effects of low-dose bolus subcutaneous rhIGF-I (40 microg/kg and 20 microg/kg) on insulin sensitivity, growth hormone (GH) and glucagon levels in seven young adults with insulin-dependent diabetes mellitus (IDDM) using a randomized double-blind placebo-controlled crossover study design. Each was subjected to a euglycemic clamp (5 mmol/L) protocol consisting of a variable-rate insulin infusion clamp (6:00 PM to 8:00 AM) followed by a two-dose hyperinsulinemic clamp (insulin infusion of 0.75 mU x kg(-1) x min(-1) from 8 to 10 AM and 1.5 mU x kg(-1) x min(-1) from 10 AM to 12 noon) incorporating [6,6 2H2]glucose tracer for determination of glucose production/utilization rates. Following rhIGF-I administration, the serum IGF-I level (mean +/- SEM) increased (40 microg/kg, 655 +/- 90 ng/mL, P < .001; 20 microg/kg, 472 +/- 67 ng/mL, P < .001; placebo, 258 +/- 51 ng/mL). Dose-related reductions in insulin were observed during the period of steady-state euglycemia (1 AM to 8 AM) (40 microg/kg, 48 +/- 5 pmol/L, P = .01; 20 microg/kg, 58 +/- 8 pmol/L, P = .03; placebo, 72 +/- 8 pmol/L). The mean overnight GH level (40 microg/kg, 9.1 +/- 1.4 mU/L, P = .04; 20 microg/kg, 9.6 +/- 2.0 mU/L, P = .12; placebo, 11.3 +/- 1.7 mU/L) and GH pulse amplitude (40 microg/kg, 18.8 +/- 2.9 mU/L, P = .04; 20 microg/kg, 17.0 +/- 3.4 mU/L, P > .05; placebo, 23.0 +/- 3.7 mU/L) were also reduced. No differences in glucagon, IGF binding protein-1 (IGFBP-1), acetoacetate, or beta-hydroxybutyrate levels were found. During the hyperinsulinemic clamp conditions, no differences in glucose utilization were noted, whereas hepatic glucose production was reduced by rhIGF-I 40 microg/kg (P = .05). Our data demonstrate that in subjects with IDDM, low-dose subcutaneous rhIGF-I leads to a dose-dependent reduction in the insulin level for euglycemia overnight that parallels the decrease in overnight GH levels, but glucagon and IGFBP-1 levels remain unchanged. The decreases in hepatic glucose production during the hyperinsulinemic clamp study observed the following day are likely related to GH suppression, although a direct effect by rhIGF-I cannot be entirely discounted.     

Lung volumes and respiratory muscle strength in adult patients with childhood- or adult-onset growth hormone deficiency: effect of 12 months' growth hormone replacement therapy

We have described impairment of the respiratory function in adult patients with childhood-onset growth hormone (GH) deficiency. The aim of the present study was to evaluate lung volumes and respiratory muscle strength in patients diagnosed as GH deficient before and after 6 and 12 months of recombinant GH treatment. Ten adults diagnosed as GH deficient in childhood, ten adults diagnosed as GH deficient in adulthood and ten healthy subjects entered the study. For each subject, evaluation of respiratory function followed the same standard approach, consisting of respiratory muscle strength assessment, record of flow-volume curves, measurement of static lung volumes and lung diffusing capacity. Childhood-onset GH-deficient patients had a significant reduction of maximal inspiratory (p < 0.01) and maximal expiratory (p < 0.05) mouth pressures. Total lung capacity, vital capacity and functional residual capacity were significantly reduced compared to healthy subjects (p < 0.05). Conversely, residual volume and diffusing lung capacity did not show any significant change. No significant change of the ratio between the percentage forced expiratory volume in 1 s and the forced vital capacity was observed. The decrease of respiratory mouth pressures was not correlated to the decrease of lung volumes. Adult-onset GH-deficient patients had only a significant reduction of maximal expiratory pressure compared to healthy subjects (p < 0.05). After 6 months of treatment no significant differences in any of the evaluated parameters were found. After 12 months of treatment patients with childhood-onset GH deficiency show a significant improvement of lung volumes (p < 0.01) and maximal respiratory mouth pressures (p < 0.005), whereas adult-onset GH-deficient patients show a significant improvement of maximal expiratory pressure (p < 0.05). In conclusion, the results of this study showed that adult patients affected with childhood-onset GH deficiency suffer from an impairment of the ventilatory function due to a reduction of lung volumes and a decrease of respiratory pressures probably due to a reduction of respiratory muscle strength. This impairment was reversed after 12 months of treatment with recombinant GH. Conversely, adult-onset GH-deficient patients had only an impairment of the maximal expiratory pressure, probably due to respiratory muscle weakness re-established after 12 months of GH therapy.     

Cognitive changes during growth hormone replacement in adult men

Prostaglandins (PGs) lower intraocular pressure by increasing uveoscleral outflow, presumably via a receptor-mediated mechanism coupled to a second messenger pathway in the ciliary muscle. In the present study, we examined the effect of prostanoids on cyclic AMP production in cultured human ciliary muscle cells. Cells were identified based on their expression of smooth muscle specific alpha-actin and monoclonal antibody against desmin. Cyclic AMP production in confluent cells incubated with buffer solution containing various concentrations of prostanoids was analyzed by radioimmunoassay. PGE2 caused a time-dependent increase in cyclic AMP concentrations which reached a maximum after 10 mins. With the exception of PGD2, all prostanoids produced a concentration-dependent increase in cyclic AMP levels with the following rank order of activity: PGE2 > 11-deoxy-PGE1 > 16,16-dimethyl PGE2 > sulprostone > PGF2alpha. PGE2-induced increase on cyclic AMP levels was unaffected by AH6809, an antagonist at both PGD2 (DP) and E2 (EP1) receptors. Flurbiprofen decreased basal cyclic AMP concentrations suggesting that intramurally-generated PGs stimulate the formation of the nucleotide in ciliary smooth muscle cells. PGE2-induced increases in cyclic AMP production was synergistic with those induced by the diterpene activator of adenylyl cyclase, forskolin. We conclude that prostanoids active at EP2-receptors can stimulate cyclic AMP production in cultured human ciliary muscle cells.     

Acute growth hormone effects on amino acid and lipid metabolism

The anabolic actions of GH are well known, although specific tissue responses and the mechanism of nitrogen conservation are less well understood. This study was designed to examine the acute metabolic effects of GH on whole body and regional protein metabolism, using an experimental protocol which controlled for confounding perturbations in other hormones by a simultaneous infusion of somatostatin. Control subjects received replacement doses of insulin, glucagon, and GH for the entire 7-h study period, whereas GH subjects received an identical protocol, except for an increased dose of GH sufficient to increase serum concentrations into the high-physiological range (12-20 ng/mL) for the final 3.5 h of the study (P < 0.001). Thirteen young, healthy male subjects were studied in the postabsorptive period; five served as control subjects and eight as treatment (GH) subjects. Each received continuous iv infusions of somatostatin, L-[13-C]leucine, and L-[2H5]phenylalanine throughout the study. Femoral arterial and venous sampling allowed for simultaneous measurements across the leg and in the whole body. C-Peptide levels were suppressed throughout the infusion; insulin, glucagon, insulin-like growth factor I, cortisol, epinephrine, norepinephrine, and glucose concentrations were not different between groups. Glycerol concentrations increased 3-fold in GH subjects during the final 3.5-h period (P = 0.04). Concentrations of several amino acids declined through the study, but no differences were observed between treatment groups. Leucine oxidation was reduced in GH compared to control subjects (P = 0.04). No changes in CO2 production or whole body leucine or phenylalanine flux were observed, whereas nonoxidative disposal of leucine was marginally higher in GH compared to control subjects (P = 0.07). By contrast, rates of appearance and disappearance of both leucine and phenylalanine across the leg all were relatively lower in GH compared to control subjects; leucine balance across the leg was reduced by GH (P = 0.03), whereas phenylalanine balance was not influenced by GH. Our data thus demonstrate an acute stimulatory effect of GH on lipolysis, a decrease in leucine oxidation, and no stimulation of muscle protein synthesis in spite of enhanced protein synthesis in nonmuscle tissue.     

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.     

The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency

Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.     

The modulating effect of the thyrotropin-releasing hormone on genetically induced mechanisms of morphine sensitivity

The influence of thyrotropin-releasing hormone (TRH) on morphine-induced analgesic and reinforced responses was studied in two inbred strains of rats, Fischer-344 (F344) and Wistar Albino Glaxo/GSto (WAG). Conditioned place preference, voluntary consumption of morphine solution and analgesic action of morphine in tail immersion test were studied. There were interstrain differences in pain sensitivity, i.e., F344 rats had longer latency of tail immersion and deeper analgesic effect of morphine (5 mg/kg, ip) than WAG rats. TRH (1 mg/kg, ip) produced a stronger analgesic effect in WAG rats, while F344 rats demonstrated only slight increase in pain threshold. Administration of TRH in combination with morphine significantly stronger potentiated the effect of the latter in WAG than in F344 rats. F344 rats preferred morphine in the two-bottle choice test and consumed relatively larger amount of morphine solution in the drinking paradigm than WAG rats. Morphine in the dose of 5 mg/kg (ip) induced place preference in both rat strains. Intraventricular administration of TRH (1 mcg) produced a slight effect of place preference only in F344 rats. Preceded by morphine, such injection reduced the effect of place preference. It is suggested that WAG and F344 rats have different sensitivity of brain structures to TRH. This is probably determined by genetic differences in dissociation of analgesic and reinforcing effects of morphine.     

The effect of L-dopa and chlorpromazine on prolactin and growth hormone secretion in normal women

The time course of simultaneous changes in prolactin (PRL) and growth hormone secretion in response to a single dose of L-dopa and chlorpromazine was determined in normal women. L-Dopa induced greater, but shorter (30 minutes), growth hormone release than concomitant suppression of PRL secretion. The PRL peak following chlorpromazine occurred at the same time as the nadir of PRL after L-dopa (3.5 hours). The quantity of PRL release inhibited by L-dopa equaled the amount of PRL secretion during the period of rebound, suggesting L-dopa inhibits PRL release, but not synthesis, by the pituitary.     

Effects of growth hormone, insulin-like growth factor-I, and cortisol on periparturient antibody response profiles of dairy cattle

The objectives of this study were to determine hormone and antibody response profiles from the prepartum period to peak lactation, and evaluate potential immunomodulatory effects of the classic endocrine hormones, growth hormone (GH), insulin-like growth factor-I (IGF-I) and cortisol. Specifically, 33 Holstein cows were immunized with ovalbumin (OVA) and Escherichia coli J5 at weeks -8 and -3 prior to parturition. At parturition (week 0), cows received an additional immunization of OVA. Blood was collected at weeks -8, -3, 0, 3 and 6 relative to parturition and various samples were used to determine plasma hormone concentration, serum immunoglobulin (Ig), and specific antibody response to OVA and E. coli. Colostrum and milk samples were also collected post-parturition to monitor local immunoglobulin and antibody responses. Results indicated that not all periparturient cows exhibited depressed immune response, and that antibody response to OVA could be used to partition cows into 3 groups recognizing animals with sustained measurable antibody response before and after parturition (Group 1), animals which responded poorly to immunization at parturition (Group 2), and animals which did not respond to immunizations at week -3 or parturition (Group 3). Cows with the highest antibody response to OVA (Group 1) also tended (P < or = 0.10) to have the highest response to E. coli J5 at parturition and had the lowest incidence of disease, particularly mastitis. Antibody response to OVA measured in milk tended to be higher in Group 1 cows, particularly at week 0 (P < or = 0.06) compared to cows of Group 3. IGF-I was higher (P < or = 0.05) in cows of Group 1 than Group 3 at peak lactation (week 6).     

The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity

OBJECTIVE: To investigate the metabolic effects of losartan (Cozaar) in patients with essential hypertension. METHODS: Twenty patients with mild hypertension (office blood pressure > 140/95 mmHg and home diastolic blood pressure > 90 mmHg) were examined in a double-blind, placebo-controlled cross-over study of 4 weeks of treatment with 50-100 mg losartan. The effects on glucose metabolism were assessed by euglycaemic glucose clamp examinations [glucose disposal rate (GDR, mg/kg per min)] and oral glucose-tolerance tests (OGTT). RESULTS: Supine blood pressure was reduced from 146 +/- 3/90 +/- 3 mmHg on placebo to 134 +/- 4/83 +/- 3 mmHg on losartan and the difference was maintained during 120 min of insulin infusion and glucose clamping. GDR was 6.2 +/- 0.5 mg/kg per min on placebo and 6.4 +/- 0.5 mg/kg per min on losartan. The glucose and insulin responses (the area under the curve) during OGTT were similar with placebo and losartan (0.86 +/- 0.3 versus 0.88 +/- 0.4 and 341 +/- 60 versus 356 +/- 60, respectively; arbitary units). Serum cholesterol was 5.3 +/- 0.2 mmol/l on placebo and 5.1 +/- 0.2 mmol/l losartan treatment. High-density lipoprotein cholesterol and triglycerides were, respectively, 1.1 +/- 0.1 and 1.5 +/- 0.2 mmol/l with placebo, and 1.1 +/- 0.1 and 1.4 +/- 0.1 mmol/l with losartan treatment. CONCLUSION: In mildly hypertensive patients, selective angiotensin II receptor antagonism with losartan for 4 weeks lowers blood pressure at rest and during 120 min of glucose clamping, and has neutral effects on insulin sensitivity, glucose metabolism and serum lipids.     

Comparison of the effects of growth hormone and insulin-like growth factor I on substrate oxidation and on insulin sensitivity in growth hormone-deficient humans

Insulin-like growth factor-I (IGF-I) is considered to be the mediator of the growth-promoting effects of growth hormone (GH). The metabolic effects of these two hormones, however, are different. Whereas GH treatment leads to elevated insulin and glucose levels, reduced insulin sensitivity, and impaired glucose tolerance, IGF-I treatment leads to reduced insulin and GH levels and enhanced insulin sensitivity. IGF-I may, therefore, not only be the mediator of the growth-promoting effects of GH but also a modulator of the effects of GH on insulin action and glucose metabolism. To study the influence of GH and IGF-I on substrate metabolism and insulin sensitivity (assessed by euglycemic, hyperinsulinemic clamping combined with indirect calorimetry and glucose tracer infusion), we have treated eight GH-deficient adults with GH (2 IU/m2 daily subcutaneously [s.c.]), IGF-I (10 micrograms/kg.h s.c.), or both hormones together for 7 d, respectively, and compared the effects of these treatment regimens with a control phase. Our findings suggest that (a) both GH and IGF-I promote lipolysis and lipid oxidation, albeit by different mechanisms; (b) treatment with either hormone is followed by enhanced energy expenditure and reduced protein oxidation; and (c) IGF-I reverses the insulin resistance induced by GH.     

Growth hormone regulation of lipid metabolism in cells transfected with growth hormone receptor cDNA

We have studied, by histological methods, cytological progression, frequency and distribution of apoptosis in the external granular layer of the cerebellum after whole-body irradiation of 14-day-old rats by gamma-rays from 60 Co. After acute exposure to 0.25, 0.5, 1.5 and 3 Gy (18 cGy/min), the duration of the apoptotic process gradually increased with dose from 6-9 h after 0.25 Gy, to > 24 h after 3 Gy. Up to 1 Gy, maximal frequency was found 6 h after exposures, and at this postirradiation time a linear increase in apoptosis with dose was observed. No effect of dose-rate on apoptosis induction could be demonstrated 6 h after delivering 1 Gy at dose-rates from 2.2 to 18 cGy/min. Continuous irradiation at 1.8 cGy/h induced a gradual increase of apoptosis that remained at a plateau value of about 3% from 15 to 29 h (controls 0.12%, SD = 0.07) and then gradually decreased to 1% at 53 h. At this time the mitotic index was similar to that measured in controls. Apoptosis occurring 3 h after acute irradiation, confined to proliferative cells, was only observed for doses of 1.5 and 3 Gy.