9,154 research outputs found
Growth hormone (GH) provocation tests and the response to GH treatment in GH deficiency
No full textObjective: To identify factors, particularly the growth hormone (GH) provocation test result, affecting growth response to GH treatment in children with GH deficiency (GHD).Subjects: A total of 337 prepubertal GHD patients aged,10 years from the UK Pharmacia KIGS database (GH response to provocation test >20 mU/l).Outcome measure: Annual change in height standard deviation score (SDS) (revised UK reference) in the first and second years of treatment.Results: Height increased by 0.74 SDS units (SD 0.39) in the first year of treatment and 0.37 units (SD 0.27) in the second. Adjusting for age, height, weight, midparent height, and injection frequency, the strongest predictor of first year growth response was the GH provocation test result; halving the result predicted an extra height increment of 0.09 units (p<0.0001). It predicted the second year response less well (p<0.0002) and after adjusting for the first year response was not predictive at all.Conclusions: Among patients referred for possible GHD, the GH provocation test, though not a gold standard for diagnosis, is a valuable predictor of growth response in the first year of treatment. A year's treatment is recommended for cases with a marginal provocation test result, with the option to continue treatment if the response is adequate. The value of unified protocols for single or repeated provocation tests needs to be assessed
Lack of regulation of 11 beta-hydroxysteroid dehydrogenase type 1 during short-term manipulation of GH in patients with hypopituitarism
No full textObjective: Evidence from long-term clinical studies measuring urinary steroid ratios. and from in vitro studies, suggests that GH administered for longer than 2 months down-regulates 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), thereby reducing cortisol regeneration in liver and adipose tissue. We aimed to measure acute effects of GH on 11 beta-HSD1 in liver and adipose tissue in vivo, including using a stable isotope tracer.Design: Observational studies of GH withdrawal and reintroduction in patients with hypopituitarism.Methods: Twelve men with benign pituitary disease causing GH and ACTH deficiency on stable replacement therapy for > 6 months were studied after GH withdrawal for 3 weeks, and after either placebo or GH injections were reintroduced for another 3 weeks. We measured cortisol kinetics during 9,11,12,12-H-2(4)-cortisol (d4-cortisol) infusion, urinary cortisol/cortisone metabolite ratios, liver 11 beta-HSD1 by appearance of plasma cortisol after oral cortisone, and 11 beta-HSD1 mRNA levels in subcutaneous adipose biopsies.Results: GH withdrawal and reintroduction had no effect on 9.12,12-[H-2](3)-cortisol (d3-cortisol) appearance, urinary cortisol/cortisone metabolite ratios, initial appearance of cortisol after oral cortisone, or adipose 11 beta-HSD1 mRNA. GH withdrawal increased plasma cortisol 30-180 min after oral cortisone, increased d4-cortisol clearance. and decreased relative excretion of 5 alpha-reduced cortisol metabolites.Conclusions: In this setting GH did not regulate 11 beta-HSD1 rapidly in vivo in humans. Altered cortisol metabolism with longer term changes in GH may reflect indirect effects on 11 beta-HSD1. These data do not suggest that glucocorticoid replacement doses need to be increased immediately after introducing GH therapy to compensate for reduced 11 beta-HSD1 activity, although dose adjustment may be required in the longer term.</p
Growth hormone (GH) deficiency type II: a novel GH-1 gene mutation (GH-R178H) affecting secretion and action
No full textContext and Objective: Main features of the autosomal dominant form of GH deficiency (IGHD II) include markedly reduced secretion of GH combined with low concentrations of IGF-I leading to short stature. Design, Setting, and Patients: A female patient presented with short stature (height -6.0 sd score) and a delayed bone age of 2 yr at the chronological age of 5 yr. Later, at the age of 9 yr, GHD was confirmed by standard GH provocation test, which revealed subnormal concentrations of GH and a very low IGF-I. Genetic analysis of the GH-1 gene revealed the presence of a heterozygous R178H mutation. Interventions and Results: AtT-20 cells coexpressing both wt-GH and GH-R178H showed a reduced GH secretion after forskolin stimulation compared with the cells expressing only wt-GH, supporting the diagnosis of IGHD II. Because reduced GH concentrations found in the circulation of our untreated patient could not totally explain her severe short stature, functional characterization of the GH-R178H performed by studies of GH receptor binding and activation of the Janus kinase-2/signal transducer and activator of transcription-5 pathway revealed a reduced binding affinity of GH-R178H for GH receptor and signaling compared with the wt-GH. Conclusion: This is the first report of a patient suffering from short stature caused by a GH-1 gene alteration affecting not only GH secretion (IGHD II) but also GH binding and signaling, highlighting the necessity of functional analysis of any GH variant, even in the alleged situation of IGHD II
A multi-cohort study of polymorphisms in the GH/IGF axis and physical capability: the HALCyon programme
No full textBackground: Low muscle mass and function have been associated with poorer indicators of physical capability in olderpeople, which are in-turn associated with increased mortality rates. The growth hormone/insulin-like growth factor (GH/IGF)axis is involved in muscle function and genetic variants in genes in the axis may influence measures of physical capability.Methods: As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women from seven UKcohorts aged between 52 and 90 years old were genotyped for six polymorphisms: rs35767 (IGF1), rs7127900 (IGF2),rs2854744 (IGFBP3), rs2943641 (IRS1), rs2665802 (GH1) and the exon-3 deletion of GHR. The polymorphisms have previouslybeen robustly associated with age-related traits or are potentially functional. Meta-analysis was used to pool within-studygenotypic effects of the associations between the polymorphisms and four measures of physical capability: grip strength,timed walk or get up and go, chair rises and standing balance.Results: Few important associations were observed among the several tests. We found evidence that rs2665802 in GH1 wasassociated with inability to balance for 5 s (pooled odds ratio per minor allele = 0.90, 95% CI: 0.82–0.98, p-value = 0.01,n = 10,748), after adjusting for age and sex. We found no evidence for other associations between the polymorphisms andphysical capability traits.Conclusion: Our findings do not provide evidence for a substantial influence of these common polymorphisms in the GH/IGF axis on objectively measured physical capability levels in older adults
IGHD II: A Novel GH-1 Gene Mutation (GH-L76P) Severely Affects GH Folding, Stability, and Secretion
No full textCONTEXT
The autosomal dominant form of GH deficiency (IGHD II) is characterized by markedly reduced GH secretion combined with low concentrations of IGF-1 leading to short stature.
OBJECTIVE
Structure-function analysis of a missense mutation in the GH-1 gene converting codon 76 from leucine (L) to proline (P) yielding a mutant GH-L76P peptide.
DESIGN, SETTINGS, AND PATIENTS
Heterozygosity for GH-L76P/wt-GH was identified in a nonconsanguineous Spanish family. The index patients, two siblings, a boy and a girl, were referred for assessment of their short stature (-3.2 and -3.8 SD). Their grandmother, father, and aunt were also carrying the same mutation and showed severe short stature; therefore, IGHD II was diagnosed.
INTERVENTIONS AND RESULTS
AtT-20 cells coexpressing both wt-GH and GH-L76P showed a reduced GH secretion (P < .001) after forskolin stimulation when compared with the cells expressing only wt-GH. In silico mutagenesis and molecular dynamics simulations presented alterations of correct folding and mutant stability compared with wt-GH. Therefore, further structural analysis of the GH-L76P mutant was performed using expressed and purified proteins in Escherichia coli by thermofluor assay and fast degradation proteolysis assay. Both assays revealed that the GH-L76P mutant is unstable and misfolded compared to wt-GH confirming the bioinformatic model prediction.
CONCLUSIONS
This is the first report of a family suffering from short stature caused by IGHD II, which severely affects intracellular GH folding and stability as well as secretion, highlighting the necessity of functional analysis of any GH variant for defining new mechanisms as a cause for IGHD II
Effects of growth hormone (GH) replacement therapy on very low density lipoprotein apolipoprotein B100 kinetics in patients with adult GH deficiency: a stable isotope study
No full textPatients with adult GH deficiency are often dyslipidemic and may have an increased risk of cardiovascular disease. The secretion and clearance of very low density lipoprotein apolipoprotein B 100 (VLDL apoB) are important determinants of plasma lipid concentrations. This study examined the effect of GH replacement therapy on VLDL apoB metabolism using a stable isotope turnover technique. VLDL apoB kinetics were determined in 14 adult patients with GH deficiency before and after 3 months GH or placebo treatment in a randomized double blind, placebo-controlled study using a primed constant [1-(13)C]leucine infusion. VLDL apoB enrichment was determined by gas chromatography-mass spectrometry. GH replacement therapy increased plasma insulin-like growth factor I concentrations 2.9 +/- 0.5-fold (P < 0.001), fasting insulin concentrations 1.8 +/- 0.6-fold (P < 0.04), and hemoglobin A1C from 5.0 +/- 0.2% to 5.3 +/- 0.2% (mean +/- SEM; P < 0.001). It decreased fat mass by 3.4 +/- 1.3 kg (P < 0.05) and increased lean body mass by 3.5 +/- 0.8 kg (P < 0.01). The total cholesterol concentration (P < 0.02), the low density lipoprotein cholesterol concentration (P < 0.02), and the VLDL cholesterol/VLDL apoB ratio (P < 0.005) decreased. GH therapy did not significantly change the VLDL apoB pool size, but increased the VLDL apoB secretion rate from 9.2 +/- 2.0 to 25.9 +/- 10.3 mg/kg x day (P < 0.01) and the MCR from 11.5 +/- 2.7 to 20.3 +/- 3.2 mL/min (P < 0.03). No significant changes were observed in the placebo group. This study suggests that GH replacement therapy improves lipid profile by increasing the removal of VLDL apoB. Although GH therapy stimulates VLDL apoB secretion, this is offset by the increase in the VLDL apoB clearance rate, which we postulate is due to its effects in up-regulating low density lipoprotein receptors and modifying VLDL composition
Effects of growth hormone (GH) replacement therapy on low-density lipoprotein apolipoprotein B100 kinetics in adult patients with GH deficiency: a stable isotope study
No full textGH replacement therapy has been shown to improve the dyslipidemic condition in a substantial proportion of patients with adult GH deficiency. The mechanisms are not yet fully elucidated. Low-density lipoprotein (LDL) apolipoprotein B100 (apoB) formation and catabolism are important determinants of plasma cholesterol concentrations. This study examined the effect of GH replacement therapy on LDL apoB metabolism using a stable isotope turnover technique. LDL apoB kinetics was determined in 13 adult patients with GH deficiency before and after 3 months GH/placebo treatment in a randomized, double-blind, placebo-controlled study. LDL apoB (13)C-leucine enrichment was determined by isotope-ratio mass spectrometry. Plasma volume was assessed by standardized radionuclide dilution technique. GH replacement therapy significantly decreased LDL cholesterol, LDL apoB concentrations, and LDL apoB pool size compared with placebo. Compared with baseline, GH replacement therapy resulted in a significant increase in plasma volume and fractional catabolic rate, whereas LDL formation rate remained unchanged. LDL lipid content did not significantly change after GH and placebo. This study suggests that short-term GH replacement therapy decreases the LDL apoB pool by increasing removal of LDL particles without changing LDL composition or LDL apoB production rate. In addition, it is possible that the beneficial effects of GH on the cardiovascular system contribute to these findings
Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH
No full textShort stature caused by biologically inactive GH is clinically characterized by lack of GH action despite normal-high secretion of GH, pathologically low IGF1 concentrations and marked catch-up growth on GH replacement therapy
Short term growth hormone (GH) treatment of GH-deficient adults increases body sodium and extracellular water, but not blood pressure
No full textInitiation of GH treatment in adults is frequently complicated by the development of symptomatic fluid retention. To investigate the mechanism and extent of fluid retention that occurs with dosages of GH used in the treatment of GH-deficient adults, we conducted a double blind study in which seven GH-deficient patients (aged 24-74 yr) each received in random order daily sc injections of placebo, a physiological dose of GH (0.04 U/kg, low dose), and a supraphysiological dose of GH (0.08 U/kg, high dose) for 7 days, separated by 21-day washout periods. On the seventh day, measurements were made of serum insulin-like growth factor I, body weight, exchangeable sodium, plasma volume, angiotensinogen, PRA, aldosterone, atrial natriuretic peptide (ANP), and mean 24-h ambulatory heart rate and blood pressure. GH significantly increased mean insulin-like growth factor I levels from 105 ± 11 to 304 ± 45 μg/L during low dose treatment (P = 0.006) and 400 ± 76 μg/L during high dose treatment (P = 0.004). High dose GH caused a 1.2 ± 0.3 kg increase in body weight (P = 0.01) and a 193 ± 65 mmol increase in exchangeable sodium (P = 0.008). Low dose GH had a lesser effect, with no significant increase in body weight, but an increase in exchangeable sodium of 113 ± 37 mmol (P = 0.02). Plasma volume was not significantly affected by GH treatment. Mean supine angiotensinogen levels were significantly higher during both GH treatments compared to placebo (low dose, P = 0.017; high dose, P = 0.028) as were mean supine pRA levels (low dose, P = 0.0002; high dose, P = 0.0025). Supine angiotensin II, aldosterone, and ANP levels were not significantly affected by GH treatment. There was no significant change from placebo in any of the sodium-regulating hormones in the erect posture. The mean 24-h heart rate was significantly higher during low dose (82 ± 2 beats/min; P = 0.0001) and high dose (88 ± 3 beats/min; P = 0.0001) GH treatment than during placebo (67 ± 3 beats/min). However, no significant change in mean 24-h systolic or diastolic blood pressure was observed. In summary, acute GH administration using doses currently employed in treating adults causes a dose-related increase in body weight and body sodium, but no associated increase in blood pressure. We conclude that 1) sodium retention is a physiological effect of GH, but does not cause an acute rise in blood pressure; and 2) the mechanism of sodium and fluid retention is not primarily due to enhanced aldosterone secretion or inhibition of ANP release, but more likely to a direct renal tubular effect
HCMV spread and cell tropism are determined by distinct virus populations.
No full textHuman cytomegalovirus (HCMV) can infect many different cell types in vivo. Two gH/gL complexes are used for entry into cells. gH/gL/pUL(128,130,131A) shows no selectivity for its host cell, whereas formation of a gH/gL/gO complex only restricts the tropism mainly to fibroblasts. Here, we describe that depending on the cell type in which virus replication takes place, virus carrying the gH/gL/pUL(128,130,131A) complex is either released or retained cell-associated. We observed that virus spread in fibroblast cultures was predominantly supernatant-driven, whereas spread in endothelial cell (EC) cultures was predominantly focal. This was due to properties of virus released from fibroblasts and EC. Fibroblasts released virus which could infect both fibroblasts and EC. In contrast, EC released virus which readily infected fibroblasts, but was barely able to infect EC. The EC infection capacities of virus released from fibroblasts or EC correlated with respectively high or low amounts of gH/gL/pUL(128,130,131A) in virus particles. Moreover, we found that focal spread in EC cultures could be attributed to EC-tropic virus tightly associated with EC and not released into the supernatant. Preincubation of fibroblast-derived virus progeny with EC or beads coated with pUL131A-specific antibodies depleted the fraction that could infect EC, and left a fraction that could predominantly infect fibroblasts. These data strongly suggest that HCMV progeny is composed of distinct virus populations. EC specifically retain the EC-tropic population, whereas fibroblasts release EC-tropic and non EC-tropic virus. Our findings offer completely new views on how HCMV spread may be controlled by its host cells
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