Recombinant human growth hormone increases albumin and prolongs survival in patients with chronic liver failure: A pilot open, randomized, and controlled clinical trial

OBJECTIVE: To evaluate the efficacy and safety of recombinant human growth hormone (rhGH) in the treatment of patients with chronic liver failure. SUBJECTS AND METHODS: One hundred and fourteen patients with chronic liver failure were randomly divided into two groups: (1) 56 patients in the rhGH treatment group received 4.5IU of rhGH intramuscularly daily for 4 weeks and (2) 58 patients in the control-treatment group. Fifteen healthy subjects served as normal controls. Symptoms and complications were recorded. The prognosis was analysed by Kaplan-Meier survival analysis. The serum GH, IGF-1, IGFBP-3, and insulin levels were determined using ELISA. RESULTS: The efficacy of rhGH treatment was 87.5% (vs. 38.1% in the controls-treatment group, p<0.01). The serum GH, IGF-1, IGFBP-3, and insulin levels in patients with chronic liver failure were significantly different than the levels in the normal controls (5.50+/-4.21 vs. 1.57+/-1.27, 80.45+/-69.99 vs. 172.97+/-78.12, 109.93+/-87.53 vs. 373.41+/-119.07, and 31.99+/-49.87 vs. 6.72+/-1.09, respectively, p<0.05-0.001). The serum IGF-1, IGFBP-3, albumin, proalbumin, and cholesterol levels were significantly increased after rhGH treatment; however, the serum GH and insulin levels were decreased. The survival rate of the rhGH treatment and control-treatment groups after 2 weeks, 1 month, 3 months, and 6 months of treatment was 98.21% vs.75.86%, 91.07% vs.62.07%, 66.07% vs.22.41%, and 55.36% vs.13.79%, respectively. Cox regression analysis showed that rhGH was an independent factor in predicting the survival of patients after 3 and 6 months of treatment with rhGH. CONCLUSIONS: rhGH replacement therapy increased albumin and tended to improve survival in adult patients with chronic liver failure.     

Insulin-like growth factor-I (IGF-I), insulin-like growth factor binding proteins (IGFBP) and insulin-like growth factor type I receptor in children with various status of chronic renal failure

Chronic renal failure in childhood causes severe growth retardation. The aim of the study was to identify whether changes in the IGF system could account for the growth retardation observed in children with chronic renal failure. Insulin-like growth factor (IGF-I) serum concentrations, insulin-like growth factor binding proteins (IGFBP) and/or IGF-I binding to erythrocyte type I receptor of IGF were analysed in 69 children (mean age 11.6 +/- 4.3 years) with chronic renal failure and growth retardation (mean height -2.6 +/- 1.8 SD). The study population was separated into three groups, according to their renal status, children on conservative treatment (CRF group: n = 30), on haemodialysis (ESRD group: n = 26) and those transplanted (RT group: n = 13). Nineteen of these children, some from each of the three groups, received recombinant growth hormone therapy (rhGH). Mean basal IGF-I serum concentrations were -0.7 +/- 1.2 SD in the CRF group, + 2.1 +/- 3 SD in the ESRD group and + 1.1 +/- 2 SD in the RT group. Under rhGH therapy, as height velocity improved, mean IGF-I concentrations increased up to + 3.1 +/- 0.6 SD in the CRF group, to + 6.9 +/- 2.8 SD in the ESRD group and to + 3.9 +/- 2 SD in the RT group. Basal IGFBP-3 levels, studied by Western Ligand Blot were low in the CRF group and high in the ESRD and normal in the RT groups, whereas IGFBP-2 and a 30-32 kDa IGFBP were always high in all cases. Western immunoblot analysis showed that this 30-32 kDa IGFBP was mostly composed of IGFBP-1 and IGFBP-6 in all three groups, but IGFBP-6 was particularly abundant in the ESRD group. IGFBP-6 concentrations assessed by RIA were moderately increased in CRF children (392 +/- 177 ng/mL) and very high in children on ESRD (2094 +/- 1525 ng/mL) when compared to normal values (131 +/- 42 ng/mL). Binding studies of IGF type I receptor showed that there was no particular difference in IGF-I binding between renal failure patients and normal children. In poorly growing children, especially in ESRD children and to a lesser extent in RT children, high concentrations of IGF-I and IGFBP-1, 2, 3 and 6, suggest a resistance mainly by a sequestration mechanism. Moreover, in the CRF group, especially in the younger children, low levels of IGF-I and IGFBP-3 are evocative of an associated resistance at the GH receptor level.     

Effects of one year of recombinant human growth hormone (GH) therapy on cardiac mass and function in children with classical GH deficiency

Cardiac mass and function were evaluated in 10 children with classical GH deficiency. Echocardiograms were performed at baseline, 3, 6, and 12 months after initiation of recombinant human (rh) GH therapy (0.3 mg/kg.wk). Before treatment, left ventricular (LV) mass indexed to body surface area (BSA) was low or low normal (<50 g/m(2)) in five children compared with reference control data. Height SD score (-3.2 +/- 0.9 vs. -1.8 +/- 1.3 yr; P < 0.01), growth velocity SD score (-2.7 +/- 1.6 vs. 5.8 +/- 3.1; P < 0.01), LV mass (36 +/- 9 vs. 60 +/- 30 g; P < 0.02), LV mass/BSA (51 +/- 12 vs. 72 +/- 11 g/m(2); P < 0.01), LV mass/height (36 +/- 9 vs. 54 +/- 15 g/m; P < 0.02), and LV mass/m(2.7) (36 +/- 12 vs. 45 +/- 8; P < 0.05) increased significantly with rhGH therapy. Pretreatment LV mass/BSA correlated inversely with fold increase in LV mass/BSA over the year (r = -0.83; P < 0.01). Load-dependent indices of diastolic performance were normal at baseline and did not change with rhGH therapy. Percentage increase of mean velocity of circumferential shortening, an index of systolic function, correlated with fold increase in LV mass/BSA (r = 0.88; P < 0.02) over the year of rhGH administration. LV mass can be lower than predicted for body size in some children with severe GH deficiency but is responsive to rhGH replacement. LV mass/BSA increases into the normal range during the first year of rhGH therapy. The rate of increase of LV mass is greater than the increase in BSA during rhGH treatment, suggesting that GH could also be a trophic factor for the heart.     

Renal clearance, metabolic clearance rate, and half-life of human growth hormone in young and aged subjects.

We studied the renal clearance, MCR, and half-life of the synthetic 22K form of human GH [recombinant hGH (rhGH)] in seven healthy young and five aged men by means of the constant iv infusion technique. rhGH was infused at a rate of 2 micrograms/kg.2 mL/h for 150 min, after which its disappearance was followed for 50 min. Changes in GH levels in plasma and urine were measured by a highly sensitive enzyme immunoassay. The mean (+/- SD) renal clearance of GH was significantly greater in the aged group than in the young group (14.3 +/- 2.5 vs. 4.2 +/- 1.0 microL/min; P < 0.05). The mean MCR was greater in the young group than in the aged group (187.1 +/- 43.7 vs. 120.5 +/- 39.5 mL/min; P < 0.05), but the MCR adjusted for body weight was not different between the two groups (2.9 +/- 0.6 vs. 2.3 +/- 0.8 mL/min.kg). No difference was noted in the half-life of GH between the two groups (13.8 +/- 0.9 vs. 14.2 +/- 0.4 min). These findings indicate that GH reabsorption from the renal tubule may be impaired in elderly subjects, but the disappearance rate of GH is not influenced by age.     

A randomized controlled trial of low-dose recombinant human growth hormone in the treatment of malnourished elderly medical patients

High-dose recombinant human GH (rhGH) has been shown to improve the nutritional status of malnourished older adults. It is uncertain whether low-dose rhGH is effective and whether its effect on nutritional status will lead to any improvement in physical function. There is also no data on the outcome after a short course of rhGH treatment. The objectives of this study were to determine the efficacy of low-dose rhGH treatment for 4 weeks in malnourished elderly patients, its effect on physical functions, and the intermediate term outcome after a 4-week rhGH treatment. The study design was a randomized, placebo-controlled, double-blind trial conducted in a university teaching hospital. The patients were 19 medically stable malnourished elderly subjects. Intervention in the rhGH group was as follows: rhGH (Saizen, Serono, Switzerland) 0.09 IU/kg body weight (BW) 3 times weekly were given together with appropriate dietary intervention as prescribed by the dietitian. In the placebo group, equal volumes of normal saline per kilogram BW were given 3 times weekly together with the dietary intervention. The baseline demographic, anthropometric, nutritional, and hematological variables, measures of physical function, and insulin-like growth factor I levels in both groups were comparable. Compared with the placebo group, the GH-treated group showed a more rapid gain in BW (after 3 weeks, +1.27 +/- 0.36 vs. -0.28 +/- 0.37 kg; P = 0.008), total lean body mass (change after 3 weeks by bio-impedance analysis, +1.45 +/- 0.36 vs. -0.37 +/- 0.48 kg; P = 0.009) and a faster improvement in 5-m walking time (decrease after 4 weeks, 23.79 +/- 9.41 vs. 0.45 +/- 4.62 sec; P = 0.047). The hemoglobin level rose more in the rhGH than the placebo groups (change at 8 weeks, +0.84 +/- 0.34 vs. -0.42 +/- 0.29 g/dL; P = 0.012). Serum albumin level also showed a greater delayed increase in the rhGH group than in the placebo group (change at 8 weeks, +5.1 +/- 0.8 vs. 1.6 +/- 1.2 g/dL; P = 0.023). There was no statistically significant difference for other nutritional variables. There was a greater rise in the mean serum insulin-like growth factor I level at 4 weeks in the GH than in the placebo groups (197 +/- 58 vs. 54 +/- 26 U/L; P = 0.034). The improvement in the rhGH group gradually diminished on follow-up and became statistically insignificant 8 weeks after stopping rhGH treatment. There were no GH-related adverse effects. Low-dose rhGH was an effective and safe adjuvant to dietary augmentation for stable malnourished elderly subjects. It led to a faster gain in total lean body mass, which was associated with greater improvement in walking speed when compared with dietary intervention alone. There were no apparent side effects.     

Time course and mechanism of growth hormone's negative feedback effect on its own spontaneous release.

Endogenous pulsatile GH secretion is blunted by the administration of exogenous GH; however, few data are available on the time course of GH negative feedback, and the mechanism by which this occurs still remains unclear. In the present study, we examined the temporal pattern of the inhibitory effect induced by an acute (single) and chronic (5 days) sc recombinant human (rh) GH injection regimen on spontaneous GH release in the rat and assessed the possible involvement of the hypothalamic GH-inhibitory peptide, somatostatin (SRIF), in this response. Eight-hour (0800-1600 h) GH secretory profiles, obtained from free-moving adult male rats administered a single sc injection of 200 micrograms rhGH at 0800 h, revealed a marked suppression of spontaneous GH pulses (GH peak amplitude: 45.7 +/- 10.9 vs. 207.8 +/- 31.7 ng/ml in H2O-injected control rats; P less than 0.001) lasting for up to 4.1 +/- 0.1 h after the injection (mean 4-h plasma GH level: 13.6 +/- 3.6 vs. 49.4 +/- 7.0 ng/ml in H2O-injected controls; P less than 0.01). During the subsequent 4- to 8-h period, recovery of spontaneous GH secretory bursts was evident, and neither the GH peak amplitude nor mean 4-h plasma GH level of rhGH-treated rats was significantly different from that of H2O-injected controls. The magnitude, time course, and recovery of the rhGH-induced inhibitory effect on pulsatile GH release after chronic rhGH treatment was similar to that after a single injection. Passive immunization of rhGH-treated rats with SRIF antiserum reversed the rhGH-induced inhibition of spontaneous GH pulses (peak amplitude: 131.7 +/- 53.7 vs. 7.1 +/- 3.4 ng/ml in rhGH-treated control rats given normal sheep serum; P less than 0.05) and restored both the GH peak amplitude and mean plasma GH level to values similar to those in H2O-injected controls. Taken together, these results demonstrate that: 1) the inhibitory effect of rhGH on endogenous pulsatile GH release is of short duration (approximately 4 h); 2) the time course of this response does not change after 5-day repeated rhGH administration; and 3) the feedback effect of GH on its own spontaneous release is exerted, at least in part, by increasing hypothalamic SRIF secretion. Such a mechanism of GH feedback may be important in the physiological control of pulsatile GH secretion.     

Intestinal permeability in adult patients with growth hormone deficiency

Pathological disruption of the intestinal mucosa increases the paracellular pathway, leading to an increase in the penetration of large molecules. Since growth hormone (GH) has a trophic intestinal effect, we used a double marker test to enable examination of intestinal permeability, which reflects the state of integrity of the intestinal mucosa. We recruited 22 adult patients, mean age 54+/-13.3 years, with GH deficiency due to partial or total hypopituitarism. None had received GH treatment at any time, although they were all in optimized replacement therapy. A control group was composed of 19 healthy age-matched relatives. The intestinal permeability test was performed with lactulose (5 g) and mannitol (1 g) after an oral load of 100 ml of aqueous solution. The urinary lactulose/mannitol ratio and the percentages of lactulose and mannitol excreted were determined on a 5-h urine collection. There were no significant differences between the patients and the control group in the lactulose/mannitol ratio (0.087+/-0.059 vs 0.077+/-0.064, respectively) or in the urinary excretion percentages of lactulose (0.067+/-0.048% vs 0.073+/-0.070%, respectively) or mannitol (5.127+/-3.269% vs 5.068+/-2.985%, respectively). In conclusion, no increase in intestinal permeability was detected in patients with GH deficiency, so that in spite of the known trophic effects of GH on the epithelial crypt cells, there was no intestinal hyperpermeability in these patients.     

Impact of experimental blockade of peripheral growth hormone (GH) receptors on the kinetics of endogenous and exogenous GH removal in healthy women and men

Organs that respond to and metabolize GH are enriched in cognate high-affinity receptors. However, whether isologous receptors mediate the de facto access of ligand to cellular degradative pathways is not known. To address this query, we assessed the distribution and whole-body elimination kinetics of (endogenous and exogenous) GH before and after administration of a novel, potent, and selective recombinant human (rh) GH receptor antagonist peptide, pegvisomant. Sixteen healthy young adults (nine men and seven women) participated in a double-blind, prospectively randomized, within-subject cross-over study. The intervention comprised a single sc injection of placebo vs. a high dose of pegvisomant (1 mg/kg sc) timed 62 and 74 h before the overnight sampling and daytime infusion sessions, respectively. The half-life, metabolic clearance rate (MCR), and distribution volume of GH were quantitated by way of: 1) deconvolution analysis of serum GH concentration time series collected every 10 min for 10 h; 2) exponential regression analysis of the decay of GH concentrations after a 6-min iv pulse of rhGH (1 and 10 micro g/kg); 3) calculation of the MCR during constant iv infusion of rhGH (0.5 and 5.0 micro g/kg every 2 h); and 4) exponential fitting of the elimination time-course of GH concentrations following cessation of each constant infusion. Concentrations of GH and pegvisomant were measured in separate, noncross-reactive, two-site monoclonal, immunofluorometric assays. Pegvisomant concentrations averaged 4860 +/- 480 micro g/liter (+/-SEM) across the infusion interval, thus exceeding low steady state GH concentrations by 3000-fold. Inhibitory efficacy of the GH receptor antagonist peptide was affirmed by way of a 34% reduction in the serum total IGF-I concentration, i.e., from 257 +/- 37 (placebo) to 170 +/- 24 (drug) micro g/liter (P < 0.001); and a reciprocal 77% elevation of the (10-h) mean GH concentration, i.e., from 1.3 +/- 0.23 (placebo) to 2.3 +/- 0.42 (drug) micro g/liter (P = 0.003). ANOVA disclosed that prior administration of pegvisomant (compared with placebo) did not alter: 1) the calculated half-life (minutes) of secreted GH, which averaged 15 +/- 1.3 (placebo) and 14 +/- 0.69 (drug); 2) the half-time of disappearance (minutes) of an iv pulse of rhGH, 15 +/- 1.0 (placebo) and 13 +/- 0.5 (drug) (for the 10 micro g/kg dose); 3) the distribution volume (milliliters per kilogram) of rhGH, 59 +/- 6.2 (placebo) and 58 +/- 3.5 (drug); 4) the steady state GH concentration (micrograms per liter) attained during constant iv infusion of rhGH (at a rate of 5 micro g/kg every 2 h), 18.2 +/- 2.4 (placebo) and 18.3 +/- 2.3 (drug); 5) the half-life (minutes) of elimination of GH from equilibrium, 16 +/- 0.98 (placebo) and 16 +/- 1.8 (drug); and 6) the steady state MCR (liters per kilogram per day) of rhGH, 3.8 +/- 0.32 (placebo) and 3.5 +/- 0.31 (drug). In ensemble, the present data refute the a priori postulate that vascular-accessible GH receptors determine the in vivo pseudoequilibrium kinetics of GH disappearance in the human.     

The negative GH auto-feedback in childhood: effects of rhGH and/or GHRH on the somatotroph response to GHRH or hexarelin, a peptidyl GH secretagogue, in children

Aim of the present study was to further clarify the negative GH auto-feedback mechanisms in childhood. To this goal we studied the effects of rhGH and/or GHRH administration on the GH response to GHRH or hexarelin (HEX), a peptidyl GH secretagogue, in normal short children. In 34 prepubertal children (12 girls and 22 boys, age 8.2- 14.2 yr) with normal short stature (normal height velocity and IGF-I levels) the following tests were performed: group A (no.=11): GHRH (GHRH 1 - 29, Geref, Serono; 1 microg/kg iv at 150 min) preceded by saline or GHRH at 0 min; group B (no.=6): GHRH preceded by saline or rhGH (0.005 IU/kg iv at 0 min); group C (no.=6): GHRH preceded by rhGH alone or combined with GHRH; group D (no.=6): HEX (2 microg/kg iv at 150 min) alone or preceded by rhGH. In group A, the GH response to GHRH was not modified by pre-treatment with GHRH (GH peak, mean+/-SEM: 16.7+/-2.9 vs 15.1+/-2.3 microg/l, respectively). In group B, the GH response to GHRH was clearly inhibited by rhGH (8.7+/-2.3 vs 38.8+/-4.5 microg/l, p<0.001); the GH rise after rhGH in group B overlapped with that after GHRH in group A. In group C, the GH response to GHRH after pre-treatment with rhGH (13.2+/-4.0 microg/l) was similar to that in group B and was not significantly modified by pre-treatment with rhGH+ GHRH (6.9+/-2.7 microg/l); the GH rise after rhGH+GHRH was higher (p<0.05) than that after rhGH alone. In group D, the GH response to HEX was significantly blunted by pre-treatment with rhGH (34.1+/-11.7 vs 51.2+/-17.9 microg/l, p<0.05). Our results demonstrate that in childhood the somatotroph response to GHRH is preserved after GHRH while it is inhibited after rhGH administration, which is also able to blunt the GH response to HEX. Thus, the somatostatin-mediated negative GH auto-feedback is already operative in childhood; the reason why the GHRH- induced GH rise is not inhibited by GHRH pre-treatment is unexplained.     

重组人生长激素治疗不同生长激素分泌状态青春前期矮小患儿追赶性生长模式分析

目的 比较不同生长激素(GH)分泌状态矮小患儿重组人生长激素(rhGH)治疗后的初始追赶性生长模式,初步探讨其机制.方法 回顾性分析62例青春前期不同GH分泌状态矮小患儿对rhGH治疗1年半的追赶性生长模式并定期监测体格指标、促生长素轴的血清指标和骨龄.结果 各组在初始追赶性生长的幅度相似,特发性矮小(ISS)组比完全性生长激素缺乏症(GHD)组更早出现生长减速,并与生长激素结合蛋白(GHBP)水平降低和胰岛素样生长因子结合蛋白3的标准差分数(SDS)增值较小显著相关.GH激发峰值(Ghmax)>7μg/L的部分性GHD组与ISS组有类同的生长追赶的模式.结论 GH受体的降调节和受体后效应的降低可能是ISS组较早出现生长减速的机制.以Ghmaxμg/L作为GHD诊断的界值并相应选择rhGH治疗剂量有更充分的依据和临床意义.     

Short-term treatment with low doses of recombinant human GH stimulates lipolysis in visceral obese men

This study was designed to explore whether low doses of recombinant human (rh)GH affect lipid, glucose, or protein metabolism in men with visceral obesity. Four different studies were performed in six, otherwise healthy, obese men (age, 42 +/- 3; body mass index, 33 +/- 1 kg/m(2); waist circumference, 111 +/- 3 cm; mean +/- SEM). Lipid, glucose, and protein kinetics was estimated by infusing stable isotopes (glycerol, glucose, leucine) in the basal state and after 1 wk of treatment with sc bedtime injections of either placebo, 2.5 (GH2.5), or 3.3 (GH3.3) microg rhGH/kg body weight per day. When compared with baseline, placebo had no effect on lipid, glucose, or protein fluxes. In contrast, GH2.5 and GH3.3 increased lipolysis by approximately 25% (P < 0.04) without changing glucose and protein turnover rates. The two rhGH treatments increased within the normal range serum IGF-I (by approximately 30%; P < 0.01), whereas they augmented insulin secretion (P < 0.04) in a dose-dependent manner (GH2.5 by 19%, GH3.3 by 37%). C-peptide secretion was increased (P = 0.01) only by GH3.3 (by 28%). In conclusion, 1 wk of treatment with low doses of rhGH is sufficient to increase lipolysis in visceral obese men, but it does not modify glucose and protein turnover rates. The results of this study provide the rationale to design clinical trials using low doses of rhGH to attempt to reduce fat mass.     

The IGF-I response to very low rhGH doses is preserved in human ageing

OBJECTIVES: The activity of the GH/IGF-I axis varies during life and is clearly reduced in the elderly. In fact, GH, IGF-I and IGFBP-3 levels in older people are clearly reduced and similar to those observed in patients with GH deficiency. The declining activity of the GH/IGF-I axis with advancing age may contribute to changes in body composition, structure, function and metabolism. In fact, treatment with pharmacological doses of rhGH restored plasma IGF-I levels, increased lean body mass and muscle strength while decreased adipose tissue mass in healthy elderly subjects. At present it is unclear whether peripheral GH sensitivity is preserved in aging. To clarify this point, we aimed to verify the effect of both single dose and short term treatment with very low rhGH doses on the IGF-I levels in normal elderly subjects. Normal young adults were studied as controls. DESIGN: We studied the IGF-I response to rhGH administration after single (20 micrograms/kg s.c.) or repeated administrations (5 micrograms/kg s.c. for 4 days) in two groups of young and elderly subjects. SUBJECTS: Twenty-seven healthy elderly (ES, 14 F and 13 M, age mean +/- SEM: 69.4 +/- 1.3 years, BMI: 23.9 +/- 0.5 kg/m2) and 21 young adult subjects (YS, 12 F and 9 M, 29.8 +/- 1.2 years, 23.8 +/- 0.5 kg/m2) were studied, divided into two groups. MEASUREMENTS: Group 1: blood samples for IGF-I and IGFBP-3 assay were drawn basally and 12 h after rhGH administration (20 micrograms/kg). Group 2: blood samples for IGF-I, IGFBP-3, glucose and insulin assays were drawn basally, 12 h after the first and the last rhGH administration (5 micrograms/kg). Free T3 (fT3), free T4 (fT4) and TSH levels were also assayed basally and after the last rhGH administration; oestradiol and testosterone levels were measured basally. RESULTS: Basal IGF-I levels were lower in ES (whole group) than in YS (whole group) (123.1 +/- 8.9 vs. 230.4 +/- 16.1 micrograms/l, P < 0.001) while IGFBP-3 levels in the two groups were similar (2.7 +/- 0.2 vs. 3.1 +/- 0.2 mg/l). No sex-related differences in IGF-I and IGFBP-3 levels were recorded in either group. Group 1: the single administration of 20 micrograms/kg rhGH induced a significant (P < 0.001) IGF-I rise both in YS (318.0 +/- 25.3 vs. 256.0 +/- 21.6 micrograms/l) and ES (187.2 +/- 16.8 vs. 100.4 +/- 9.5 micrograms/l). IGF-I levels after rhGH in ES persisted lower than those in YS (P < 0.001), but the percentage IGF-I increase after rhGH was higher (P < 0.001) in ES (91.6 +/- 12.9%) than in YS (23.9 +/- 5.0%) subjects. Both in YS and ES IGFBP-3 levels were significantly increased to the same extent by 20 micrograms/kg rhGH (3.0 +/- 0.2 vs. 2.3 +/- 0.2 mg/l; 2.9 +/- 0.2 vs. 2.6 +/- 0.2 mg/l, P < 0.001 vs. baseline). Group 2: basal glucose, insulin, fT3, fT4 and TSH levels in YS and ES were similar; testosterone levels in aged and young men were similar while oestradiol levels in aged women were lower (P < 0.01) than in the young ones. IGF-I levels were significantly increased 12 h after the first administration of 5 micrograms/kg rhGH both in ES (166.6 +/- 15.7 vs. 138.3 +/- 12.1 micrograms/l, P < 0.03) and YS (272.2 +/- 16.1 vs. 230.4 +/- 16.1 micrograms/l, P < 0.001). Twelve hours after the last rhGH administration IGF-I levels were further increased (P < 0.001) both in ES (208.7 +/- 21.1 micrograms/l) and YS (301.7 +/- 17.6 micrograms/l). IGF-I levels in ES persisted lower than those in YS at each time point (P < 0.001); however, the percentage IGF-I increase after rhGH in ES and YS was similar (after the first administration: 22.4 +/- 5.1 vs. 21.7 +/- 5.1%; after the last administration: 52.9 +/- 9.5 vs. 39.5 +/- 9.9%). No significant variation in IGFBP-3, glucose, insulin, fT3, fT4 or TSH levels was recorded in either ES or YS. CONCLUSIONS: Our data demonstrate that IGF-I levels in aging are reduced but the peripheral sensitivity to rhGH is preserved. In fact, in aged subjects the percentage rhGH-induced IGF-I increase is similar or even highe     

Effects of growth hormone on the tempo of sexual maturation in female rhesus monkeys

The signal that initiates and maintains the developmental change in LHRH and, consequently, LH secretion in primates, thus regulating the tempo of puberty, is not known. Given the close association between reproductive development and bone maturation, we examined the hypothesis that GH was involved in developmental increases in LH release, specifically by augmenting the decrease in estradiol (E2) negative feedback inhibition of LH that characterizes late puberty in primates. Recombinant human GH (rhGH; 250 micrograms/kg) was given (sc) three times weekly to immature female rhesus monkeys to determine if developmental increases in basal serum LH would occur at an earlier age, and if menarche and first ovulation also would be advanced. The study groups included intact females receiving rhGH (INT + GH; n = 5), intact control animals (INT; n = 6), ovariectomized females receiving E2 plus rhGH (E2OVX + GH; n = 5), and E2-treated ovariectomized control monkeys (E2OVX; n = 4). The females were studied from 20 months of age until their serum LH levels increased (E2OVX groups) or until the occurrence of first ovulation (intact groups). After 12 months of rhGH treatment, the crown-rump lengths were significantly increased, regardless of ovarian status, an effect maintained in the intact females through 21 months of treatment. The mean age at the time of the initial rise in serum LH was advanced by rhGH treatment in intact females (29.6 +/- 0.4 vs. 31.3 +/- 0.3 months), but not E2OVX females. Subsequent maturational elevations in LH secretion were similar in the E2OVS + GH and E2OVX animals even after an incremental increase in E2. Ages at menarche were similar in the INT + GH and INT groups, whereas first ovulation was significantly advanced in three of five INT + GH females (31.5 +/- 0.7 months) compared to that in INT females (43.5 +/- 0.3 months). The remaining INT + GH females ovulated at an age (42.4 +/- 0.4 months) similar to that of INT females. Those females that ovulated by 32 months had higher skeletal maturity scores than the later ovulating INT females, with the other INT + GH females being intermediate. Furthermore, rhGH resulted in a significant increase in serum E2 levels within 12 h of injection, which remained elevated through 24 h. This effect of rhGH on ovarian E2 secretion did not occur until females had shown elevations in basal serum LH.(ABSTRACT TRUNCATED AT 400 WORDS)     

Kinetics of phytohemaglutinin-induced IFN-γ and TNF-α expression in peripheral blood mononuclear cells from patients with chronic hepatitis B after liver transplantation

AIM: To study the association between host immunity and hepatitis B virus (HBV) recurrence after liver transplantation. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from 40 patients with hepatitis B and underwent orthotopic liver transplantation (OLT) before and 2, 4, 8 wk after surgery. After being cultured in vitro for 72 h, the levels of INF-gamma and TNF-alpha in culture supernatants were detected with ELISA. At the same time, the quantities of HBV DNA in serum and PBMCs were measured by real time PCR. RESULTS: The levels of INF-gamma and TNF-alpha in PBMC culture supernatants decreased before and 2, 4 wk after surgery in turns (INF-gamma 155.52+/-72.32 ng/L vs 14.76+/-9.88 ng/L vs 13.22+/-10.35 ng/L, F = 6.946, P = 0.027 < 0.05; TNF-alpha 80.839+/-46.75 ng/L vs 18.59+/-17.29 ng/L vs 9.758+/-7.96 ng/L, F = 22.61, P = 0.0001 < 0.05). The levels of INF-gamma and TNF-alpha were higher in groups with phytohemagglutinin (PHA) than in those without PHA before surgery. However, the difference disappeared following OLT. Furthermore, INF-gamma and TNF-alpha could not be detected in most patients at wk 4 and none at wk 8 after OLT. The HBV detection rate and virus load in PBMC before and 2, 4 wk after surgery were fluctuated (HBV detected rate: 51.4%, 13.3%, 50% respectively; HBV DNA: 3.55+/-0.674 log10 copies/mL vs 3.00+/-0.329 log10 copies/mL vs 4.608+/-1.344 log10 copies/mL, F = 7.582, P = 0.002 < 0.05). HBV DNA in serum was 4.48+/-1.463 log10 copies/mL before surgery and <10(3) copies/mL after OLT except for one with 5.72 x 10(6) copies/mL 4 wk after OLT who was diagnosed as HBV recurrence. The levels of INF-gamma and TNF-alpha were lower in patients with a high HBV load than in those with a low HBV load (HBV DNA detected/undetected in PBMCs: IFN-gamma 138.08+/-72.44 ng/L vs 164.24+/-72.07 ng/L, t = 1.065, P = 0.297 > 0.05, TNF-alpha 80.75+/-47.30 ng/L vs 74.10+/-49.70 ng/L, t = 0.407, P = 0.686 > 0.05; HBV DNA positive/negative: IFN-gamma 136.77+/-70.04 ng/L vs 175.27+/-71.50 ng/L, t = 1.702, P = 0.097 > 0.05; TNF-alpha 75.37+/-43.02 ng/L vs 81.53+/-52.46 ng/L, t = 0.402, P = 0.690 > 0.05). CONCLUSION: The yielding of INF-gamma and TNF-alpha from PBMCs is inhibited significantly by immunosuppressive agents following OLT with HBV load increased, indicating that the impaired immunity of host is associated with HBV recurrence after OLT.     

High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group

GH production rates markedly increase during human puberty, mostly as an amplitude-modulated phenomenon. However, GH-deficient children have been dosed on a standard per kg BW basis similar to prepubertal children. This randomized study was designed to compare the efficacy and safety of standard recombinant human GH (rhGH) therapy (group I, 0.3 mg/kg x week) vs. high dose therapy (group II, 0.7 mg/kg x week) in GH-deficient adolescents previously treated with rhGH for at least 6 months. Ninety-seven children with documented evidence of GH deficiency (peak GH in response to stimuli, <10 ng/mL), with either organic or idiopathic pathology, were recruited. Both groups were matched for sex (group I, 42 males and 7 females; group II, 41 males and 7 females), age [group I, 14.0+/-1.6 (+/-SD) yr; group II, 13.7+/-1.6], standardized height (group I, -1.4+/-1.1; group II, -1.2+/-1.1), bone age (group I, 13.1+/-1.3 yr; group II, 13.1+/-1.3) etiology, maximum stimulated GH, previous growth rate, and midparental target height. All subjects were in puberty (Tanner stage 2-5) at study entry. Of the 97 subjects enrolled, 45 were treated for 3 yr or more; 48 completed the study. Of the subjects who discontinued the study, the most common reason was satisfaction with their height, although others discontinued for adverse events or personal reasons. The frequency of patients who discontinued was the same in both groups. The primary efficacy analysis was the difference between dose groups for near-adult height, defined as the height attained at a bone age of 16 yr or more in males and 14 yr or more in girls; all subjects who qualified were included in the analysis. This difference was statistically significant at 4.6 cm by analysis of covariance (ANCOVA; P < 0.001; n = 75). For subjects who received at least 4 yr of rhGH treatment, the difference between dose groups at that time point was 5.7 cm (by ANCOVA, P = 0.024; n = 20). The mean height SD score at near-adult height was -0.7+/-0.9 in the standard dose group and 0.0+/-1.2 in the high dose group. At 36 months the cumulative change in height (centimeters) was 21.5+/-5.3 cm (group I) vs. 25.1+/-4.9 (group II; P < 0.001, by ANCOVA); the change in Bayley-Pinneau predicted adult height was 4.8+/-4.2 cm (group I) vs. 8.4+/-5.7 (group II; P = 0.032). Median plasma IGF-I concentrations at baseline were 427 microg/L (range, 204-649) in group I and 435 microg/L (range, 104-837) in group II; at 36 months they were 651 microg/L (range, 139-1079) in group I vs. 910 microg/L (range, 251-1843) in group II (P = NS). No difference in change in bone age was detected between groups at any interval. High dose rhGH was well tolerated, with a similar safety profile as standard dose treatment and no difference in hemoglobin A1c or glucose concentrations between groups. In summary, compared to conventional treatment, high dose rhGH therapy in adolescents 1) increased near-adult height and height SD scores significantly, 2) did not increase the rate of skeletal maturation, and 3) appears to be well tolerated and safe. In conclusion, high dose rhGH therapy may have a beneficial effect in adolescent GH-deficient patients, particularly those who are most growth retarded at the start of puberty.     

Changes of soluble CD26 and CD30 levels correlate with response to interferon plus ribavirin therapy in patients with chronic hepatitis C

BACKGROUND: Clearance of hepatitis C virus (HCV) is attributed to host cellular immune responses, in which T helper cells play a critical role. The purpose of the present paper was therefore to study the serial changes of serum soluble markers released from T helper 1 (Th1) and 2 (Th2) and their correlations with treatment responses in chronic hepatitis C patients receiving interferon-alpha plus ribavirin for 24 weeks. METHODS: Serum markers (soluble CD26 and CD30 levels) of T helper cells were quantified before and 6 months after combination therapy in 33 chronic hepatitis C patients and in 20 healthy controls. RESULTS: Compared to healthy controls, chronic hepatitis C patients had significantly lower serum soluble CD26 levels before (140.4 +/- 63.9 ng/mL vs 200.6 +/- 60.3 ng/mL, P < 0.0001) and after (115.9 +/- 32.9 ng/mL vs 200.6 +/- 60.3 ng/mL, P < 0.0001) combination therapy. The level was even lower in those with non-sustained virologic response (non-SVR; 139.0 +/- 50.9 ng/mL vs 117.7 +/- 40.3 ng/mL, P = 0.039). In contrast, soluble CD30 levels at 6 months after combination therapy were significantly lower in patients with SVR than those with non-SVR (6.4 +/- 3.5 U/mL vs 10.4 +/- 5.4 U/mL, P = 0.021). CONCLUSION: Chronic hepatitis C patients have a weak Th1 response as reflected by lower soluble CD26 levels and the levels are even lower in non-sustained responders. In sharp contrast, downregulation of Th2 response with serial changes of soluble CD30 level is associated with successful treatment of HCV infection.     

Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: a 3-year randomized study

CONTEXT: Long-term glucocorticoid therapy adversely affects growth and body composition in children with juvenile idiopathic arthritis (JIA). In previous studies, recombinant human GH (rhGH) halted the progression of these complications without inducing catch-up growth. OBJECTIVES: The objective of the study was to evaluate the impact on growth and body composition of rhGH started early after glucocorticoid initiation and to record adverse effects in children with JIA. DESIGN: This is a 3-yr randomized controlled study. SETTING: This study was conducted in a teaching hospital. PATIENTS: Thirty children, 12-15 months into glucocorticoid therapy for severe JIA, were enrolled. INTERVENTION: Patients received rhGH (0.46 mg/kg.wk) in daily sc injections (n = 15) or no rhGH therapy (n = 15) for 3 yr. MAIN OUTCOME MEASURE: Difference in height sd score (SDS) change between the two groups was assessed. Height velocity, body composition, and oral glucose tolerance were evaluated yearly. RESULTS: Mean height SDS increase was larger with rhGH (+0.37 +/- 1.5 SDS) than without (-0.96 +/- 1.2 SDS) (P = 0.04). Mean height velocity returned to normal within the first year of rhGH treatment and remained normal thereafter. Mean lean mass increase was greater with rhGH treatment (+7.3 +/- 2.9 kg vs. +4.4 +/- 2.8 kg; P = 0.03). Fat mass and bone mineralization were not significantly different in the two groups. Fasting serum insulin increased significantly in rhGH-treated patients (5.2 +/- 16 mIU/liter) compared with untreated controls (-2.3 +/- 5 mIU/liter) (P = 0.04); fasting glycemia was unchanged. CONCLUSIONS: rhGH started early in the course of JIA preserved normal growth velocity and height. Although rhGH was well tolerated, carbohydrate metabolism should be monitored closely.     

鸟氨酸-天门冬氨酸联合乳果糖治疗肝性脑病疗效观察

目的探讨鸟氨酸-天门冬氨酸(雅博司)联合乳果糖治疗肝性脑病的疗效.方法选择56例肝性脑病患者,在综合性治疗的基础上,给鸟氨酸-天门冬氨酸20g/d静脉滴注;乳果糖20ml口服或鼻饲,每日三次.另选36例患者作为对照组,给一般综合性治疗,同时给乙酰谷酰胺1.0g/d静脉滴注,分别治疗20天.结果治疗组病死率明显下降,与对照组相比,有显著性差异(x2=4.02,P＜0.05),在降低血氨及促进脑电图改善方面,两组也存在显著性差异.结论雅博司联合乳果糖治疗慢性重型肝炎合并的肝性脑病,疗效显著,值得研究和应用.     

The effects of recombinant human growth hormone (rhGH) supplementation on adipokines and C-reactive protein in obese subjects.

OBJECTIVE: Obese subjects have functional growth hormone deficiency (GHD). Recombinant human GH (rhGH) treatment of pituitary GHD improves serum levels of leptin, adiponectin and C-reactive protein (CRP). This study was undertaken to determine whether these rhGH-induced changes occur in obese subjects during rhGH supplementation. DESIGN: Randomized double-blind placebo-controlled trial of low-dose rhGH (200 microg/day for the first month, then 400 microg/day for men and 600 microg/day for women thereafter) or placebo supplementation as an adjuvant to a standard weight loss program. SUBJECTS: Forty healthy obese subjects, 28 premenopausal menstruating women (35+/-7 SD years) and 12 men (37+/-6 years). MEASUREMENTS: Body weight, BMI, body composition (assessed by dual energy X-ray absorptiometry [DEXA]), and serum levels of glucose, insulin, IGF-I, IGFBP-3, insulin resistance index (homeostasis modal assessment [HOMA]), leptin, CRP and adiponectin were performed at baseline and at 6 months. RESULTS: For similar entry BMI values, women when compared with men had higher percent body fat (BF) (43.5+/-4.6% vs. 29.8+/-4.0%, p<0.001), higher leptin levels (16.9+/-8.4 microg/L vs. 4.2+/-3.0 microg/L, p<0.001), and higher CRP levels (13.8+/-16.8 mg/L vs. 2.4+/-3.2mg/L, p=0.04). Serum levels of leptin and CRP, but not adiponectin, correlated significantly with BF in both sexes. Recombinant human GH treatment increased levels of IGF-I Z-Score between baseline and 6 months (from -0.7+/-0.9 SD to 0.1+/-1.1 SD, p=0.01) and modestly decreased BF (from 38.4+/-7.8% to 35.6+/-7.5%, p=0.046). Despite increased IGF-I, there were no differences between rhGH and placebo with regard to changes in leptin, CRP, or adiponectin. CONCLUSION: It is concluded that in obesity, although rhGH treatment significantly increases IGF-I and modestly reduces body fat, the lack of significant changes in serum leptin, adiponectin or CRP levels suggests that rhGH treatment does not have a significant effect on these serum markers of adiposity.     

慢性乙型肝炎患者外周血单核细胞Toll样受体2和4的变化

目的探讨慢性乙型肝炎和慢性重型乙型肝炎患者外周血单核细胞Toll样受体2 （TLR2）和Toll样受体4（TLR4）的变化情况及其意义。方法用流式细胞仪检测正常对照、慢性乙型肝炎患者和慢性重型乙型肝炎患者外周血单核细胞表面TLR2和TLR4的表达,ELISA法检测上述患者血清TNFα的水平。Student-t检验比较3组间TLR2、TLR4和TNFα表达的差异;3组病例TLR2、TLR4的表达水平间及它们与血清TNFα水平间的相关性分析采用线性相关分析。结果正常对照组（30例）、慢性乙型肝炎组（31例）和慢性重型乙型肝炎组（30例）外周血单核细胞TLR2和TLR4的平均免疫荧光强度（MFI）分别为21．5±2．7、39．0±4．1．47．7±21．4和2．3±1．1、3．7±2．3、6．9±4．1;外周血清TNFα（ng／L）水平分别为53．8±38．1、164．3±89．9、359．8±1 40．0,自正常对照组到慢性乙型肝炎组及慢性重型乙型肝炎组外周血单核细胞TLR2、TLR4表达强度和外周血清TNFα水平均依次显著升高;经线性相关分析研究发现,外周血单核细胞TLR2、TLR4表达水平和血清TNFα表达水平间均呈现显著的正相关性。结论TLR2和TLR4可能与慢性乙型肝炎及慢性重型乙型肝炎的发病有关。