Differential effects of growth hormone therapy in malnourished hemodialysis patients

BACKGROUND: Malnutrition is common in chronic hemodialysis patients and is associated with increased morbidity and mortality. Several factors such as metabolic acidosis, hyperparathyroidism, and insulin as well as growth hormone (GH) resistance may lead to enhanced protein catabolism. Recombinant human growth hormone (rhGH) has been proposed as treatment of malnutrition because of its anabolic effects. METHODS: In the present placebo-controlled, double blind study, the effects of three months of rhGH therapy on nutritional and anthropometric parameters, on bone metabolism and bone mineral density (BMD), as well as on polymorphonuclear leukocyte (PMNL) function and quality of life (QoL) were evaluated in 19 malnourished hemodialysis patients (10 females and 9 males) with a mean age of 59.3 +/- 13.4 years. RhGH (0.125 IU/kg) was given three times a week during the first four weeks and 0.25 IU/kg thereafter three times a week after each dialysis session. RESULTS: Insulin-like growth factor I (IGF-I) concentration rose significantly from 169.2 +/- 95.6 ng/mL to 262.9 +/- 144.4 ng/mL (p< 0.01) in the group receiving rhGH. Albumin, prealbumin, transferrin, cholesterol, high-density lipoprotein (HDL) cholesterol, cholinesterase, predialytic creatinine, and blood urea nitrogen showed no significant changes during the three months in both groups. Total body fat (%TBF) was slightly reduced after three months (P = NS) in the patients receiving GH, whereas lean body mass (LBM) remained stable during therapy. Procollagen I carboxy terminal peptide (PICP), a marker of bone formation, increased significantly after three months from 250.1 +/- 112.6 to 478.5 +/- 235.2 microg/L (P < 0.01) in the GH-treated patients, whereas parameters of bone resorption like telopeptide ICTP showed only a slight increase (50.3 +/- 18.5 vs. 70.0 +/- 39.5 microg/L, P = NS). BMD at the lumbar spine decreased significantly after three months in the treatment group (0.8 +/- 0.17 vs. 0.77 +/- 0.16 g/cm2, P < 0.01), whereas BMD at the femoral neck remained stable in both groups. Phagocytic activity of PMNLs increased significantly after three months of therapy with rhGH, whereas other parameters of PMNL function were not affected by GH. QoL was slightly improved in the GH treated group, but decreased markedly in the placebo group. CONCLUSIONS: Three months of treatment with rhGH in malnourished patients on chronic hemodialysis causes a significant increase in IGF-I levels without significant changes in nutritional and anthropometric parameters. In contrast, bone turnover was enhanced with an initial decrease in BMD at the lumbar spine, and phagocytic activity of PMNLs was increased.     

Growth hormone treatment in hemodialysis patients--a randomized, double-blind, placebo-controlled study

OBJECTIVE: Renal failure and hemodialysis (HD) affect the anabolic growth hormone (GH)-insulin-like growth factor (IGF) axis. A positive correlation between serum IGF-I and normalized protein catabolic rate (PCRn) in HD patients has been reported, and the aim of this study was to assess the metabolic impact of recombinant human (rh)GH in these patients. MATERIAL AND METHODS: In a randomized, double-blind, placebo-controlled study, rhGH was given to 35 HD patients for 8 weeks: 0.025 IU/kg/day for 1 week, increasing to 0.05 IU/kg/day. Patients with diabetes, malignancy or clinical signs of infection and those receiving steroid treatment were excluded. RESULTS: All patients completed the study. Side-effects were rare and equally distributed between the two groups. Post-treatment, serum IGF-I and IGF-I standard deviation score (IGF-I SD) increased in the rhGH group compared to the placebo group: 283+/-33 vs 151+/-16 mg/l (p = 0.001) and 1.8+/-0.6 vs -0.2+/-0.6 (p = 0.002), respectively. IGF binding protein-3 was higher in the rhGH group compared to the placebo group: 5859+/-285 vs 4369+/-321 mg/l (p = 0.002). PCRn was significantly higher in the rhGH group compared to the placebo group: 1.09+/-0.06 vs 0.90+/-0.06 g/kg/day (p = 0.029). No differences were found in body weight, serum albumin or leptin between the two groups. There was no change in C-reactive protein (CRP) in the rhGH group compared to the placebo group: 17.4+/-9.0 vs 12.3+/-4.6 mg/l (p = NS). When the patients were subgrouped according to the CRP level (< or > 10 mg/1), the effect on PCRn persisted only in rhGH-treated subjects with a normal CRP level: 1.10+/-0.08 vs 0.81+/-0.09 g/kg/day (p = 0.025). CONCLUSION: Treatment of HD patients with rhGH at a moderate dose causes augmentation of PCRn which is considered to indicate a higher dietary protein intake. The anabolic effect of rhGH seems to be abolished by subclinical inflammation.     

Beneficial effects of extended growth hormone treatment after hospital discharge in pediatric burn patients

OBJECTIVE: To study the efficacy of growth hormone given to severely burned children from discharge to 12 months after burn and for 12 months after the drug was discontinued. SUMMARY BACKGROUND DATA: We have previously shown that low-dose recombinant human growth hormone (rhGH), given to children after a severe thermal injury, successfully improved lean muscle mass, bone mineral content, and growth. The aim of the present study was to investigate long-term functional improvements after treatment. METHODS: Forty-four pediatric patients with over 40% total body surface area burns were studied for 24 months after burn. Patients were randomized to receive either rhGH (0.05 mg/kg body weight) or placebo. Height, weight, body composition, serum hormones, resting energy expenditure, cardiac function, muscle strength, and number of reconstructive procedures performed were measured during rhGH treatment and for 12 months after treatment was discontinued. Statistical analysis used Tukey's multiple comparison test. Significance was accepted at P < 0.05. RESULTS: Height, weight, lean body mass, bone mineral content, cardiac function, and muscle strength significantly improved during rhGH treatment compared with placebo (P < 0.05). This treatment significantly increased GH, IGF-I, and IGFBP-3, whereas serum cortisol decreased (P < 0.05). The number of operative reconstructive procedures was significantly lower with rhGH (P < 0.05). Improvements in height, bone mineral content, and IGF-1 concentrations persisted after rhGH treatment (P < 0.05). No side effects with rhGH were observed. CONCLUSIONS: Administration of rhGH for 1 year after burn was safe and improved recovery. These salutary effects continued after rhGH treatment was discontinued.     

Short-term recombinant human growth hormone therapy does not modify growth hormone, thyrotropin and prolactin responses to thyrotropin-releasing hormone in adult dialysis patients.

BACKGROUND: We recently have reported the first randomized, controlled study on the effects of short-term recombinant human growth hormone (rhGH|| therapy on the nutritional status of a group of malnourished adult dialysis patients. In order to evaluate whether rhGH administration exerts any influence on GH, thyrotropin (TSH|| and prolactin (PRL|| responses to TSH-releasing hormone (TRH||, we assessed these responses before and after rhGH therapy. METHODS: GH, PRL and TSH responses to TRH before and 1 month after rhGH therapy in a group of adult dialysis patients were evaluated. Seventeen dialysis patients (11 on continuous ambulatory peritoneal dialysis/six on haemodialysis|| were studied (rhGH group, n=8; control group, n=9||. In the rhGH group, 0.2 IU/kg/day rhGH was administered subcutaneously. Each patient was tested with TRH (400 microg bolus i.v.|| on two separate occasions, just before and immediately after the treatment period. RESULTS: rhGH treatment did not modify baseline serum GH concentrations (6.6+/-2.7 vs 4.1+/-1.1 microg/l||, paradoxical GH responses to TRH (six out of eight patients||, GH peak (11.9+/-4.6 vs 11.2+/-5.3 microg/l, NS|| or area under the secretory curve of GH (GH AUC; 19.1+/-4.5 vs 12.1+/-3.1 microg/h/l||. Both basal PRL (35.5+/-7.1 vs 36.7+/-8.6 microg/l|| and TSH (2.3+/-1.1 vs 2.8+/-1.7 mU/l|| concentrations, as well as their responses to TRH stimulation (PRL peak, 59.9+/-16.6 vs 59. 5+/-11.8 microg/l; TSH peak, 6.2+/-2.6 vs 7.1+/-3.9 mU/l||, were also unaffected by rhGH therapy. CONCLUSION: These results suggest that short-term rhGH therapy does not significantly influence the magnitude of the somatotropic, lactotropic or thyrotropic response to TRH in adult dialysis patients. However, this finding has to be interpreted with caution due to the two different patient groups included in this study.     

Effect of growth hormone replacement on BMD in adult-onset growth hormone deficiency.

To determine if replacement of GH improves BMD in adult-onset GHD, we administered GH in physiologic amounts to men and women with GHD. GH replacement significantly increased spine BMD in the men by 3.8%. INTRODUCTION: Growth hormone (GH) deficiency (GHD) acquired in adulthood results in diminished BMD; the evidence that replacement of GH improves BMD is not conclusive. We therefore performed a randomized, placebo-controlled trial to determine whether GH replacement would increase lumbar spine BMD in a combined group of men and women with adult-onset GHD. MATERIALS AND METHODS: We randomized 67 men and women to receive GH (n=33) or placebo (n=34) for 2 yr. The GH dose was initially 2 microg/kg body weight/d, increased gradually to a maximum of 12 microg/kg/d and adjusted to maintain a normal IGF-I concentration for age and sex. BMD was assessed before treatment and at 6, 12, 18, and 24 mo of treatment. Fifty-four subjects completed the protocol. RESULTS: BMD of the lumbar spine in the entire group increased by 2.9 +/- 3.9% above baseline in the GH-treated subjects, which was significantly (p=0.037) greater than the 1.4 +/- 4.5% increase in the placebo-treated subjects. In a secondary analysis, spine BMD in GH-treated men increased 3.8 +/- 4.3% above baseline, which was significantly (p=0.001) greater than that in placebo-treated men (0.4 +/- 4.7%), but the change in GH-treated women was not significantly different from that in placebo-treated women. Treatment with GH did not increase total hip BMD more than placebo treatment after 2 yr. CONCLUSIONS: We conclude that GH replacement in men who have adult-onset GHD improves their spine BMD, but we cannot draw any conclusions about the effect of GH replacement on spine BMD in women with adult-onset GHD.     

Growth hormone prevents steroid-induced growth depression in health and uremia.

Treatment with supraphysiological doses of corticosteroids results in protein wasting and impairment of growth, whereas exogenous growth hormone (GH) causes anabolism and improvement of growth. We wanted to know whether the growth depressing effects of methylprednisolone (MP) are more expressed in an organism which is chronically diseased and whether these effects can be counterbalanced by concomitant treatment with recombinant human growth hormone (rhGH). MP in doses from 1 to 9 mg/kg/day caused a dose dependent reduction of length gain, weight gain and weight gain/food intake ratio in 140 g healthy female Sprague-Dawley rats. Food intake was not affected by MP. This points to a change in food metabolism as a mechanism for growth impairment. In addition, treatment with MP inhibited endogenous GH secretion, documented by serum GH concentration profiles over seven hours, decreased IGF-1 serum concentration and disturbed growth cartilage plate architecture. Concomitant treatment with 2.5 to 20 IU/rhGH/kg/day prevented the negative effects of MP on growth in a dose dependent manner and normalized growth plate architecture. In uremic rats in which food efficiency and growth was already reduced, 6 mg MP/kg/day further decreased length gain and prevented weight gain completely by bringing the weight gain/food conversion ratio to the nadir. All effects of MP including reduction of muscle mass could be prevented by concomitant treatment with 10 IU rhGH/kg/day. The effects of MP and rhGH on food efficiency and growth in uremic animals were numerically nearly identical to those in pair fed ad libitum fed controls, but this may be more relevant in the diseased organism in which basal growth is already suppressed.     

Homologous growth hormone accelerates healing of segmental bone defects

The effect of homologous recombinant porcine growth hormone (r-pGH) on secondary fracture healing was investigated in a diaphyseal defect of the tibia in Yucatan micropigs. A 1 cm defect of the tibia was created surgically and stabilized with an AO 3.5 mm DCP plate. The treatment group (12 animals) received 100 microg of r-pGH per kilogram of body weight subcutaneously once per day, whereas the control pigs (12 animals) received 1 mL of sodium chloride as placebo. For evaluation of the GH-axis, serum levels of insulin-like growth factor-I (IGF-I) were sampled every fourth day. The animals were killed 6 weeks after surgery. Quantitative computed tomography (qCT) was performed to determine bone mineral density (BMD) and bone mineral content (BMC) of the defect zone. The torsional stiffness and the torsional failure load were measured by destructive torsional testing of the defect and contralateral tibiae. qCT measurements revealed a significant increase in the BMC of the defect zone in the treatment group compared with controls (GH BMC = 2833 +/- 679 mg, placebo BMC = 2215 +/- 636 mg; p < 0.05), whereas the BMD values were similar in both groups (GH BMD = 668 +/- 60 mg/mm(2), placebo BMD = 629 +/- 52 mg/mm(2), p = 0.12). Torsional failure load was 70% higher and torsional stiffness 83% higher in the treatment group than in the control group (p < 0.05). The mean serum level of IGF-I in the treatment group increased to 382% of the preoperative basal level and decreased to 69% in the control group, and this difference was highly significant (p < 0.001). Our data indicate that daily administration of recombinant GH leads to an increase of serum IGF-I levels and stimulates secondary fracture healing, resulting in increased mechanical strength and stiffness of the callus.     

重组人生长激素对肝硬化大鼠肝部分切除术后生长激素/胰岛素样生长因子-1轴的影响

目的探讨rhGH对肝硬化大鼠肝部分切除术后GH/IGF-1轴的影响。方法6只正常大鼠作为正常对照组,24只肝硬化大鼠随机分为术前组6只,肝部分切除术后1d组6只,肝部分切除后行PN5d组6只,肝部分切除术后行rhGH+PN5d组6只。测大鼠肝功能、血糖及血清GH、IGF-1、IGFBP-3水平,用RT-PCR法检测肝ALBmRNA、IGF-1mRNA、IGFBP-3mRNA的表达。肝组织行Ki67免疫组化染色。结果与PN组比较,rhGH+PN组血清ALP显著下降(P<0·05),血清ALB显著升高(P<0·05),血糖显著升高(P<0·05),血清GH、IGF-1、IGFBP-3水平显著升高(P<0·05),肝ALBmRNA、IGF-1mRNA表达水平显著升高(P<0·05),肝Ki67指数也显著升高(P<0·05)。且血清GH水平与血糖呈正相关(P<0·05),血清IGF-1、IGFBP-3水平与血清AST、ALT、ALP呈负相关(P<0·05),与血清ALB量正相关(P<0·05)。结论rhGH可以改善肝硬化大鼠肝部分切除术后GH/IGF-1轴,血清IGF-1、IGFBP-3水平有助于判断营养支持的效果。     

Growth hormone receptor abundance in tibial growth plates of uremic rats: GH/IGF-I treatment

BACKGROUND: Children with chronic renal failure (CRF) exhibit growth retardation and a disturbed growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. Treatment of children with CRF with GH or GH/IGF-I can partially restore linear growth. The molecular basis for decreased longitudinal growth is not known but may involve an impaired action of GH. METHODS: We used the growth-retarded uremic rat model to determine the abundance and distribution of GH receptors (GHRs) in the tibial epiphyseal growth plate and the influence of GH, IGF-I, or combined GH/IGF-I treatment. Pair-fed rats were used as the control. RESULTS: While all treatment regimes increased body length and weight in both rat groups, only GH/IGF-I treatment increased the total growth plate width. This involved an increase in cell number in the hypertrophic zone, which could also be induced by IGF-I alone. Immunohistochemical analysis showed that uremic rats had decreased abundance of GHRs in the proliferative zone, and only GH/IGF-I therapy could overcome this decrease. These data thus suggest that growth retardation in uremic rats is, at least in part, due to a decrease in GHR abundance in chondrocytes of the proliferative zone of the tibial growth plate. This decreased GHR abundance can be overcome by combined GH/IGF-I therapy, thus enhancing generation and proliferation of hypertrophic zone chondrocytes and increasing growth-plate width. CONCLUSION: These studies point to a mechanism for the growth retardation seen in children with CRF, and suggest that combined GH/IGF-I treatment may provide more effective therapy for these patients than GH alone.     

Systemic metabolic effects of combined insulin-like growth factor-I and growth hormone therapy in patients who have sustained acute traumatic brain injury

OBJECT: Hypermetabolism, hypercatabolism, refractory nitrogen wasting, hyperglycemia, and immunosuppression accompany traumatic brain injury (TBI). Pituitary dysfunction occurs, affecting growth hormone (GH) and plasma insulin-like growth factor-I (IGF-I) concentrations. The authors evaluated whether combination IGF-I/GH therapy improved metabolic and nutritional parameters after moderate to severe TBI. METHODS: The authors conducted a prospective, randomized, double-blind study comparing combination IGF-I/GH therapy and a placebo treatment. Ninety-seven patients with TBI were enrolled in the study within 72 hours of injury and were assigned to receive either combination IGF-I/GH therapy or placebo. All patients received concomitant nutritional support. Insulin-like growth factor-I was administered by continuous intravenous infusion (0.01 mg/kg/hr), and GH (0.05 mg/kg/day) was administered subcutaneously. Placebo control group patients received normal saline solution in place of both agents. Nutritional and metabolic monitoring continued throughout the 14-day treatment period. The two groups did not differ in energy expenditure, nutrient intake, or use of insulin treatment. The mean daily serum glucose concentration was higher in the treatment group (123 +/- 24 mg/dl) than in the control group (104 +/- 11 mg/dl) (p < 0.03). A positive nitrogen balance was achieved within the first 24 hours in the treatment group and remained positive in that group throughout the treatment period (p < 0.05). This pattern was not observed in the control group. Plasma IGF-I concentrations were above 350 ng/ml in the treatment group throughout the study period. Overall, the mean plasma IGF-I concentrations were 1003 +/- 480.6 ng/ml in the treatment group and 192 +/- 46.2 ng/ml in the control group (p < 0.01). CONCLUSIONS: The combination of IGF-I and GH produced sustained improvement in metabolic and nutritional endpoints after moderate to severe acute TBI.     

Effects of growth hormone on insulin-like growth factors and binding proteins before and after renal transplantation

A bstract. Three short children with severe chronic renal failure were treated with recombinant human growth hormone (rhGH) for 2 years. Each received a transplant in the 2nd year. Serum collected before and during rhGH therapy was analysed retrospectively by Western ligand blot and immunoblotting techniques. In addition, radioimmunoassays for insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), acid-labile subunit (ALS) and IGFBP-1 were performed. IGFBPs in serum, detected by Western ligand blot, were identified as IGFBP-3, -2, -1 and -4 by immunoblot. The serum concentration of IGF-I in each child rose approximately fourfold with rhGH before transplantation and subsequently remained elevated. IGFBP-3 levels rose to double the pretreatment value, but dropped to normal levels following transplantation, while ALS rose with rhGH treatment and remained increased after transplantation. IGFBP-1 levels changed little with rhGH but fell following transplantation. A low molecular weight form of IGFBP-3 was noted at 30 kilodaltons on immunoblot which was not clearly seen on the ligand blot. IGFBP-2 was present as a distinct band on Western ligand blot before transplantation and appeared decreased in intensity subsequently. IGFBP-1, seen on immunoblot clearly before transplant, disappeared after the transplant. rhGH successfully improved growth in these children, in association with a fourfold increase in IGF-I levels, which was maintained following transplantation. The reduction in IGFBPs following transplantation suggests correction of impaired clearance by the diseased kidney. Received September 5, 1994; received in revised form November 8, 1995; accepted November 21, 1995     

Antitumor activity of the growth hormone receptor antagonist pegvisomant against human meningiomas in nude mice

OBJECT: The authors have previously demonstrated that modulation of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis can significantly affect meningioma growth in vitro. These studies were performed to evaluate the efficacy of GH receptor blockade in vivo. METHODS: Primary cultures from 15 meningioma tumors obtained in humans were xenografted into athymic mice. Approximately 1.5 million cells from each of the 15 tumors were implanted into the flanks of two female mice, one pair for each tumor. One animal from each of the 15 pairs was then treated with the GH receptor antagonist pegvisomant and the other with vehicle alone for 8 weeks. The tumor volume was measured using digital calipers three times per week. The mean tumor volume at the initiation of injections was 284 +/- 18.8 mm3 in the vehicle group and 291.1 +/- 20 mm3 in the pegvisomant group. After 8 weeks of treatment, the mean volume of tumors in the pegvisomant group was 198.3 +/- 18.9 mm3 compared with 350.1 +/- 23.5 mm3 for the vehicle group (p < 0.001). The serum IGF-I concentration in the vehicle group was 319 +/- 12.9 microg/L compared with 257 +/- 9.7 in the pegvisomant group (p < 0.02). A small but significant decrease was observed in circulating IGF binding protein (IGFBP)-3 levels, whereas slight increases occurred with respect to serum IGFBP-1 and IGFBP-4 levels. In the placebo group the tumor weight was 0.092 +/- 0.01 g compared with 0.057 +/- 0.01 g in the pegvisomant group (p < 0.02). The IGF-I and IGF-II concentrations were measured in the tumors by using a tissue extraction method. These human-specific immunoassays demonstrated that there was no autocrine production of IGF-I in any of the tumors, either in the pegvisomant or vehicle group. The IGF-I levels were highly variable (0-38.2 ng/g tissue) and did not differ significantly between treatment groups. CONCLUSIONS: In an in vivo tumor model, downregulation of the GH/IGF-I axis significantly reduces meningioma growth and, in some instances, causes tumor regression. Because the concentrations of IGF-II in tumor did not vary with pegvisomant treatment and there was no autocrine IGF-I production by the tumors, the mechanism of the antitumor effect is most likely a decrease of IGF-I in the circulation and/or surrounding host tissues. Because the authors have previously demonstrated that the GH receptor is ubiquitously expressed in meningiomas, direct blockade of the GH receptor on the tumors may also be contributing to inhibitory actions.     

Growth hormone/insulin-like growth factor system in children with chronic renal failure

Disturbances of the somatotropic hormone axis play an important pathogenic role in growth retardation and catabolism in children with chronic renal failure (CRF). The apparent discrepancy between normal or elevated growth hormone (GH) levels and diminished longitudinal growth in CRF has led to the concept of GH insensitivity, which is caused by multiple alterations in the distal components of the somatotropic hormone axis. Serum levels of IGF-I and IGF-II are normal in preterminal CRF, while in end-stage renal disease (ESRD) IGF-I levels are slightly decreased and IGF-II levels slightly increased. In view of the prevailing elevated GH levels in ESRD, these serum IGF-I levels appear inadequately low. Indeed, there is both clinical and experimental evidence for decreased hepatic production of IGF-I in CRF. This hepatic insensitivity to the action of GH may be partly the consequence of reduced GH receptor expression in liver tissue and partly a consequence of disturbed GH receptor signaling. The actions and metabolism of IGFs are modulated by specific high-affinity IGFBPs. CRF serum has an IGF-binding capacity that is increased by seven- to tenfold, leading to decreased IGF bioactivity of CRF serum despite normal total IGF levels. Serum levels of intact IGFBP-1, -2, -4, -6 and low molecular weight fragments of IGFBP-3 are elevated in CRF serum in relation to the degree of renal dysfunction, whereas serum levels of intact IGFBP-3 are normal. Levels of immunoreactive IGFBP-5 are not altered in CRF serum, but the majority of IGFBP-5 is fragmented. Decreased renal filtration and increased hepatic production of IGFBP-1 and -2 both contribute to high levels of serum IGFBP. Experimental and clinical evidence suggests that these excessive high-affinity IGFBPs in CRF serum inhibit IGF action in growth plate chondrocytes by competition with the type 1 IGF receptor for IGF binding. These data indicate that growth failure in CRF is mainly due to functional IGF deficiency. Combined therapy with rhGH and rhIGF-I is therefore a logical approach.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

mRNA expression of the IGF system in the kidney of the hypersomatotropic rat

AIM: To examine the response of the insulinlike growth factor (IGF) system in the kidney during a state of extreme growth. METHODS: We studied the mRNA expression of IGF-I, IGF-I receptor, and IGF-binding proteins (BP) using sensitive RNase protection assays following subcutaneous implantation of growth hormone pituitary cells (GH(3)) in rats. RESULTS: Within 5 weeks, the serum GH levels increased from 18.0 +/- (SE) 5.0 ng/ml in control animals to 389.8 +/- 30.3 ng/ml in GH(3) rats (n = 5, p < 0.001). The circulating IGF-I levels were also elevated. The kidney weights increased from 0.74 +/- 0.01 g in controls to 1.06 +/- 0.03 g in GH(3) animals (n = 5, p < 0.001). Similar changes were observed at week 10. The renal IGF-I mRNA averaged 1.0 +/- (SD) 0.33 relative densitometry units in controls (n = 4) and increased to 2.11 +/- 0.13 relative densitometry units in GH(3) rats (n = 5, p < 0.001). On the other hand, mRNA for the type I IGF receptor decreased in hypersomatotropic rats. Messenger RNAs for IGFBP-1 and IGFBP-4, which have been localized to renal tubules, both decreased significantly following growth induction, while IGFBP-3, the mRNA of which has an interstitial localization, was increased at week 10. CONCLUSION: These data suggest that there is a dynamic relationship between tubular and interstitial compartments with regard to the IGF system in the kidney which may be important in the regulation of the cell mass.     

生长激素荷人结肠癌裸鼠GH/IGF-I/IGFBP-3轴的影响

目的：探讨外源性生长激素（GH）对荷瘤裸鼠GH/胰岛素样生长因子（IGF）/胰岛素样生长因子结合蛋白3（IGFBP-3）轴的影响。方法：采用人结肠癌细胞株（HCT116）建立人结肠癌细胞裸鼠移植瘤模型。取48只荷瘤裸鼠随机均分为生理盐水处理组（NS组）、氟尿嘧啶处理组（FU组）、GH处理组（GH组）,FU+GH处理组（FU+GH组）。每组连续给药6 d,在给药结束后24,72 h分别处死每组6只动物,取血及移植瘤标本,应用ELISA法检测血清GH,IGF-I,IGFBP-3含量和RT-PCR法检测移植瘤IGF-I,IGF-I受体（IGF-IR）,IGFBP-3的mRNA表达。结果：ELISA结果显示,给药结束后24 h,GH组和FU+GH组血清GH,IGF-I,IGFBP-3含量较NS组与FU组明显升高（均P<0.05）;给药结束后72 h,各组GH,IGF-I的水平无统计学差异（均P>0.05）,但GH组和FU+GH组IGFBP-3水平仍高于NS组和FU组（均P<0.05）。RT-PCR结果显示,给药结束后24 h,GH,FU,FU+GH组移植瘤组织IGF-I mRNA与IGF-IR mRNA的表达较NS组明显降低,而IGFBP-3 mRNA表达明显增加;给药结束后72 h,IGF-I mRNA与IGF-IR mRNA表达各组间无差别,但GH组,FU组和FU+GH组IGFBP-3 mRNA表达量仍明显高于NS组。结论：短期应用外源性GH所致GH/IGF/IGFBP-3轴的变化对人结肠癌移植瘤生长无促进作用。

     

Influence of growth hormone and insulin-like growth factor-I on kidney function and kidney growth

Decreased glomerular filtration rate (GFR) in hypopituitarism and increased GFR in acromegaly suggest that growth hormone (GH) has a substantial effect on renal haemodynamics. Extractive and recombinant human (rh) GH in healthy volunteers increased effective renal plasma flow (ERPF) and GFR by 10% and 15% respectively. Renal response to GH was delayed and occurred at the same time as an increase in plasma insulin-like growth factor (IGF)-I values, whereas infusion of rhIGF-I promptly increased GFR and ERPF, indicating that the haemodynamic response of the kidney to GH is mediated by IGF-I. In chronic renal failure (CRF), the acute effect of GH on GFR is obliterated. This might protect the diseased kidney against the undesired consequences of hyperfiltration. Indeed, rhGH treatment for 1 year in children with CRF did not lead to an accelerated decline in GFR compared with the year before treatment. GH and IGF-I also effect renal growth. Exposure to excessive GH in transgenic mice causes renomegaly and progressive glomerular selerosis. In acromegalic humans, increased renal size and weight and increased glomerular diameter are well known, whereas renal failure is not a long-term hazard. At least in normal and hypophysectomized rats treated with doses comparable with the therapeutic regimens used in stunted children, rhGH increased renal weight but in proportion to the increase in body weight indicating an isometric effect of GH on renal growth. From these data, major renal longterm side effects of rhGH treatment in children with CRF appear unlikely.     

Plasma levels of soluble CD30 are increased in children with chronic renal failure and with primary growth deficiency and decrease during treatment with recombination human growth hormone.

BACKGROUND: Previous studies have suggested that in vivo Th2 lymphocyte activation is related to increased soluble CD30 (sCD30) plasma levels. As various hormones (dehydroepiandrosterone, glucocorticoids, progesterone) can regulate the Th1/Th2 balance, and because growth hormone (GH) enhances lymphocyte function, we measured sCD30 plasma levels, before and after treatment with recombinant human GH (rhGH), in children with growth failure due to chronic renal failure (CRF) or to isolated GH deficiency in order to evaluate the potential effects of rhGH treatment on Th1/Th2 balance. METHODS: sCD30 plasma levels were determined by ELISA assay in 30 children with CRF (mean age 10.7+/-3.7 years), in five children with isolated GH deficiency (mean age 11.4+/-2.6 years), and in 10 normal controls (mean age 10.1+/-3.5 years). RESULTS: sCD30 levels were higher in the 30 children with CRF than in the 10 controls (179.8+/-79.4 vs 11.3+/-10.9 U/ml, P<0.001) exhibiting an inverse correlation with glomerular filtration rate (GFR) (r=-0.7860, P<0.001). In 11 children with CRF, after 19.9+/-16.7 months of rhGH treatment, a decrease of sCD30 plasma level (170+/-50 vs 134+/-49 U/ml, P<0.01) was observed. The five children with primary GH deficiency had higher sCD30 plasma level than controls (mean 147+/-105 vs 11+/-10 U/ml, P<0.004) and sCD30 plasma levels decreased to 95.2+/-109.6 U/ml after rhGH treatment. CONCLUSIONS: The finding that rhGH treatment decreased sCD30 plasma levels in children with CRF, and that children with primary GH deficiency had higher sCD30 plasma levels than controls, suggest that GH may regulate CD30 expression and possibly the balance of Th1/Th2. Whether the uraemia-induced increase in sCD30 is due to decreased renal excretion, to overproduction or both, remains to be determined.     

Somatic and renal effects of growth hormone in rats with chronic renal failure

Recombinant human growth hormone (rhGH) has been widely used to improve growth in children with chronic renal failure (CRF). However, there has been great concern that GH may aggravate renal disease and hasten the progression to end-stage renal failure. We therefore investigated the effect of prolonged administration of rhGH at various doses on somatic growth and renal function and structure in rats with CRF, divided into four groups based on rhGH dose (vehicle, 0.4, 2.0, and 10.0 IU/day). rhGH was administered subcutaneously daily for 8 weeks. The mean growth was significantly greater in rats treated with high-dose rhGH (10.0 IU) than those treated with low-dose rhGH (P = 0.0089) or vehicle (P = 0.0011). Body weight gain increased in parallel with body length (Creatinine clearance at the end of the experiment was significantly lower in rats on high or medium-dose rhGH than those on low-dose rhGH and controls (P <0.05). The glomerular sclerosing index was greater in rats treated with higher doses of rhGH. There were significant differences between rats treated with high-dose rhGH and controls (P = 0.0144) and also between rats on medium-dose rhGH and controls (P = 0.0065). Although there was no significant difference, rats treated with higher doses of rhGH tended to excrete more protein. Renal insulin-like growth factor-I (IGF-I) content and circulating IGF-I and IGF-II levels did not significantly differ among groups. We conclude that: (1) GH improves somatic growth failure in rats with CRF, but prolonged administration of GH dose-dependently induces deterioration in renal function and structure and (2) this effect was induced neither via circulating IGF-I and IGF-II nor by local production of IGF-I, but seems to be direct. Received June 7, 1996; received in revised form and accepted November 19, 1996     

Effects of cholinergic muscarinic blockade on growth hormone responses to growth hormone-releasing hormone in uraemic patients.

BACKGROUND: Several alterations in growth hormone (GH) secretion have been reported in patients with chronic renal insufficiency. However, cholinergic modulation of somatotopic cell function has not been fully clarified in uraemic patients. To gain further insight into the disrupted mechanism of GH regulation in chronic renal failure, we investigated whether the blockade of cholinergic muscarinic receptor with pirenzepine could modify the response of GH to its physiological releasing hormone. METHODS: Eight uraemic male patients on peritoneal dialysis and six normal controls were studied. All subjects underwent two endocrine tests in random order. In one of them placebo was administered 60 min before the injection of GH-releasing hormone (GHRH, 100 microg, i.v. in bolus at 0 min). In another the muscarinic blocking agent pirenzepine, 100 mg p.o., was administered at that time. Blood samples for GH were collected at -60, 0, 15, 30, 45, 60 and 90 min. RESULTS: Baseline plasma GH concentrations were similar in patients and controls. GH responses to GHRH were characterized by great interindividual variability in uraemic patients with regard to the amount and the time to maximal peak. In the placebo plus GHRH test, the maximum GH concentrations in patients (14.0 +/- 3.2 microg/l) were similar to those reached by controls (18.0 +/- 3.1 microg/l), although GH secretion was more sustained in patients. The area under the secretory curve (AUC) of GH secretion in patients was also similar to that found in controls (14.4 +/- 2.9 vs 15.4 +/- 3.3 microg/h/l). When subjects were given pirenzepine before GHRH injection an abolishment of GHRH-induced GH release was observed in all controls and in all but one of the uraemic patients. The AUC of GH secretion was, therefore, significantly reduced both in uraemic patients (4.1 +/- 2.0 microg/h/l, P<0.05) and in control subjects (2.0 +/- 0.3 microg/h/l, P<0.05). CONCLUSION: These results suggest that GH secretion in uraemic patients is modulated, at least in part, by a cholinergic mechanism. The muscarinic blockade, possibly acting via an increase in somatostatin release, is able to inhibit GH release in response to direct pituitary stimulation with GHRH.     

Growth hormone,insulin growth factor-1, and igf binding protein-3 axis relationship with bone mineral density among healthy men

The aim of this study was to investigate serum levels of growth hormone (GH), insulin growth factor-I (IGF-I), and insulin growth factor binding protein-3 (IGFBP-3) in 363 healthy caucasian men with and without decreased bone density, who had never experienced fractures. Mean age was 51+/-8.7 years. Height and weight were measured and BMI was calculated using the formula weight (kg)/height (m(2)). Bone mineral density (BMD) was assessed: in 4 skeletal sites (lumbar spine [LS], femoral neck [FN], Ward's triangle [WT], and trochanter [T]) using dual-energy X-ray absorpsiometry (DEXA). After an overnight fasting, blood samples were taken at 8:00 a.m. Serum concentrations of GH, IGF-I, and IGFBP-3 were measured using the immunofunctional (GH) and IRMA (IGF-I and IGFBP-3) methods. The BMD at the 4 skeletal sites is expressed as mean value+/-SD in g/cm(2) and T score. Forty-four men (11%) had bone mineral density (BMD)<-2.5 SD (T score). Mean GH, IGF-I, and IGFBP-3 levels were 0.2+/-0.1, 186.1+/-177.3, and 4990+/-1460 ng/mL, respectively. There were no significant differences between men with normal BMD and men with reduced BMD concerning GH, IGF-I, and IGFBP-3 measurements. In normal men (319), mean GH, IGF-I, and IGFBP-3 levels were 0.4+/-0.1, 192+/-87, and 4960+/-1530 ng/mL, respectively. In the subgroup with reduced BMD (44), mean GH, IGF-I and IGFBP-3 levels were 0.2+/-0.1, 179+/-72 and 5230+/-1270 ng/mL, respectively. An age-dependent attenuation of GH, IGF-I, and IGFBP-3 levels was also found. No correlation was revealed between BMD and GH in the 4 skeletal sites tested. On the contrary, a positive correlation was established between BMD and IGF-I levels in 3 skeletal sites (LS, FN, T). The same was true between BMD and IGFBP-3 in 2 skeletal sites (LS, FN). In conclusion, 11% of Greek healthy males had decreased bone density. No fractures were demonstrated in any individuals. No significant differences were found between men with normal and reduced BMD, with regards to serum GH, IGF-I, and IGFBP-3, although these levels decreased with age. No correlation was found between BMD and GH levels in the 4 skeletal sites. A positive correlation was found between BMD and IGF-I levels in 3 skeletal sites and IGFBP-3 in 2 skeletal sites.