老年肺部感染患者生长激素-胰岛素样生长因子轴的变化与蛋白代谢关系

目的　研究老年肺部感染患者生长激素胰岛素样生长因子轴(GH -IGF轴)的变化及其与蛋白代谢的关系。方法　检测2002-07~2003-01首都医科大学宣武医院老年科和急诊科的20例老年肺部感染患者的血清生长激素(GH)、胰岛素样生长因子Ⅰ(IGF -Ⅰ)、胰岛素样生长因子结合蛋白1 (IGFBP -1 )、胰岛素样生长因子结合蛋白3 (IGFBP -3)、总蛋白、白蛋白、前白蛋白、转铁蛋白的质量浓度,并与老年正常对照组相比。结果　(1)肺部感染患者的血清IGF- Ⅰ质量浓度显著低于正常对照组(P<0 .05),而血清GH、IGFBP- 1质量浓度显著高于对照组(P<0 .05); (2)肺部感染患者的血清总蛋白、白蛋白、前白蛋白、转铁蛋白的质量浓度显著低于正常对照组(P<0. 01); (3)血清GH、IGF -Ⅰ、IGFBP- 1、IGFBP -3与血清白蛋白、前白蛋白、转铁蛋白之间呈相关关系。结论　老年肺部感染患者存在着GH -IGF轴的变化,此变化与蛋白代谢相关。     

重组人生长激素对肝炎肝硬化患者生长激素抵抗状况改善的研究

评价重组人生长激素对不同Child -Pugh积分肝炎肝硬化患者生长激素抵抗的改善及对低蛋白血症的影响 ,根据Child -Pugh积分分为 <9组 ,2 5例 ; 9组 ,2 6例两组。再采用随机区组设计方法对上述患者分组治疗 ,治疗组 (各 16、15例 )用重组人生长激素 (0 2 5U/kg·d) ,对照组 (各 9、11例 )予人血白蛋白 (10g/d)治疗 10天。用放射免疫法测定治疗前、治疗后 2 4h及治疗结束时的血清生长激素 (GH ,μg/L)、类胰岛素生长因子 (IGF) - 1(μg/L)。肝硬化患者GH水平高于健康人 (P <0 0 5 ) ,但IGF - 1水平明显降低 (P <0 0 1)。经重组人生长激素治疗后 ,肝硬化患者生长激素抵抗均有不同程度改善 (P <0 0 1)。观察结束两治疗组比较 ,积分高组较之低组GH一直维持较高水平 (9 91± 7 6 1,4 75± 3 94 ,P <0 0 5 ) ,且IGF - 1上升幅度低 (4 8 4 3± 16 88,6 3 4 7± 2 2 19,P <0 0 5 )。两治疗组治疗后血清白蛋白 (ALB)均有明显升高。重组人生长激素可以克服肝硬化患者 ,尤其Child -Pugh积分低者的生长激素抵抗现象 ,并纠正其低蛋白血症     

老年男性骨质疏松患者血清IGF-1、IGFBP-3与骨密度的关系

目的　探讨胰岛素样生长因子 - 1 (IGF - 1 )、胰岛素样生长因子结合蛋白 - 3(IGFBP - 3)与老年男性骨质疏松患者骨密度的关系。方法　通过测定 60例老年男性骨质疏松患者及 60例对照组IGF - 1 ,IGFBP - 3及骨钙素 (BGP)、I型胶原异构C端肽 (β-CTX)等指标 ;同时测量骨密度 (BMD)。结果　老年男性骨质疏松患者腰椎和左股骨颈BMD显著低于对照组 (均P <0 .0 1 ) ;血清IGF - 1 ,IGFBP - 3低于对照组 (均P <0 .0 1 ) ;血清BGP低于对照组 (P <0 .0 5) ;血清 β-CTX高于对照组 (P <0 .0 5) ;而血钙 ,血磷水平在两者之间无显著差异 (P >0 .0 5) ,对照组和骨质疏松组腰椎侧位 ,左股骨颈BMD均与IGF - 1 ;IGFBP - 3 ;BGP呈正相关 ,与 β -CTX呈负相关 ,而与血钙、血磷无关。 结论　IGF - 1、IGFBP - 3、BGP、β -CTX水平都与骨含量具有良好的相关性。检测上述指标可作为诊断老年男性骨质疏松的一项参考指标     

血清胰岛素样生长因子及其结合蛋白诊断儿童生长激素缺乏症的价值

为了解血清胰岛素样生长因子1（IGF－1），胰岛素样生长因子结合蛋白－3（IGFBP－3）浓度与生长激素缺乏症（GHD）患儿生长激素（GH）激发试验中血清生长激素峰值的关系，以确定血清IGF－1，IGFBP－3浓度诊断GHD的价值，为其代替GH激发试验提供依据，选择GHD患儿62例（男39例，女23例）为GHD组，60例健康儿童（男38例，女22例）为对照组。分别用放射免疫分析（RIA）法，免疫放射分析（IRMA）法检测GHD组血清IGF－1，IGFBP－3浓度，同时被GH激发试验，测定血清GH峰值，并比较其与IGF－1，IGFBP－3的关系，测定对照组血清IGF－1，IGFBP－3。结果显示，GHD组血清IGF－1，IGFBP－3均显著低于对照组（t分别为3.116,11.579,p均＜0．01）；GHD组血清IGF－1，IGFBP－3浓度与GH激发试验中的GH峰值呈显著正相关（r分别为。331，0。347，P均＜0．01）；GHD组血清IGF－1，IGFBP－3降低的阳笥率分别为97．58％，98．38％，与激发试验的阳性率（100％），比较无统计学意义（x^2分别为.3074,2.033,P均＞0．05）。表明血清中IGF－1，IGFBP－3浓度检测对诊断GHD有重要价值，认为检测血清中IGF－1，IGFBP－3浓度可以替代GH激发试验。     

血清IGF-Ⅰ、IGF-BP3及GH水平对急性白血病影响的研究

目的：揭示血清胰岛素样生长因子(IGF—Ⅰ)、胰岛素样生长因子结合蛋白3(IGF—BP3)、生长激素(GH)水平对急性白血病(AL)的发生、病情变化、治疗及预后分析的作用。方法：采用放射免疫分析法测定38例初治AL、l6例化疗后完全缓解(CR)的AL患者和l0例健康对照者血清IGF—Ⅰ、IGF—BP3、GH水平及外周血白细胞计数、原始细胞百分比和骨髓原始细胞百分比。结果：①治疗前急性非淋巴细胞白血病(ANNL)与急性淋巴细胞白血病(ALL)患者血清IGF—Ⅰ水平均低于CR组与正常对照组(P＜0．05或P＜0．01)。②治疗前ANNL与ALL患者血清IGF—BP3水平均低于CR组与健康对照组(P＜0．05或P＜0．01)。③初治AL组、缓解组和健康对照组比较，血清GH水平差异无显著性意义(P＞0．05)。结论：血清IGF—Ⅰ、IGF—BP3、GH水平对急性白血病的发生、病情变化、治疗及预后分析有重要的临床意义。     

061 用rhGH治疗成人血液透析患者的生长激素、胰岛素样生长因子及其结合蛋白的研究

[英]／Jenseen PB…//Clin Nephrol．-1999·52.-103～109 本研究用重组人生长激素(rhGH)治疗行血液透析(HD)的成年患者后，对血清生长激素(GH)、胰岛素样生长因子(IGF)-Ⅰ、IGF-Ⅱ、IGF结合蛋白(IGFBP)-1、1G-FBP-3变化及rhGH作用进行评价。 病人与方法采用双盲、随机、安慰剂对照研究，选择了20名有超过6个月血液透析史的成人尿毒症患者(12男，8女，平均年龄48．6岁)。其中rhGH治疗组9例(4女，平均年龄49岁，平均体重56 kg)，给予rhGH治疗[4 IU／(m2·d)，每天晚8：00点皮下给药]，治疗6个月，对照安慰剂治疗组11例(7男4女，平均48．3岁，平均体重61．5kg)。所有患者肾小球滤过率(GFR)<6ml／mm。分别检测血清GH、IG-Ⅰ、IGF-Ⅱ、IGFBP-1、3。空腹血样在每两个月透析前早晨采集，冷藏于-80℃中。 结果 ①rhGH治疗期间，患者血清GH有显著变化(P=0．0034)，在治疗4个月时平均由基础2．2升至13．5μg／L(P=0．01)，然后降至7．5μg／L(P=0．13)。安慰剂组无显著变化。②血清IGF-Ⅰ在rhGH治疗4个月时由213升至594μg／L(P=0．008)，然后在第6个月时下降至348μg／L(P=0．01)，但仍高于正常值。安慰剂组无显著变化。③血清IGF-Ⅱ在两组中均无显著变化，但均较正常值显著升高。④血清IGFBP-1在治疗前均较正常高，但在rhGH治疗2个月时明显下降，在4个月后降至最低水平(由基值53．1μg／L降至10．7μg／L，P=0．004)，然后在后2个月升至24．7μg／L，但仍明显低于基值。安慰剂组无改变。⑤治疗期间血清胰岛素由13 mU／L升至17 mU／L(P=0．03)，而血糖保持稳定。血清IGF与胰岛素之间变化存在相关性。⑥血清IGFBP-3在治疗4个月后由5 620升至最高值7 950μg／L(P=0．004)，然后降至7 100μg／L(P=0．004)。安慰剂组无明显变化。⑦血清IGF-Ⅰ／血清IGBP-3比值在rhGH治疗后显著升高(P=0．0043)，而安慰剂组比值明显下降(P=0．01)。⑧尽管GH治疗期间体重无明显变化，但脂肪平均下降3．33kg，而肌肉平均增加了3．18kg。血清IGF-Ⅰ虽与肌肉变化无明显相关性但有相关倾向[R(s)=0．60，P=0．09]。 结论 研究表明，尿毒症患者rhGH治疗后，血清IGF-Ⅰ及血清IGF-Ⅰ／IGBP-3比值均升高，而IGFBP-Ⅰ下降，可能与血清胰岛素水平升高有关。在rhGH治疗中很少出现副作用及不适反应。rhGH治疗使患者IGF-Ⅰ水平增高，伴随肌肉重量增加及脂肪重量减少，表明长期用rhGH治疗行血液透析的成年尿毒症患者，可通过IGF-Ⅰ生物活性增加改善患者营养状况。 (魏莉莉 董 红摘 李新东校)     

老年2型糖尿病GH-IGF轴的变化及与脂质代谢关系

目的观察老年2型糖尿病患者生长激素胰岛素样生长因子(GHIGF)轴的变化,并探讨老年2型糖尿病患者胰岛素样生长因子Ⅰ(IGFⅠ),胰岛素样生长因子结合蛋白1(IGFBP1),胰岛素样生长因子结合蛋白3(IGFBP3)与大血管病危险因素糖、脂质代谢紊乱的关系。方法检测35例老年2型糖尿病患者(其中19例伴大血管病变,16例不伴大血管病变)的血清生长激素(GH),IGFⅠ,IGFBP1,IGFBP3,并与18名健康的老年人作对照。同时还进行了IGFⅠ、IGFBP1、IGFBP3与总胆固醇(TC),甘油三酯(TG),高密度脂蛋白胆固醇(HDLC),低密度脂蛋白胆固醇(LDLC),糖化血红蛋白(HbA1c)之间的相关关系的分析。结果(1)老年2型糖尿病伴大血管病变患者的IGFⅠ的水平显著低于对照组和不伴大血管病变患者(P<0.05),而血清GH、IGFBP1的水平显著的高于对照组和不伴大血管病变的患者(P>0.05),TGFBP3的水平3组之间无差异(P>0.05);(2)相关关系分析结果表明,老年2型糖尿病患者IGFⅠ的水平与HDLC呈正相关关系(P<0.05),与HbA1c呈负相关关系,而IGFBP1与TG、HbA1c呈正相关关系,与HDLC呈负相关关系(P<0.05)。结论老年2型糖尿病患者存在CHIGF轴的紊乱,且此紊乱与脂质代谢的紊乱相关。     

重组人生长激素治疗重症乙型肝炎的临床研究

[目的]研究重组人生长激素(rhGH)对重症乙型肝炎(重肝)的治疗作用.[方法]选择42例住院的重肝患者,随机分成rhGH组20例和对照组22例,rhGH组给予rhGH 10 U隔日1次或3 U每日1次,肌肉注射,连续2周,观察治疗前和治疗后1、2及4周肝功能、总胆红素(TB)和血清白蛋白(Alb)水平.[结果]rhGH组治疗后肝功能、TB和Alb显著改善,与对照组和治疗前相比差异有统计学意义(P＜0.01～0.05).[结论]rhGH能有效的改善重肝的肝功能,降低胆红素和纠正低蛋白血症.     

生长激素对老年危重病人细胞免疫功能的影响

目的　探讨重组人生长激素 (rh GH)对老年危重病人细胞免疫功能的影响。方法　老年危重病人 (年龄≥ 65岁 ,APACHE 评分≥1 4分 )随机分为对照组 (2 4例 )和 rh GH组 (2 8例 )。观察两组患者细胞免疫功能、血清白蛋白浓度及血糖的变化。结果　两组病人治疗前年龄、性别、APACHE 评分、外周血 T细胞亚群 (CD3、CD4 、CD8、)、NKC活性、血清白蛋白水平、血糖均无明显差异。rh GH组使用 rh GH治疗 1 0～ 1 4 d后 CD4 、NKC活性、白蛋白水平高于治疗前 (P<0 .0 5)。对照组治疗前后上述指标无明显差异。两组病人治疗前后血糖的变化及短期预后亦无明显差异。结论　在加强治疗的同时加用 rh GH治疗能提高老年危重病人外周血 T淋巴细胞 CD4 亚群的水平、NK细胞活性 ,增加血清白蛋白的浓度 ,改善老年危重病人的细胞免疫功能及营养状况 ,对血糖无明显影响。     

重型颅脑损伤早期应用生长激素对其代谢及预后的影响研究

目的探讨重组人生长激素（rhGH）对重型颅脑损伤患者代谢调控作用的应用价值。方法将40例重型颅脑损伤患者在早期肠内、肠外营养支持的基础上随机分成rhGH治疗组（20例）与对照组（20例）,rhGH治疗组伤后或术后第2～3天开始每日皮下注射重组人生长激素4 IU,共10～14d。应用后第7、14天检测血清总蛋白、白蛋白、转铁蛋白及前白蛋白。结果 rhGH治疗组第14天后血清总蛋白、白蛋白、转铁蛋白及前白蛋白浓度高于对照组,体质量改变率低于对照组,预后优于对照组。结论重型颅脑损伤患者应用rhGH能改善机体对营养底物的利用率,促进蛋白合成、减轻重型颅脑损伤后低蛋白血症,改善预后。     

Evaluation of free insulin-like growth factor-I measurement on the diagnosis and follow-up treatment of growth hormone-deficient adult patients

OBJECTIVE: Insulin-like growth factor (IGF-I) and IGF binding protein-3 (IGFBP-3) are GH-dependent and their concentrations have been used in the diagnosis of GH deficiency. Recently, the free fraction of IGF-I has received more attention. The aim of the study was to assess the role of free IGF-I in the diagnosis of GH deficiency in adults, and in follow-up during treatment with recombinant human GH (rhGH). DESIGN AND PATIENTS: We studied 24 adult patients with pituitary disease and GH deficiency and 25 matched controls. Nine patients were re-evaluated after 6 months of treatment with rhGH (0.25 U/kg/week). MEASUREMENTS: Serum levels of IGF-I, free IGF-I, IGFBP-3 and IGFBP-1 were measured by immunoradiometric assay. RESULTS: Serum free IGF-I levels were significantly lower in the GH deficient group than in the normal group (mean: 0.84 and 1.32 micrograms/l respectively, P = 0.0009). Furthermore, serum IGF-I levels were also lower (mean: 92.24 and 230.47 micrograms/l respectively, P < 0.0001). 63% of patients had serum IGF-I concentration below the normal range. For free IGF-I, 52% of the GH deficient patients showed levels below the lowest value obtained for the normal group. Seventy-five percent of the patients showed at least one of the two determinations below the normal range. The free-total IGF-I ratio was significantly higher (P = 0.025) in GH deficient group (range: 0.19-21.29, mean: 2.53) than in normal controls (range: 0.2-2.15, mean: 0.6). Regarding IGFBP-3 and IGFBP-1 no differences were observed between the two groups. During rhGH treatment the increase in serum total and free IGF-I and IGFBP-3 paralleled the beneficial effects on body composition. CONCLUSIONS: Free IGF-I may be another useful method for the diagnosis of GH deficiency, particularly if related to total IGF-I concentration.     

Sensitivity to exogenous GH and reversibility of the reduced IGF-I gene expression in aging rats.

BACKGROUND: IGF-I gene expression and IGF-I plasma concentration decline with age. A decreased sensitivity to GH has been suggested to be a contributory mechanism to this, in addition to attenuated GH secretion. OBJECTIVE: This study focuses on the sensitivity to exogenous GH and the reversibility of the reduced IGF-I gene expression in aging male rats. DESIGN: Three groups of male Wistar rats aged 3 months (young adult), 11 months (middle-aged) and 27 months (old), received recombinant human GH (rhGH) (150 microg/12 h s.c.) for seven consecutive days. RESULTS: This rhGH treatment completely reversed plasma immunoreactive IGF-I (IR-IGF-I) and hepatic IGF-I mRNA levels in 11-month-old and 27-month-old animals to the levels of the young group of animals. The sensitivity in the old group (percentage of increment after the same or lower dose of rhGH per body weight) was increased for both parameters; serum IGF-I increment: 15% in 3-month-old, 42.6% in 11-month-old and 119.1% in 27-month-old rats; and hepatic IGF-Ib mRNA increase: 45% in 3-month-old, 27.8% in 11-month-old and 64.3% in 27-month-old rats. IGF binding protein-3 (IGFBP-3) mRNA level in the liver was significantly decreased in the old group and only a partial reversion occurred in this group after rhGH treatment; the percentage of increment was also higher in the old group of rats. In extrahepatic tissues IGF-I mRNA was not significantly different in the kidney and the testis of the three groups, and the rhGH treatment produced a significant and similar increase of IGF-I mRNA level in the kidney of the three groups of rats and in the testis of the 27-month-old animals. The GHr/GHBP mRNA remained unchanged in the liver and in the kidney or the testis of the three groups, and was not influenced by the rhGH treatment. Exogenous rhGH decreased pituitary GH mRNA accumulation in a more intense manner in the old group versus control of each group: young adult, 25%; middle-aged, 41.2%; and old rats, 55%. The action of rhGH on pituitary immunoreactive GH (IR-GH) content was only significantly evident in the young group. CONCLUSIONS: These results establish that exogenous rhGH recovers the attenuated liver IGF-I gene expression and the diminished plasma IR-IGF-I in old rats to the levels of young adult animals. They also indicate that the hepatic and extrahepatic (kidney and testis) sensitivity to one established dose per weight of exogenous rhGH is not altered in old animals, or could be potentially increased in some tissues.     

IGF-I and IGF-I-binding proteins in rats with adjuvant-induced arthritis given recombinant human growth hormone

Adjuvant-induced arthritis in rats is associated with growth failure, hypermetabolism and accelerated protein breakdown. We have previously reported that adjuvant-induced arthritis in rats results in a decrease in body weight gain, pituitary GH mRNA, circulating GH and IGF-I together with an increase in serum IGF-binding proteins (IGFBPs). The aim of this study was to analyze the role of GH in the decrease in body weight and in the alterations in the IGF-I system observed in chronic inflammation. Male Wistar rats were injected with complete Freund's adjuvant and 16 days later arthritic rats were injected daily with recombinant human GH (rhGH) (3 IU/kg s.c.) for 8 days; control rats received 250 microl saline. Arthritis significantly decreased body weight gain and serum IGF-I. These decreases were not due to the reduced food intake, since in pair-fed rats they were not observed. Furthermore, administration of rhGH to arthritic rats increased body weight gain without modifying food intake. To further investigate the effect of GH administration, 14 days after adjuvant injection both control and arthritic rats were treated with 0, 1.5, 3 or 6 IU/kg of rhGH. GH treatment at the dose of 3 and 6 IU/kg significantly increased body weight gain in arthritic rats. GH administration, at the higher dose of 6 IU/kg, increased hepatic and serum concentrations of IGF-I in both control and arthritic rats. In control rats, rhGH at the three doses assayed increased circulating IGFBP-3. GH treatment in arthritic rats decreased IGFBP-1 and -2, and did not modify IGFBP-4. GH treatment at the dose of 3 IU/kg also decreased circulating IGFBP-3 in arthritic rats. These data suggest that GH treatment can ameliorate the catabolism observed in adjuvant-induced arthritis, an effect mediated, at least in part, by modifications in the circulating IGFBPs.     

Short-term growth hormone or IGF-I administration improves the IGF-IGFBP system in arthritic rats

ObjectiveAdjuvant-induced arthritis is an experimental model of rheumatoid arthritis that inhibits the GH-IGF-I axis and decreases body weight gain and muscle mass. Although chronic GH or IGF-I treatment increases body weight gain in arthritic rats, muscle resistance to GH and IGF-I is a very common complication in inflammatory diseases. In this study we examine the effect of short-term administration of rhGH and rhIGF-I on liver and muscle IGF-I, IGFBP-3 and ? 5 as well as on the ubiquitin-ligases MuRF1 and atrogin-1 in the muscle of arthritic rats.DesignArthritis was induced in adult male Wistar rats by an intradermal injection of 4 mg of Freund's adjuvant. Fifteen days after adjuvant injection, 300 μg/kg of rhGH or 200 μg/kg of rhIGF or saline was administrated 18 and 3 h before decapitation. A pair-fed group injected with saline was included in order to discard a possible effect of decreased food intake. Gene expression of IGF-I, GHR, IGFBP-3, IGFBP-5, atrogin-1 and MuRF1 were quantified using RT-PCR. In serum, IGF-I was measured by radioimmunoassay (RIA) and IGFBP-3 by ligand blot.ResultsArthritis decreased serum IGF-I and IGF mRNA in liver (P < 0.05), but not in skeletal muscle. In arthritic rats, rhGH increased serum IGF-I and liver IGF-I mRNA similar to the levels of pair-fed rats. Arthritis increased atrogin-1, MuRF1, IGFBP-3 and IGFBP-5 mRNA in muscle (P < 0.01). IGFBP-3 mRNA was downregulated by rhIGF-I, but not by rhGH, administration in control and arthritic rats (P < 0.05). Administration of rhGH and rhIGF-I increased IGFBP-5 in the gastrocnemius of arthritic rats.ConclusionsShort-term rhGH and rhIGF-I administration was found to increase muscle IGFBP-5 mRNA, whereas only rhIGF-I administration decreased muscle IGFBP-3 mRNA in control and arthritic rats. These data suggest that arthritis does not induce GH or IGF-I resistance in skeletal muscle.     

Monitoring serum insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth

OBJECTIVE: Serum IGF-I levels are monitored during GH replacement treatment in adults with GH deficiency (GHD) to guide GH dose adjustment and to minimize occurrence of GH-related side-effects. This is not routine practice in children treated with GH. The aim of this study was to evaluate changes in (1) serum IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio, and (2) serum leptin, an indirect marker of GH response, during the first year of GH treatment in children with disordered growth. DESIGN: An observational prospective longitudinal study with serial measurements at five time points during the first year of GH treatment was carried out. Each patient served as his/her own control. PATIENTS: The study included 31 patients, grouped as (1) GHD (n = 20) and (2) non-GHD (Turner syndrome n = 7; Noonan syndrome n = 4), who had not previously received GH treatment. MEASUREMENTS: Serum IGF-I, IGFBP-3 and leptin levels were measured before treatment and after 6 weeks, 3 months, 6 months and 12 months of GH treatment, with a mean dose of 0.5 IU/kg/wk in GHD and 0.7 IU/kg/wk in non-GHD groups. IGF-I, IGFBP-3 and the calculated IGF-I/IGFBP-3 molar ratio were expressed as SD scores using reference values from the local population. RESULTS: In the GHD group, IGF-I SDS before treatment was lower compared with the non-GHD (-5.4+/-2.5 vs. -1.8+/-1.0; P<0.001). IGF-I (-1.8 SDS +/- 2.2) and IGFBP-3 (-1.1 SDS +/- 0.6) levels and their molar ratios were highest at 6 weeks and remained relatively constant thereafter. In the non-GHD group, IGF-I levels increased throughout the year and were maximum at 12 months (0.3 SDS +/- 1.4) while IGFBP-3 (1.1 SDS +/- 0.9) and IGF-I/IGFBP-3 molar ratio peaked at 6 months. In both groups, IGF-I SDS and IGF-I/IGFBP-3 during treatment correlated with the dose of GH expressed as IU/m2/week (r-values 0. 77 to 0.89; P = 0.005) but not as IU/kg/week. Serum leptin levels decreased significantly during GH treatment in the GHD (median before treatment 4.0 microg/l; median after 12 months treatment 2.4 microg/l; P = 0.02) but not the non-GHD (median before treatment 3.0 microg/l; median after 12 months treatment 2.6 microg/l). In the GHD group, serum leptin before treatment correlated with 12 month change in height SDS (r = 0.70, P = 0.02). CONCLUSIONS: The pattern of IGF-I, IGFBP-3 and their molar ratio during the first year of GH treatment differed between the GHD and non-GHD groups. Calculation of GH dose by surface area may be preferable to calculating by body weight. As a GH dose-dependent increase in serum IGF-I and IGF-I/IGFBP-3 may be associated with adverse effects, serum IGF-I and IGFBP-3 should be monitored routinely during long-term GH treatment. Serum leptin was the only variable that correlated with first year growth response in GHD.     

Enhancement of the peripheral sensitivity to growth hormone in adults with GH deficiency

OBJECTIVE: Adults with severe GH deficiency (GHD) need recombinant human growth hormone (rhGH) replacement to restore body composition, structure functions and metabolic abnormalities. The optimal rhGH dose for replacement has been progressively reduced to avoid side effects. The aim of the present study was to define the minimal rhGH dose able to increase both IGF-I and IGF binding protein (BP)-3 levels in GHD and to verify the possible change in GH sensitivity. DESIGN AND PATIENTS: To this goal, we studied the effect of 4-day treatment with 3 rhGH doses (1.25, 2.5 and 5.0 microg/kg/day) on IGF-I and IGFBP-3 levels in 25 panhypopituitary adults with severe GHD (12 males and 13 females, age: 44.5+/-3.0 years, body mass index (BMI): 27.0+/-0.9 kg/m(2)) and 21 normal young adult volunteers (NV, 12 males and 9 females, age: 30.5+/-2.0 years, BMI: 20.8+/-0.5 kg/m(2)). RESULTS: Basal IGF-I and IGFBP-3 levels in GHD were lower (P<0.001) than in NV. In NV the 1.25 microg/kg dose of rhGH did not modify IGF-I levels. The dose of 2.5 microg/kg rhGH significantly increased IGF-I levels in men (P<0.001) but not in women, while the 5.0 microg/kg dose increased IGF-I levels in both sexes (P<0.001). IGFBP-3 levels were not modified by any of the administered rhGH doses. In GHD patients, all rhGH doses increased IGF-I levels 12 h after both the first (P<0.01) and the fourth rhGH dose (P<0.001). At the end of treatment percentage increases in IGF-I were higher (P<0.001) in GHD patients than in NV. In contrast with NV, in GHD patients the IGF-I response to short-term stimulation with rhGH was independent of gender. Moreover, GHD patients showed increases in IGFBP-3 after the fourth administration of both 2.5 and 5.0 microg/kg rhGH. CONCLUSION: The results of the present study demonstrate that the minimal rhGH dose able to increase IGF-I and IGFBP-3 levels in GHD patients is lower than in normal subjects, at least after a very short treatment. This evidence suggests an enhanced peripheral GH sensitivity in GH deprivation.     

Arthritis-induced increase in serum levels of IGF-binding protein-3 in rats is secondary to the decrease in its proteolytic activity

Adjuvant-induced arthritis is a chronic inflammatory illness that induces a catabolic state, with a decrease in pituitary GH and hepatic IGF-I synthesis. We have previously observed an increase in serum IGF-binding protein-3 (IGFBP-3) in arthritic rats, and found that GH administration prevents the increase in circulating IGFBP-3 in arthritic rats. The aim of this work was therefore to study IGFBP-3 synthesis in the liver as well as its proteolysis in serum as the two possible causes of the increased circulating IGFBP-3 in arthritic rats. The effect of recombinant human GH (rhGH) administration was also analysed. Adult male Wistar rats were injected with complete Freund's adjuvant or vehicle, and 14 days later they were injected s.c. daily until day 22 after adjuvant injection with rhGH (3 IU/kg) or saline. Three hours after the last GH injection, all rats were killed by decapitation. Arthritis increased serum IGFBP-3 levels (P<0.01). The increase in serum IGFBP-3 levels in arthritic rats seems to be due to decreased proteolysis (P<0.01) rather than to an increased synthesis, since liver IGFBP-3 mRNA content was not modified by arthritis. GH administration to control rats resulted in an increase in both hepatic IGFBP-3 mRNA content and in serum IGFBP-3 levels in spite of the increase in IGFBP-3 proteolysis in serum. In arthritic rats, GH treatment did not modify liver IGFBP-3 synthesis, but it increased serum proteolysis of IGFBP-3, leading to a serum concentration of IGFBP-3 similar to that of control rats. Furthermore, there was a negative correlation between circulating IGFBP-3 and its proteolytic activity in the serum of adjuvant-induced arthritic rats. These data suggest that in chronic arthritis the increase in IGFBP-3 serum concentration is secondary to a decrease in proteolytic activity, rather than to an increase in hepatic IGFBP-3 gene expression.     

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     

IGFs and IGF-binding proteins in short children with steroid-dependent nephrotic syndrome on chronic glucocorticoids: changes with 1 year exogenous GH

OBJECTIVE: Children with steroid-dependent nephrotic syndrome (SDNS), despite being in remission on glucocorticoids, continue to have growth retardation and short stature. The mechanism is uncertain as both chronic glucocorticosteroids and the nephrotic syndrome may independently affect growth. We investigated the changes in the IGFs and IGF-binding proteins (IGFBPs) in a group of short SDNS children, and studied the changes prospectively with 1 year's treatment with GH. DESIGN AND METHODS: Total and 'free' IGF-I, IGFBP-3 and acid-labile subunit (ALS) were studied in eight SDNS boys (mean age=12.6 years; mean bone age=9.1 years) on long term oral prednisolone (mean dose 0.46 mg/kg per day) before, during, and after, 1 year's treatment with GH (mean dose 0.32 mg/kg per week). Pretreatment comparisons were made with two control groups, one matched for bone age (CBA; mean bone age=9.2 years), and another for chronological age (CCA; mean chronological age=13 years). Subsequently, three monthly measurements of serum and urine IGFBPs were carried out in the GH-treated SDNS patients using Western ligand blot and Western immunoblot. RESULTS: Pre-treatment serum total IGF-I levels and the IGF-I/IGFBP-3 ratio were elevated significantly in SDNS compared with CBA, and were similar to CCA. Serum free IGF-I levels were elevated significantly compared with both control groups, but serum IGFBP-3 did not differ significantly. Urinary IGFBP-2, IGFBP-3 and ALS were detectable in the SDNS children only. With GH treatment, IGF-I and IGFBP-3, but not IGF-II, increased significantly compared with pre-treatment values, and returned to baseline after cessation of GH treatment. Urinary IGFBPs did not change significantly with GH treatment. CONCLUSIONS: There is persistent urinary loss of IGFBP-2, IGFBP-3 and ALS in children with SDNS in remission with growth retardation. However, the significant elevation in serum IGF-I suggests that glucocorticoid-induced resistance to IGF is the main factor responsible for the persistent growth retardation in these children. Exogenous GH was able to overcome this resistance by further increasing serum IGF-I.     

Short and long term effects of growth hormone on circulating levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-1, and insulin: a placebo-controlled study.

The short and long term effects of GH on serum concentrations of insulin-like growth factor-I (IGF-I), IGF-binding protein-1 (IGFBP-1), and insulin were investigated in women participating in an in vitro fertilization program. In this placebo-controlled study, sterile saline (eight women) or 24 IU GH (eight women) were given im on alternate days, starting on cycle day 4, in combination with GnRH and human menopausal gonadotropin. IGFBP-1 levels decreased significantly during the first 4 h after GH administration, whereas no significant changes were seen in the placebo group. The concentrations of serum IGF-I and insulin did not change during 4 h after GH injection. During the 11-day follow-up period, serum levels of both IGF-I and insulin were significantly higher in GH-treated than in placebo-treated women. These results suggest that the serum concentration of IGFBP-1 is not completely GH independent. They also support the earlier findings that long term treatment with GH increases serum IGF-I and insulin levels.