重组人生长激素对老年肺部感染患者蛋白代谢的影响

目的　观察重组人生长激素 (rhGH)对老年肺部感染患者GH IGF轴的影响 ,探讨rhGH对老年肺部感染合并低蛋白血症的患者的蛋白代谢的作用。方法　将 2 0例老年肺部感染合并低蛋白血症的患者随机分为GH治疗组和非GH治疗组 ,疗程 1 0d,GH治疗组病人给予rhGH 9IU/d ,于研究前及研究结束后观察血清IGF Ⅰ、IGFBP 1、IGFBP 3、GH、血清免疫球蛋白水平。同时分别于研究前、研究第 6天、研究结束时检测血清总蛋白、白蛋白、前白蛋白、转铁蛋白水平。结果　 (1 )研究结束时 ,GH治疗组的血清GH、IGF Ⅰ、IGFBP 3的水平显著高于研究前 (P <0 0 1 )和非GH治疗组 (P <0 0 5) ,而血清IGFBP 1水平显著低于研究前 (P <0 0 1 )和非GH治疗组 (P <0 0 1 ) ;(2 )研究结束后GH治疗组的血清前白蛋白、转铁蛋白的水平显著高于研究前和非GH治疗组 (P <0 0 1 )。 (3)用药前后血清免疫球蛋白的水平无显著的变化。结论　rhGH可使IGF Ⅰ、IGF BP 3水平增加 ,使IGFBP 1降低 ,从而促进蛋白质的合成 ,改善老年肺部感染患者的蛋白代谢。     

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.     

Free dissociable insulin-like growth factor I (IGF-I), total IGF-I and their binding proteins in girls with Turner syndrome during long-term growth hormone treatment

OBJECTIVE: To investigate the effect of GH treatment on free IGF-I levels in girls with Turner syndrome (TS) and to verify relationships between free IGF-I levels and total IGF-I, IGFBP-1, 2 and 3. Additionally, to analyse whether free IGF-I, total IGF-I, IGFBP-3 or its ratio were related to IGF-I bioactivity outcome parameters. DESIGN: Sixty-five girls with TS were randomly assigned to three different GH-dosage groups (1.3, 2.0 and 2.7 mg/m2/day). Mean duration of GH therapy was mean (SD) 8.7(2.0) years. Free IGF-I, total IGF-I and IGFBP-1, -2, -3 were determined at baseline, first, second, third and fifth year of GH therapy, before the start of oestrogen therapy, during the final year of GH treatment, 6 months after GH and 4.8(2.0) years after GH discontinuation. MAIN OUTCOME: During GH treatment, mean free IGF-I levels stayed < +2 standard deviation score (sds), whereas mean total IGF-I and IGF-I/IGFBP-3 ratio were > +2 sds. There were no differences in free IGF-I levels between the three GH groups, whereas total IGF-I and ratio levels were significantly higher in the highest GH group. The following variables contributed significantly to predicting the square root of free IGF-I levels: age, GH dose, oestrogen dose, IGFBP-1, IGFBP-3, body mass index and total IGF-I or IGF-I/IGFBP-3 ratio. However, the explaining variance did not exceed 55%. Several IGF-I bioactivity outcome parameters positively correlated with total IGF-I and IGF-I/IGFBP-3 ratio, whereas free IGF-I did not. CONCLUSIONS: During long-term GH therapy in girls with TS, mean free IGF-I levels stayed within the normal range, whereas mean total IGF-I and IGF-I/IGFBP-3 ratio exceeded the upper normal range. Although total IGF-I and the IGF-I/IGFBP-3 ratio did not accurately represent free IGF-I levels, they seemed to better represent the IGF-I bioactivity than the measured free IGF-I.     

Usefulness of different biochemical markers of the insulin-like growth factor (IGF) family in diagnosing growth hormone excess and deficiency in adults.

The diagnostic approach to acromegaly and GH deficiency frequently includes measurement of several components of the insulin-like growth factor (IGF) system. IGF-I levels are reported to be good predictors of active and cured acromegaly, but are commonly found within the normal age-adjusted range in adult GH-deficient (GHD) patients. Circulating concentrations of IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and free IGF-I reflect the GH secretory status, but their diagnostic accuracy is still debated. In this study serum levels of total and free IGF-I, IGFBP-3, ALS, and IGFBP-3-IGF-I and IGFBP-3-ALS complexes were determined in patients previously diagnosed with active (n = 67) or inactive (n = 16) acromegaly and adult GHD (n = 34) and compared with results obtained in 58 healthy controls. In healthy subjects, IGF-I, IGFBP-3, ALS, and both IGFBP-3 complexes declined with age; a correlation was found between IGF-I and IGFBP-3 (r = 0.59; P < 0.001), ALS (r = 0.67; P < 0.001), and free IGF-I (r = 0.40; P < 0.05). Active acromegalic patients showed a significant increase in all parameters tested. IGF-I concentrations were above +2 SD in 100% of patients, whereas slightly lower sensitivities were shown for IGFBP-3 (85%), ALS (88%), and free IGF-I (94%). In this group, IGF-I exhibited a slightly higher correlation with IGFBP-3 (r = 0.83; P < 0.001) than with ALS levels (r = 0.78; P < 0.001). In cured acromegalic patients, we observed the normalization of all parameters but free IGF-I levels. Adult GHD patients showed a significant reduction of all hormones. Unlike active acromegalic patients, all parameters had only a modest sensitivity in GHD; suppression below -2 SD was observed in 41% of GHD patients for IGF-I, 47% for IGFBP-3, 32% for ALS, and 35% for free IGF-I measurements. Previous radiotherapy and GH peak response below 3 microg/L were associated with significantly lower IGF-I, IGFBP-3, and ALS levels. IGF-I levels were significantly correlated to ALS (r = 0.68; P < 0.001) and IGFBP-3 (r = 0.64; P < 0.001) as well as with free IGF-I (r = 0.67; P < 0.001) levels. By multiple regression analysis, the number of anterior pituitary hormones impaired was the most predictive indicator of IGF-I, IGFBP-3, and free IGF-I levels in GHD patients; conversely, the GH peak response better anticipated ALS concentrations. The pattern of IGFBP-3 complexes paralleled previous hormonal findings. In active acromegalic patients, IGFBP-3-IGF-I levels were 5.4-fold higher than in controls and were above +2 SD in 95% of patients, whereas IGFBP-3-ALS levels were elevated in 15% of cases. On the other hand, both IGFBP-3 complexes were able to predict GHD in only a minority of cases. Taken together, these data support the diagnostic role of IGF-I in acromegaly and suggest that free IGF-I and the IGFBP-3-IGF-I complex can assist diagnostic strategies in this condition. All markers are of limited predictive value in adult GHD, as hormonal values are commonly found within the normal limits. In these patients, low IGFBP-3 and IGF-I concentrations can add further clinical information on the residual GH activity.     

Free/dissociable insulin-like growth factor (IGF)-I, not total IGF-I, correlates with growth response during growth hormone treatment in children born small for gestational age

CONTEXT: IGF-I plays an important role in pre- and postnatal growth. Its serum levels are regulated by metabolic and genetic factors. Mean total IGF-I in short, small for gestational age (SGA) children is reduced, but within the normal range. Free/dissociable IGF-I is the bioactive form of IGF-I. Objectives: The aim of the study was to investigate changes in free IGF-I during GH treatment in short SGA children and to evaluate whether free IGF-I levels contribute to predicting first-year growth response and/or adult height. DESIGN, SETTING, AND INTERVENTION: We conducted a randomized, double-blind GH dose-response study with a GH dose of either 1 mg/m(2).d (group A) or 2 mg/m(2).d (group B). Free IGF-I, total IGF-I, and IGF binding protein (IGFBP)-3 were determined at baseline, after 1 and 5 yr, at stop, and 6 months after GH discontinuation. PATIENTS: We studied 73 (46 male) short SGA children (36 group A) with a baseline mean age of 7.7 (2.2) yr and a mean GH duration of 8.2 (2.1) yr. MAIN OUTCOME MEASURES: Untreated SGA children had a mean free IGF-I sd score (SDS) of -0.2 (1.2), not related to total IGF-I. During GH therapy, free IGF-I significantly increased to 1.6 (0.7) SDS, as did total IGF-I and IGFBP-3 [2.0 (0.8) and 1.3 (0.9), respectively]. Multiple regression analysis showed that baseline free IGF-I and IGFBP-3 were negatively correlated with adult height SDS, whereas baseline bone age delay, target height SDS, baseline height SDS, and GH dose were positively correlated. Free IGF-I was also negatively correlated with first-year growth response. CONCLUSIONS: Circulating baseline free IGF-I and IGFBP-3 were better predictors for adult height in GH-treated SGA children than total IGF-I, or total IGF-I to IGFBP-3 ratio. This suggests a possible role for free IGF-I measurement in predicting the effect of GH therapy in short SGA children.     

Acromegalic features in growth hormone (GH)-deficient patients after long-term GH therapy

BACKGROUND: Craniofacial, hand, foot and somatic growth depend on normal GH secretion. Acromegalic features have been described in children with GH insensitivity after IGF-I treatment. We observed patients with acromegalic features such as increase of foot size, nose and jaw enlargement among our cases with GH deficiency, treated with standard recombinant (rh)GH doses. The aim of our study was to analyse the possible factors involved in the development of acromegalic features in these patients. PATIENTS: We evaluated 21 patients, 17 with combined pituitary hormone deficiency and four with isolated GH deficiency treated with rhGH (0.05-0.15 U/kg/day, sc, at night) for 2-12 years who achieved final height. IGF-I and IGFBP-3 were measured before and every 6 months during therapy and bone age was evaluated yearly. At the end of therapy, patients' hand and foot sizes and height were measured and plotted on nomograms for hand according to height and age, and foot size according to height. Lateral radiographs of the face were performed to obtain the linear measurement of the lower jaw length. RESULTS: Foot size was greater than 97th percentile in 8/21 patients and lower jaw length was greater than +2SD in 4/21 patients. Patients were classified in two groups: group 1 (with foot size greater than 97th percentile and/or lower jaw length greater than +2SD) consisted of 11 patients (six females); nine had combined pituitary hormone deficiency (six associated to hypogonadotrophic hypogonadism) and three had isolated GH deficiency; group 2 (with foot size smaller than 97th percentile and lower jaw length less than +2SD) consisted of 10 patients (seven boys); nine had combined pituitary hormone deficiency (six associated to hypogonadotrophic hypogonadism) and one with isolated GH deficiency. During treatment, IGF-I levels ranged from < or = 3 to +2SD and IGFBP-3 levels ranged from -3 to +2SD, in both groups. We observed no statistically significant differences between the two groups regarding chronological age, bone age, height at the beginning and at the end of therapy, pubertal development, duration of rhGH treatment and IGF-I and IGFBP-3 levels (P > 0.05). Foot size percentile exceeded final height percentile in 11/21 patients (seven girls). CONCLUSION: Long-term rhGH treatment with standard doses might be associated with acromegalic features (increased foot size and lower jaw measurements) in patients with GH deficiency who achieved final height, especially in girls. Neither the clinical nor the hormonal parameters, IGF-I and IGFBP-3 levels, were useful to predict the development of these features. Further studies are necessary to analyse the frequency of this side-effect and how to prevent it.     

Growth hormone replacement therapy in growth hormone deficient children and adults: Effects on hemochrome

Several lines of evidence have suggested a role of the GH/IGF-I axis in the regulation of hemochrome. Many studies have been carried out in GH deficient children and adults about this topic, reporting predominantly a positive effect of recombinant human GH (rhGH) on red series, with no action on serum leucocytes and platelets counts. The aim of this study was to assess the impact of GH deficiency (GHD) and of rhGH replacement on blood cells count in 17 pre-pubertal children with idiopathic isolated GHD (11 males and 6 females, aged 9.1+/-0.8 yr) and in 18 patients with adult-onset GHD (12 males and 6 females, aged 47.9+/-3.0 yr). Evaluation of absolute and SD score (SDS) values of red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets and white blood cells was performed at baseline and after 12 months of rhGH treatment (0.045+/-0.001 mg/kg bw/day and 4.2+/-0.5 microg/kg bw/day for children and adults, respectively). At baseline, all patients showed low IGF-I levels. Effectiveness of rhGH therapy was documented by significant increase in height SDS, height velocity and serum IGF-I levels in children. In adults, adequacy of rhGH was demonstrated by significant increase in serum IGF-I and significant decrease in body fat. At baseline, about 25% of patients (4 of 17 children and 4 of 18 adults) showed normochromic normocytic anemia, while the other indices were normal. In 7 of the 8 anemic patients, normal levels of hemoglobin were restored on rhGH, while no change in all the other indices was observed. In conclusion, rhGH therapy at physiological doses has no effect on erythropoiesis in GHD children and adults with normal blood cells count, while in patients with normochromic normocytic anemia rhGH is able to restore normal hemoglobin levels.     

Reduced human growth hormone (hGH) bioactivity without a defect of the GH-1 gene in three patients with rhGH responsive growth failure

BACKGROUND: A GH deficiency-like phenotype with normal or high hGH secretion, pathologically low IGF-I serum levels, and catch-up growth under treatment with recombinant hGH is suggestive of the presence of biologically inactive hGH syndrome, whose presumably heterogenous molecular basis is substantially unknown. DESIGN: Serum samples from patients who fulfilled the above criteria and from controls with idiopathic short stature were measured by polyclonal hGH-RIA, Nb2 rat lymphoma proliferation assay, and hGH immunofunctional assay (IFA). If assays were suggestive of the presence of bioinactive GH, mutational analysis of the hGH-1 gene was performed. PATIENTS: Three patients were selected because of clinical and biochemical evidence. At the time of diagnosis mean age was 3.4 (2.2, 3.5, 4.5) years, mean height -3.5 (-2.8, -3.6, -4.2) SD score (SDS) and mean growth rate -1.5 (-1.4, -1.5, -1.6) SDS. Mean IGF-I serum levels were -1.9 (-0.7, -2.4, -2.5) SDS and mean IGFBP-3 serum levels -1.2 (-1.1, -1.2, -1.2) SDS. Stimulated and spontaneous GH peaks measured by a polyclonal radioimmunoassay were all above 14 microg/l. GHBP serum levels were normal, and antihGH antibodies were not detected. Therapy with rhGH was effective in causing catch-up growth of the three children with an initial mean growth rate of + 2.9 (+ 1.7, + 2.1, + 5.0) SDS, and normalization of IGF-I (mean: -0.66 SDS: -1.8, - 1.2, + 1.1 SDS) and IGFBP-3 serum levels (mean: + 0.81 SDS: -0.2, + 0.8, + 1.8 SDS). RESULTS: In comparison to controls, the patients' serum hGH levels were much lower when measured by Nb2 rat lymphoma cell proliferation bioassay (mean: -2.3 SDS, range: -1.7- -4.1) and by the immunofunctional assay (IFA) (-1.5 SDS, range: -0.2- -3.1) than by RIA. Retesting of two of the three patients including an one year break of therapy confirmed the rhGH dependence of growth in spite of normal endogenous GH secretion. Radioactive direct sequencing of both strands of PCR-amplified genomic DNA and cDNA excluded a GH-1 gene mutation in all three children. CONCLUSION: Mutations of the GH-1 gene are probably not the main genetic defect in children with biologically inactive hGH syndrome. Posttranslational processing of hGH might reduce the biological activity of the normal translation product.     

High serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) during high-dose GH treatment in short children born small for gestational age

CONTEXT: Epidemiological studies have indicated that high serum levels of GH and IGF-I are associated with long-term risks. OBJECTIVE: The objective of the study was to evaluate the changes in serum levels of GH during overnight profiles, IGF-I, and IGF binding protein 3 (IGFBP-3) in short small for gestational age (SGA) children during GH treatment with two doses. PATIENTS: Thirty-six prepubertal short SGA children were the subjects of this study. Intervention: Subjects received 1 (group A) or 2 (group B) mg GH/m(2).d. MAIN OUTCOME MEASURES: At baseline and after 6 months of GH treatment, overnight GH profiles were performed, and serum IGF-I and IGFBP-3 levels were measured. RESULTS: After 6 months, group B had significantly higher GH levels during the profile (mean, maximum, and area under the curve above zero line) than group A (P < 0.009). In group B, maximum GH levels increased from 43.9-161 mU/liter (P < 0.0002), and in group A, from 57.2-104 mU/liter (P = 0.002). During the profile (i.e. 12 h per day), children of group B had mean GH levels of 64.4 vs. 34.8 mU/liter in group A (P = 0.001). The IGF-I and IGF-I to IGFBP-3 ratio sd scores increased significantly in both groups, but were higher in group B than A [1.5 vs. 0.2 (P = 0.002) and 1.4 vs. 0.3 (P = 0.007), respectively]. In group B, 74% of the children had IGF-I levels in the highest quintile during GH treatment compared with 19% in group A. CONCLUSION: Our study shows that high-dose GH treatment in short SGA children results in high serum GH and IGF-I levels in most children. We recommend monitoring IGF-I levels during GH therapy to ensure that these remain within the normal range.     

Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure

CONTEXT: Primary IGF deficiency (IGFD) describes the condition in which serum concentrations of IGF-I are low in the face of normal to elevated GH production. Because IGF-I, which circulates as part of a ternary complex with IGF binding protein (IGFBP)-3 and acid-labile subunit (ALS), mediates the growth-promoting effects of GH, IGFD is associated with severe growth failure in humans. OBJECTIVE: We investigated a case of IGFD in which serum IGF-I and IGFBP-3 were abnormally low, yet growth failure was modest (-2.1 sd score at 15.5 yr of age). RESULTS: The young male subject, from a consanguineous pedigree, had a postnatal growth profile consistently below the third percentile. The subject had a normal fasting GH level of 3.7 muU/ml and normal serum GH binding protein level (1258 pmol/liter; normal range 431-1892 pmol/liter), but serum IGF-I and IGFBP-3 were profoundly reduced (-5.8 and -7.2 sd score, respectively, at age 12.3 yr), even through puberty. A novel homozygous missense mutation was subsequently identified in the ALS gene, which resulted in severe deficiency of serum ALS (undetectable). CONCLUSIONS: ALS is critical for maintaining normal serum concentrations of IGF-I and IGFBP-3, most likely by prolonging the half-lives of both proteins. ALS deficiency can be associated with moderate growth failure, but in this patient, the onset and progression of puberty appear to be normal. Altogether the results support a modest role for the ternary complex in the regulation of stature.     

The ratio between serum levels of insulin-like growth factor (IGF)-I and the IGF binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients

OBJECTIVE Several in-vitro studies have suggested that the biological actions of IGF-I can be modified by the presence of specific IGF binding proteins. In man, the 24-hour serum levels of IGF-I and IGFBP-3 remain constant, but short-term changes in the IGF-l/IGFBP-3 ratio have been described following GH administration. Serum levels of IGF-I and IGFBP-3 decrease with age in normal adults and are elevated In active acromegaly due to excessive GH secretion. However, the Individual ratios between serum levels of IGF-I and IGFBP-3 in acromegalic and healthy adults have not been described previously. METHODS AND MATERIALS We studied this ratio In 198 healthy adults and In 56 acromegalic patients, grouped according to their serum GH levels (group I GH < 2mLU/l II GH 2–10mLU/l; III GH > 10mLU/l). In all subjects a single blood sample was drawn for IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 and GH measurements by specific RIAs. In 38 of the patients a 24-hour urinary collection was performed for GH determination. RESULTS In healthy adults serum levels of IGF-I and IGFBP-3 decreased with Increasing age (r =?0.52 and r=?0.34, respectively, P< 0.0001). In addition, the molar IGF-l/IGFBP-3 ratio declined with increasing age (r =?0.44, P – 0.0001). In patients with acromegaly and high serum GH levels (group III), circulating IGF-I was increased 7–97 standard deviations (SDS) and IGFBP-3 was increased 4.20 SOS (P < 0.0001). Serum levels of IGF-II were normal in all three groups (588 ± 240μ/l) whereas IGFBP-1 and IGFBP-2 levels were low and IGFBP-2 levels decreased significantly with increasing serum GH levels (P < 0.0001). The molar IGF-l/IGFBP-3 ratio in the acromegalic patients was significantly higher than in the controls (P < 0.0001) and correlated significantly with urinary GH excretion (r = 0.67, P < 0.0001) as well as with serum GH levels (r = 0.73, P < 0.0001). CONCLUSION We demonstrated a decreasing molar IGF-l/IGFBP-3 ratio with increasing age in healthy adults and an increased ratio between serum IGF-I and IGFBP-3 levels in acromegalic patients. As IGF-II is normal and IGFBP-1 and IGFBP-2 are inversely correlated to the serum GH levels In the acromegalic patients, we speculate that the molar ratio between IGF-I and IGFBP-3 reflects free (biologically active) IGF-I and Is dependent on GH levels.     

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.     

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     

Serum IGF-I and IGFBP-3 concentrations do not accurately predict growth hormone deficiency in children with brain tumours

OBJECTIVE: The growth hormone (GH)-dependent growth factors insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) may be superior to provocative GH testing in diagnosing GH deficiency (GHD) in children. In adults with brain tumours (BT) and GHD, however, provocative GH testing more accurately reflects GHD than either IGF-I or IGFBP-3. We assessed growth factor levels in children with GHD due to BT with respect to brain tumour type, pubertal stage, growth velocity, bone age delay, and body mass index (BMI). DESIGN: Retrospective case review of all patients followed at our centre with GHD following treatment of BT. PATIENTS: 72 children (51 M, 21 F) with BT diagnosed with GHD by clinical and auxological criteria, including provocative GH testing, in whom pre-GH treatment IGF-I and IGFBP-3 levels were obtained. MEASUREMENTS: Auxological data, including height, weight, growth velocity, and pubertal stage; and biochemical data, including GH response to provocative GH testing and pre-GH treatment serum IGF-I and IGFBP-3 concentrations. RESULTS: IGF-I levels were normal (above -2 SD) in 19 of 70 children (27%), and IGFBP-3 levels were normal in 21 of 42 (50%). In children with GHD, pubertal stage correlated significantly with both IGF-I (r = 0.328, p < 0.006) and IGFBP-3 (r = 0.364, P < 0.02). Normal IGF-1 levels were found in 1/15 children with craniopharyngioma (Cranio) (7%), 10/30 with primitive neuroectodermal tumours (PNET) (33%), and 5/12 children with hypothalamic/chiasmatic glioma (HCG) (42%) (P < 0. 05). IGFBP-3 levels were normal in 4/13 Cranio patients (31%), 8/15 PNET patients (53%), and 6/8 HCG patients (75%) (P = ns). Tanner staging varied significantly among tumour types: mode = 1 for Cranio and PNET vs. mode = 3 for HCG (P < 0.03). BMI did not differ between patients with low vs. normal growth factor levels. CONCLUSIONS: Low IGF-I levels were more predictive of growth hormone deficiency than low IGFBP-3 levels in our brain tumour patients, but both were poor predictors of growth hormone deficiency in children with hypothalamic-chiasmatic glioma and in pubertal children. Serum IGF-I and IGFBP-3 levels, therefore, do not always reflect growth hormone deficiency in children with brain tumours, particularly in those with hypothalamic-chiasmatic glioma or those already in puberty.     

Is IGF binding protein-3 assessment helpful for the diagnosis of GH deficiency?

OBJECTIVE The measurement of serum immunoreactive IGFBP-3 levels has been proposed as a screening test to Identify children with growth hormone deficiency (GHO). We tested the sensitivity and specificity of the IGFBP-3 assessment In comparison with the measurement of IGF-I. DESIGN We assessed the IGFBP-3 and IGF-I circulating levels in normal subjects and patients with GHD or idiopathic short stature (ISS). PATIENTS Eighty-two normal subjects, 16 GHD, and 10 children with ISS were studied. Controls were divided into three age groups: group A, 1-4 years (n= 16); group B, 5-9 years (n= 35), and group C, 10-14 years (n= 31) MEASUREMENTS All subjects underwent standard anthropometry. In short patients, GH secretory status was assessed by clonidine and arginine stimulation tests. IGFBP-3 and IGF-I circulating levels were measured by radioimmunoassay. RESULTS IGFBP-3 and IGF-I levels were closely related (r= 0.51, P < 0.0001) and IGFBP-3 was less age dependent than IGF-I (r= 0.57, P < 0.02 vsr= 0.64, P= 0.0001). Sensitivity (true positive ratio) and specificity (true negative ratio) of IGFBP-3 measurement were 50 and 92% respectively, whereas sensitivity and specificity of IGF-I assessment were 75 and 90% respectively. Below the age of 5 years, sensitivity was 20% for IGFBP-3 and 40% for IGF-I; specificity was 94% for IGFBP-3 and 88% for IGF-I. CONCLUSIONS IGFBP-3 measurement had poor sensitivity in detecting growth hormone deficient patients, offering no diagnostic advantage over IGF-I, even in the first years of life, although, due to the high specificity, the finding of subnormal levels of IGFBP-3 was strongly suggestive of growth hormone deficiency. The presence of low IGFBP-3 and IGF-I levels in a short child with normal GH response to provocative tests should prompt further Investigations, such as the determination of spontaneous GH secretion or assessment of the GH binding proteins together with an IGF-I and/or IGFBP-3 generation test, In order to Identify neurosecretory dysfunction or GH receptor deficiency. Finally, we believe that there is no definitive test for diagnosing or excluding growth hormone deficiency and detailed analysis of the results of endocrine tests, clinical findings and other laboratory and radiological Information is necessary to maximize diagnostic accuracy     

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.     

Growth hormone replacement does not increase serum prostate-specific antigen in hypopituitary men over 50 years

OBJECTIVE: Epidemiological studies have shown an increased risk for prostate carcinoma in men with serum IGF-I in the upper part of the age-related reference range. Recombinant human GH (rhGH) is widely used in patients with GH deficiency, usually raising the serum IGF-I levels into the normal range: safety surveillance is therefore mandatory, with particular regard to neoplasia. The aim was to examine whether rhGH replacement in hypopituitary adults is associated with changes in serum prostate-specific antigen (PSA) as a surrogate marker of changes in prostatic growth. DESIGN AND METHODS: A prospective longitudinal study was used with a median follow-up of 22 (range 2.5-32) months, in which 41 men aged over 50 years with adult onset hypopituitarism and GH deficiency during rhGH replacement were examined. Serum PSA and IGF-I were measured at baseline and at latest follow-up. RESULTS: Mean serum PSA remained unchanged during rhGH replacement, with a median follow-up of 2 years. No correlation was found between the individual changes in serum IGF-I and changes in serum PSA. CONCLUSIONS: These data are reassuring thus far regarding the safety of GH replacement in relation to the prostate in this patient group.     

Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 response to growth hormone is impaired in HIV-infected children

To better characterize the somatotropic axis in HIV-infected children the circadian rhythm of growth hormone (GH), and basal and stimulated (by an insulin-like growth factor I [IGF-I] generation test) plasma levels of IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3), were evaluated in 16 children (9 boys and 7 girls; age range, 7-11 years) with HIV infection. All patients were free from active opportunistic infection or liver disease at the time of the study. Sixteen age- and sex-matched healthy children (10 boys and 6 girls; age range, 7-11 years) served as control subjects. GH rhythmometric data were analyzed by single and population mean cosinor analysis. As regards the IGF-I generation test, biosynthetic human GH (hGH, 0.1 IU/kg, 0.033 mg/kg) was administered subcutaneously for 4 days and blood samples were taken from fasting subjects at baseline and on the morning after the last GH injection for measurement of IGF-I and IGFBP-3. Plasma GH levels fell within normal limits in the HIV-seropositive patients and were similar to those of healthy children (1.31 +/- 1.18 vs. 1.57 +/- 1.16 microg/liter, respectively; mean +/- SD). The population mean cosinor analysis shows that the GH circadian rhythm reached statistical significance both in the HIV-seropositive children and in the control group. Despite this, the IGF-I and IGFBP-3 levels were significantly lower in HIV-infected children than in the control group (75.6 +/- 57.2 vs. 233.3 +/- 52.5 ng/ml, p < 0.001 and 2.09 +/- 0.17 vs. 3.89 +/- 0.24 mg/liter, p < 0.01, respectively; mean +/- SD); moreover, the response of IGF-I and IGFBP-3 to the IGF-I generation test was significantly lower in HIV-infected children than in the control group (86.3 +/- 55.8 vs. 257.5 +/- 53.4 ng/ml, p < 0.001 and 3.14 +/- 0.43 mg/liter, p < 0.01, respectively; mean +/- SD). It appears that circadian GH secretion is normal in children with HIV infection, but the response to exogenous GH with regard to IGF-I and IGFBP-3 production is impaired, indicating a degree of GH insensitivity in such children.     

Normal IGF-I and enhanced IGFBP-3 response to very low rhGH dose in patients with dilated cardiomyopathy

Well-nourished patients with dilated cardiomyopathy (DCM) show slight reduction of mean basal IGF-I levels which, however, display a response to a rhGH dose as low as 5.0 microg/kg/day similar to that of age-matched control subjects (CS). To further investigate peripheral GH sensitivity, we studied the IGF-I and IGFBP-3 responses to 4-day s.c. 2.5 microg/kg/day rhGH administration, the lowest effective dose able to increase IGF-I levels in normal subjects, in 10 DCM patients [age (mean+/-SE): 57.6+/-1.0 yr, body mass index (BMI): 24.0+/-1.2 kg/m2, left ventricular ejection fraction: 26.2+/-3.2%, NYHA (New York Heart Association): I/0, II/4, III/4, IV/2] and in 9 age-matched healthy CS (age: 55.3+/-1.2 yr, BMI: 23.7+/-1.8 kg/m2). Basal IGF-I levels in DCM were lower though not significantly than those in CS (147.7+/-9.8 vs 174.7+/-17.0 microg/l). Basal IGFBP-3 levels in DCM were similar to those in CS (3.1+/-0.3 vs 2.7+/-0.2 mg/l). In CS 4-day rhGH increased IGF-I levels (222.4+/-14.9 microg/l; p<0.01 vs baseline) but did not modify IGFBP-3 levels (3.0+/-0.2 mg/l). In DCM IGF-I levels were increased by 4-day rhGH administration (175.7+/-11.0 microg/l; p<0.05 vs baseline) with a similar percent extent than in CS. On the other hand, in DCM, but not in CS, 4-day rhGH significantly increased IGFBP-3 levels (3.5+/-0.3 mg/l; p<0.05 vs baseline). Therefore, in conclusion, testing with the lowest effective rhGH dose further suggest that peripheral GH sensitivity in well-nourished DCM is preserved. On the other hand, DCM patients show enhanced IGFBP-3 sensitivity to stimulation by rhGH.     

Confirmation of severe GH deficiency after final height in patients diagnosed as GH deficient during childhood

OBJECTIVE: Human GH treatment of patients with childhood-onset (CO) growth hormone deficiency (GHD) ceases when they reach final height; this provides an opportunity to retest GH status in all patients before determining whether GH therapy will be required in adult life. At present, the diagnostic approach to these patients is not fully standardized. This study aimed to characterize a large group of previously GH-treated CO GHD patients and establish their GH status. PATIENTS AND METHODS: The multinational study included 167 patients diagnosed as GH deficient and treated with hGH to final height during childhood. Mean age was 19.2 years and mean height standard deviation score (SDS) was -1.08. Peak serum GH concentrations were determined in standard GH stimulation tests. IGF-I and IGFBP-3 concentrations were determined at a central laboratory and converted to SDS values by reference to a normal population. RESULTS: Using only a peak GH value of less than 3 microg/l (1 mg = 3 U) in stimulation tests as the cut-off, 133 (79.6%) patients would be classed as GH deficient. Using only an IGF-I value less than -2 SDS as the cut-off, 134 (80.2%) patients would be classed as GH deficient. However, by using both criteria there were 120 (71.9%) patients who were definitely severely GH deficient (group 1) and 20 (12.0%) who were not GH deficient (group 2), leaving 14 (8.4%) classed as GH deficient from IGF-I SDS only (group 3) and 13 (7.8%) classed as GH deficient from stimulation test only (group 4). There was no difference between the groups in height SDS or body mass index (BMI), but the GH-deficient patients tended to have been diagnosed at a younger age (group 1, 8.2 +/- 3.9; group 2, 10.0 +/- 4.0; P = 0.052). For patients classed as GH deficient compared with those not GH deficient, the percentage of males was lower (group 1, 64.2%; group 2, 90.0%; P = 0.022) and the percentage with multiple pituitary hormone deficiencies was higher (group 1, 81.7%; group 2, 20.0%; P < 0 .001), with the other two groups being intermediate in each case. Only the group classed as GH deficient by both criteria had a mean IGFBP-3 less than -2 SDS and both IGF-I SDS and IGFBP-3 SDS increased steadily across the four groups. CONCLUSIONS: A high percentage (71.9%) of these childhood-onset GH-deficient patients were still GH deficient in adult life and are likely to require further hGH treatment. While 12.0% could be classed as definitely no longer GH deficient, there are some patients who are intermediate (16.2%) and may be classed as GH deficient by one criterion but not the other. When GH stimulation test results and IGF-I concentration are discordant, the IGFBP-3 level does not establish diagnosis and the hGH treatment requirement of such patients remains a dilemma.