Absence of proteolysis of insulin-like growth factor binding protein-3 in serum from patients with growth hormone deficiency

Insulin-like growth factor-I (IGF-I) is predominantly bound to IGF binding protein-3 (IGFBP-3), and free form of IGF-I (fIGF-I) may be bioactive in the circulation. Proteolysis of IGFBP-3, as reported in pregnant serum, results in the lowering of the affinity for IGF-I, thereby increasing the ratio of fIGF-I to total IGF-I (f/t IGF-I ratio). Conflicting results have been reported regarding the relationship between the proteolysis and growth hormone (GH)-IGF-I axis. Proteolysis of IGFBP-3 was previously reported to be present late at night in serum from pediatric subjects with GH receptor dysfunction (GHRD or "Laron-type dwarfism"). Recently, it was reported that proteolysis of IGFBP-3 could not be detected in adult patients with GH deficiency (GHD). The purpose of this study was to investigate the possible relationship between proteolysis of IGFBP-3 and GH in patients with GHD including pediatric cases. Here, proteolysis of IGFBP-3 measured by Western immunoblotting (ages 4-25 years; n=11) and f/t IGF-I ratio measured by immunoradiometric assay (ages 4-25 years; n=10) were studied in patients with GHD, which is similar to GHRD in terms of lowered GH function. There was no significant proteolysis of IGFBP-3 in the sera from the 11 patients with GHD. No proteolysis of IGFBP-3 was observed during a 24 hour period in sera obtained every two hours from two patients with GHD. f/t IGF-I ratio was not increased in plasma from the 10 patients with GHD. Our data suggest that proteolysis of IGFBP-3 is independent of the GH-IGF-I axis.     

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.     

2型糖尿病患者血清胰岛素样生长因子Ⅰ及其结合蛋白与大血管并发症的关系

2型糖尿病(T2DM)合并大血管病变者血清游离胰岛素样生长因子Ⅰ(IGF-I)水平较无大血管病变组降低(P<0·01),胰岛素样生长因子结合蛋白1浓度与WHR、胰岛素抵抗指数呈负相关。表明低IGF-I可能参与糖尿病大血管并发症的发生。胰岛素样生长因子结合蛋白1的浓度反映了胰岛素抵抗状态。     

Growth hormone insensitivity syndrome associated with syringomyelia and type I Chiari malformation

A 49-year-old man with syringomyelia and a Type I Arnold-Chiari malformation (Chiari-I) was diagnosed with growth hormone insensitivity syndrome (GHIS). He was short in stature, had high circulating levels of GH, and low circulating levels of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3). His GH responses to the administration of growth hormone-releasing hormone (GHRH) and L-DOPA were normal, but his levels of IGF-I and IGFBP-3 did not increase after the administration of exogenous GH. Direct genomic DNA sequencing revealed neither a mutation nor deletion in this patient's GH receptor (GHR) gene, though one polymorphism was detected, indicating that his GHR gene was normal. This is the first reported case of an association of GHIS with syringomyelia and Chiari-I malformation.     

Serum levels of free insulin-like growth factor (IGF)-I and IGF-binding protein-1 in prepubertal children with idiopathic short stature

The study was performed to evaluate the relationships among serum free and total insulin-like growth factor (IGF)-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and insulin concentrations in prepubertal children with idiopathic short stature (ISS). Eighteen children with ISS and 15 age-matched controls were included in the study. All short children had a height standard deviation score of more than 2 below the mean, and maximum stimulated GH levels greater than 10 microg/l after two standard provocation tests. The serum levels of free IGF-I were significantly lower in short children (1.6 +/- 0.3 microg/l) than in the controls (2.8 +/- 0.6 microg/l, P<0.05), while total IGF-I levels were slightly, but not significantly, lower in short children than in controls. The serum levels of IGFBP-1 were significantly higher in the ISS group (124.6 +/- 5.6 microg/l) than in controls (80.0 +/- 8.7 microg/l, P < 0.0001). The fasting insulin and IGFBP-3 levels were similar in both groups. A stepwise regression analysis for all subjects revealed that IGFBP-1 is the only independent predictor of log free IGF-I (R2 = 0.23, P<0.01). The present study shows that the serum levels of free IGF-1 are significantly lower and insulin-like growth factor-binding protein-1 levels are higher in prepubertal children with idiopathic short stature, as compared with age-matched controls. The high IGFBP-1 may contribute to growth retardation in a subgroup of idiopathic short stature through a decrease in free IGF-1.     

Relationship between serum leptin and the insulin-like growth factor-I system in humans.

The growth hormone (GH)/insulin-like growth factor-I (IGF-I) system and leptin both play an important role in the regulation of body composition. Although the regulation of these two hormonal systems by insulin has been under intense investigation, the physiologic interactions between leptin and the GH/IGF-I system remain unknown. In this study, we examined the relationships among circulating leptin and key elements of the IGF-I system in 60 subjects (27 nondiabetic lean, 21 nondiabetic obese, and 12 type 1 diabetic subjects) with a wide range of insulin secretory capacity. Leptin, glucose, insulin, free IGF-I, total IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 levels were measured in the basal state after an overnight fast, and the acute insulin response to glucose (AIRG) was determined after intravenous glucose injection. AIRG was significantly higher (P < .01) in the obese (3,365+/-562 pmol/L x min) versus lean subjects (1,624+/-155 pmol/L x min). In simple regression analysis, the serum leptin concentration was positively correlated with the body mass index ([BMI] men, r = .51, P = .005; women, r = .71, P < .001), IGFBP-3 (men, r = .20, P = nonsignificant; women, r = .41, P < .025), and AIRG (men, r = .73, P < .001; women, r = .62, P < .01). There was a nonlinear correlation between leptin and IGFBP-1, but there was no correlation between leptin and free or total IGF-I. In multiple regression analysis with leptin as the dependent variable, gender, BMI, and IGFBP-3 entered the equations at a statistically significant level. The correlation of leptin with IGFBP-3 was independent of obesity and persisted after correction for AIRG, suggesting a link between leptin and GH action.     

Body mass index, waist circumference and waist-hip ratio and serum levels of IGF-I and IGFBP-3 in European women

OBJECTIVE: To examine the relationship between body mass index (BMI) and waist-hip ratio (WHR) with serum levels of insulin-like growth factor-I (IGF-I), and its binding protein (IGFBP)-3. DESIGN: Cross-sectional study on 2139 women participating in a case-control study on breast cancer and endogenous hormones. Data on lifestyle and reproductive factors were collected by means of questionnaires. Body height, weight, waist and hip circumferences were measured. Serum levels of IGF-I and insulin-like binding protein (IGFBP)-3 were measured by enzyme-linked immunosorbent assays. Adjusted mean levels of IGF-I and IGFBP-3 across quintiles of BMI, waist circumference, and WHR were calculated by linear regression. Results were adjusted for potential confounders associated with IGF-I and IGFBP-3. RESULTS: Adjusted mean serum IGF-I values were lower in women with BMI<22.5 kg/m(2) or BMI>29.2 kg/m(2) compared to women with BMI within this range (P(heterogeneity)<0.0001, P(trend)=0.35). Insulin-like growth factor-I was not related to WHR after adjustment for BMI. IGF-binding protein-3 was linearly positively related to waist and WHR after mutual adjustment. The molar ratio IGF-I/IGFBP-3 had a non-linear relation with BMI and a linear inverse relationship with WHR (P (trend)=0.005). CONCLUSIONS: Our data confirm the nonlinear relationship of circulating IGF-I to total adiposity in women. Serum IGFBP-3 was positively related to central adiposity. These suggest that bioavailable IGF-I levels could be lower in obese compared to non-obese women and inversely related to central adiposity.     

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.     

Divergent ileal IGF-I and IGFBP-3 gene expression after small bowel resection: a novel mechanism to amplify IGF action?

Changes in the levels of ileal insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) mRNA in the rat following massive small bowel resection (MSBR) have been investigated with a sensitive S1 nuclease assay. IGF-I mRNA levels vary little over 7 days; in contrast IGFBP-3 mRNA levels decreased to one-third 7 h post-MSBR, and remained suppressed for the length of this study. We postulate that decreased ileal synthesis of IGFBP-3 enhances the ability of IGF-I to stimulate the adaptive response.     

Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia

Changes in the hypothalamus-pituitary-adrenal axis (HPAA) function, entailing elevated cortisol circulating titres, occur in aging and in some neurological conditions, such as Alzheimer's disease (AD). Excess cortisol has neurotoxic effects which affect hippocampal neurones. Dehydroepiandrosterone sulphate (DHEAS) has an antiglucocorticoid activity and neuroprotective effects, but its levels decrease with aging. Glucocorticoids influence the production of insulin-like growth factor-I (IGF-I) and modify its systemic and neurotrophic biological activity by inducing changes in IGF-binding proteins (IGFBPs). We looked for relationships between cortisol, DHEAS levels, and IGF-I - IGFBPs system in AD. Cortisol, DHEAS and GH levels at 02:00, 08:00, 14:00, 20:00 h, basal IGF-I, IGFBP-1 and IGFBP-3 levels were determined by RIAs or IRMA in 25 AD patients, aged 58-89 yr, and in 12 age-matched healthy controls. AD subjects had higher cortisol, lower DHEAS levels and increased cortisol/DHEAS ratio (C/Dr) than controls. In AD cases, total IGF-I, IGFBP-3, and IGF-I/IGFBP ratios were significantly lowered, while IGFBP-1 levels were significantly higher than in controls. We found a significant inverse correlation between IGF-I and IGFBP-3 levels vs C/Dr, and between both IGF-I/IGFBPs ratios vs mean cortisol levels. IGFBP-3 correlated directly with DHEAS. Cortisol was directly and IGF-I inversely correlated with cognitive impairment. In AD patients we found that alterations in HPAA function and elevated C/Dr are related to lowered total and free IGF-I levels. These findings and their relationship to cognitive impairment suggest that changes in hormonal set-up might influence the clinical presentation of the disease.     

The insulin-like growth factor system and Type 1 diabetic retinopathy during pregnancy

AIMS/HYPOTHESIS: To find out whether the levels of insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1), highly phosphorylated IGFBP-1 (hpIGFBP-1), and IGF binding protein-3 (IGFBP-3) are related to the progression of diabetic retinopathy (DR) during pregnancy and postpartum. METHODS: In a prospective study of 42 pregnant women with Type 1 diabetes and 9 nondiabetic controls, DR was graded from fundus photographs. Levels of serum total IGF-I and two different phosphoisoform patterns of IGFBP-1 and IGFBP-3 were measured during the first and third trimester of pregnancy and 3 months postpartum. RESULTS: Both the levels of serum total IGF-I (P<.0001) and IGFBP-3 (P=.003) were lower in the diabetic than in the nondiabetic women during pregnancy and postpartum (repeated-measures ANOVA between the groups). Additionally, the IGF-I and IGFBP-3 levels tended to be lower in the diabetic women with more severe DR at baseline than in those with less severe DR. There were no statistically significant differences in the levels of IGF-I and IGFBP-3 in the diabetic women with progression of DR compared with those without. No statistical differences appeared in the IGFBP-1 phosphoisoform patterns between the groups. CONCLUSIONS/INTERPRETATION: In diabetic women, mean serum levels of IGF-1 and IGFBP-3 are lower than in nondiabetic controls during pregnancy and/or postpartum. Because there was no clear connection between the IGF system and progression of DR during pregnancy, it is unlikely that these substances mediate the tendency of DR to progress during pregnancy.     

The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs), and the IGF-binding proteins.

We studied the relationship of serum insulin-like growth factor-I (IGF-I), IGF-II, the IGF-binding proteins IGFBP-1, IGFBP-2, and IGFBP-3, and GH-binding protein (GHBP; which is postulated to be derived from the extracellular portion of the GH receptor) in normal volunteers and patients with anorexia nervosa before and after a refeeding program. Serum GHBP, IGF-I, and IGFBP-3 were all significantly decreased in low weight patients with anorexia nervosa and returned to nearly normal levels with refeeding. Fasting serum GH and serum IGFBP-1 and IGFBP-2 were significantly increased in low weight patients with anorexia nervosa and also returned to nearly normal levels with refeeding. Serum IGF-II was 27% lower in the low weight group than in normal subjects, but this difference was not statistically significant. Both serum IGF-I and IGF-II were positively correlated with serum IGFBP-3 and negatively correlated with serum IGFBP-1 and IGFBP-2. These data are consistent with the hypothesis that nutritional deprivation alters the GH-IGF axis by down-regulation of the GH receptor or its postreceptor mechanisms, and that this effect is reversible with refeeding.     

Total and free insulin-like growth factor I, insulin-like growth factor binding protein 3 and acid-labile subunit reflect clinical activity in acromegaly

The aim was to evaluate, markers of disease activity in acromegaly in relation to perceived disease activity. Thirty-seven consecutively treated, acromegalic patients, classified by clinical symptoms as inactive (n=16), slightly active (n=10) and active (n=11), entered the study. When evaluating the inactive and the active groups, we found that positive and negative predictive values (PV(pos), PV(neg)) for clinical disease activity of total and free insulin-like growth factor-I (IGF-I) were 0.59, 0.90 and 1.00, 0.82 respectively. Acid-labile subunit (ALS) showed diagnostic merit similar to insulin-like growth factor binding protein-3 (IGFBP-3) with PV(pos) of 0.69 and 0.71 and PV(neg) of 0.91 and 0.92 respectively. We conclude that free IGF-I is more closely related than total IGF-I to perceived disease activity and is as such useful when evaluating previously treated acromegaly for disease activity. Total IGF-I, IGFBP-3 and ALS possess a higher PV(neg) for the clinical disease activity. None of the parameters can at present be claimed to be superior to the others and thus all the measured parameters are recommended to be part of the evaluation of acromegalic patients.     

Failure of insulin-like growth factor-I (IGF-I) infusion to promote growth in protein-restricted rats despite normalization of serum IGF-I concentrations

Dietary protein restriction in young rats induces GH resistance characterized by growth arrest and low serum insulin-like growth factor-I (IGF-I) concentrations. To determine whether the low serum IGF-I concentrations are responsible for the stunted growth, we infused 4-week-old protein-restricted rats with recombinant human IGF-I (300 micrograms/day) or rat GH (200 micrograms/100 g body wt/day) by osmotic minipump for 1 week. Despite the normalization of serum IGF-I concentrations by IGF-I infusion, carcass growth was not stimulated. In contrast, growth of the spleen and kidney was enhanced (+45% and +28%, respectively). Serum IGF-binding protein 3 (IGFBP-3), the principal carrier of IGF-I in the serum at this age, is decreased by 34% in protein-restricted animals and restored to normal by IGF-I infusion. Contrary to the selective effects of IGF-I on growth of protein-restricted rats, well nourished hypophysectomized rats infused with 150 micrograms/day recombinant human IGF-I showed a significant growth response, including carcass and organ growth and normalization of IGFBP-3 values. These responses indicate that our IGF-I preparation and mode of delivery were effective. We conclude that: 1) dietary protein restriction causes organ-specific resistance to the growth-promoting properties of exogenous IGF-I; 2) IGF-I mediates the stimulatory effects of growth hormone on IGFBP-3 synthesis; and 3) the absence of carcass growth in the presence of normal serum IGF-I concentrations during infusion of IGF-I suggests that the growth arrest that accompanies protein restriction is mediated in part by resistance to IGF-I.     

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.     

Effects of pure ethanol and alcopops on glucose, insulin, and the insulin-like growth factor system in healthy subjects.

INTRODUCTION: Alcohol induces disturbances in insulin-like growth factor-I (IGF-I) and IGF binding protein-1 (IGFBP-1) levels. The aim of the present study was to compare pure ethanol and alcopop effects on total and free IGF-I, IGFBP-1, IGF-I:IGFBP-1 complex, insulin and plasma glucose levels in healthy subjects. METHODS: Five males and seven females (21-51 years) consumed pure ethanol and alcopops with identical alcohol content in a cross-over design after 6h fasting. Blood samples were obtained for determination of serum ethanol and plasma glucose at 0, 30, 60, 90, 120 and 180 min. Serum total and free IGF-I, IGFBP-1, IGF-I:IGFBP-1 complex, and insulin were measured at 0, 60 and 180 min. RESULTS: Area under the curve for serum ethanol concentration was significantly less following alcopop compared to pure ethanol (1124+/-201 vs. 1691+/-359 mmol/Lh, P<0.01). Serum insulin and glucose levels were unchanged by ethanol while alcopop intake was followed by a transient increase in glucose and insulin levels (P<0.05). Pure ethanol and alcopop reduced free IGF-I levels by the end of the study period (P=0.05). IGFBP-1 and the IGF-I:IGFBP-1 complex increased following ethanol intake (P<0.05) while only a small transient IGFBP-1 increase was observed following alcopop intake. No change in total IGF-I was observed. CONCLUSION: Both drinks resulted in reduced free IGF-I levels, however, only pure ethanol increased IGFBP-1 and the IGF-I:IGFBP-1 complex. Alcopop intake was associated with a transient increase in IGFBP-1 and unchanged IGF-I:IGFBP-1 complex levels probably due to marked changes in insulin and glucose levels.     

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.     

Serum concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in patients with chronic hepatitis

BACKGROUND: Insulin-like growth factor-I is a liver-derived humoral factor, which has important anabolic and metabolic actions and is predominantly bound by insulin-like growth factor binding protein-3. Low serum concentrations of both insulin-like growth factor-I and insulin-like growth factor binding protein-3 have been reported in patients with chronic liver disease, especially cirrhosis, but their conditions in chronic hepatitis are uncertain. The aim of this study was to evaluate the effect of chronic hepatitis on serum concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein-3 and their association with hepatic inflammation activity and fibrosis. METHODS: Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 were measured by RIA (ng/ml) in 17 patients with mild to severe chronic viral hepatitis (12 chronic hepatitis C, 5 chronic hepatitis B) and 16 healthy subjects. The hepatic inflammation activity and the severity of fibrosis were evaluated using Desmet classification. RESULTS: Both insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels did not correlate with inflammation activity, fibrosis or transaminase levels. In the chronic hepatitis group, insulin-like growth factor-I levels were significantly higher than the control group (mean, 263.8 +/- 27.33 versus 127.14 +/- 10.83 ng/ml, P < 0.001, respectively), whereas insulin-like growth factor binding protein-3 levels were significantly lower when compared with the controls (1643.47 +/- 60.68 versus 2728.87 +/- 284.61 ng/ml, P < 0.05, respectively). CONCLUSIONS: These results suggest that the concomitant states of serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels in patients with chronic hepatitis may be different from cirrhotic patients and high serum IGF-I levels may be a specific finding of the stage of chronic hepatitis before developing cirrhosis.     

The effects of ovine placental lactogen and bovine growth hormone on hepatic and mammary gene expression in lactating sheep

The ability of ovine placental lactogen (oPL) to bind to the growth hormone receptor (GHR) raises the possibility that oPL may exert a growth hormone (GH)-like action on galactopoiesis. We have compared the effects of treating lactating ewes for 5 days with an equimolar dose (0.1 mg/kg/day, administered as two equal doses 12 hourly) of either bovine growth hormone (bGH) (n = 10), oPL (n = 10) or saline (n = 9) on hepatic and mammary GHR, insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) gene expression and hepatic GHR number. Hepatic GHR and IGFBP-3 mRNA were unaltered by bGH or oPL treatment. Hepatic IGF-I mRNAs increased following bGH (P < 0.05) but not oPL treatment. GHR gene expression was greater in liver compared to mammary gland extracts. There was no effect of either bGH or oPL treatment on mammary GHR, IGF-I or IGFBP-3 mRNA or hepatic GHR number. These studies confirm the galactopoietic effects of bGH in lactating ruminants and suggest that the mechanism of this action is not via increased hepatic GHR number or gene expression. In addition, the increase in hepatic but not mammary IGF-I mRNA with bGH treatment suggests an endocrine action of IGF-I on milk synthesis. These studies also demonstrate that an equimolar dose of oPL is not galactopoietic or somatogenic in the lactating ewe.