IGF-I And Its Binding Proteins Research Articles

BMI and Contraceptives Affect New Age-, Sex-, and Puberty-adjusted IGF-I and IGFBP-3 Reference Ranges Across Life Span.

Various clinical factors influencing serum levels of insulin-like growth factor I (IGF-I) and its binding protein 3 (IGFBP-3) are not entirely consistently described. We asked whether body mass index (BMI), contraceptive drugs (CDs), and hormone replacement therapy (HRT) have potential effects on data for interpreting new age-, sex-, and puberty-adjusted reference ranges for IGF-I and IGFBP-3 serum levels. Subjects were mainly participants from 2 population-based cohort studies: the LIFE Child study of children and adolescents and the LIFE Adult study. We investigated 9400 serum samples from more than 7000 healthy and 1278 obese subjects between 3 months and 81 years old. Associations between IGF-I or IGFBP-3, measured with a new electrochemiluminescence immunoassay, and the predictors BMI and CDs were estimated using hierarchical linear modeling. During infancy, obese children had up to 1 SD score (SDS) higher mean predicted IGF-I values, converging with levels of normal-weight subjects up to 13 years old. Between 20 and 40 years of age, obesity was related to up to -0.5 lower IGF-I SDS values than the predicted values. Obesity had less impact on IGFBP-3. Estrogen- and progestin-based CDs, but not HRT, decreased IGF-I and increased IGFBP-3 (P < 0.01) in adolescents (β IGF-I = -0.45, β IGFBP-3 = 0.94) and adults (β IGF-I = -0.43, β IGFBP-3 = 1.12). Conversely, progestin-based CDs were significantly positive associated with IGF-I (β IGF-I =0.82). BMI and CDs must be considered when assessing and interpreting the clinical relevance of IGF-I and IGFBP-3 measurements.

Clinical Value of Circulating Lipocalins and Insulin-Like Growth Factor Axis in Pancreatic Cancer Diagnosis

Early diagnosis of pancreatic cancer (PC) in diabetic patients is difficult owing to late presentation of symptoms. Hence, finding a marker to identify cancer stage early would be useful to improve survival. We aimed to determine levels of serum retinol binding protein 4 (RBP-4), neutrophil gelatinase-associated lipocalin (NGAL), insulin-like growth factor I (IGF-I), and its binding protein 3 (IGFBP-3) in patients with PC with preexisting type 2 diabetes. Moreover, we assessed their clinical usefulness in PC diagnosis and their association with tumor severity. Twenty-three patients with PC, 32 diabetic patients, and 20 healthy controls were examined. Preoperative and postoperative samples were obtained from 15 patients with PC. Serum insulin, cancer antigen (CA 19-9), RBP-4, NGAL, IGF-I, and IGFBP-3 levels were estimated by enzyme-linked immunosorbent assay. Significant elevation in the levels of RBP-4 (60.1 [46.3-71.4] ng/mL), NGAL (142 [80-235] ng/mL), and IGF-I (174 [9.3] ng/mL) together with significant reduction in the level of IGFBP-3 (3669 [299] ng/mL) was found in patients with PC. Moreover, RBP-4 and NGAL levels were reduced in postoperative samples compared with preoperative ones. Receiver operating characteristic curve analysis revealed that they can distinguish PC from non-PC cases with significant area under the curve. Retinol binding protein 4, NGAL, IGF-I, and IGFBP-3 are associated with PC in type 2 diabetic patients. They could be useful in distinguishing PC from non-PC cases when used in combination or with cancer antigen.

Effect of obesity and glycemic control on serum lipocalins and insulin-like growth factor axis in type 2 diabetic patients

Obesity, insulin resistance (IR), and progressive decline in pancreatic β-cell function are major features of type 2 diabetes mellitus (T2DM). Altered adipokines contribute to obesity-induced IR. Hence understanding of adipokines' relation to obesity and glycemic control could be useful to improve disease outcomes. We aimed at determination of serum retinol binding protein-4 (RBP-4), lipocalin-2 (LCN-2), insulin-like growth factor-I (IGF-I), and its binding protein-3 (IGFBP-3) levels in T2DM patients with the impact of obesity and glycemic control on them and their relation to β-cell function. Serum insulin, RBP-4, LCN-2, IGF-I, and IGFBP-3 estimated by ELISA were examined in 32 T2DM patients and age- and sex-matched 20 healthy controls. Significant elevation was observed in serum RBP-4 (P<0.001), LCN-2 (P<0.01), and IGF-I/IGFBP-3 molar ratio (P<0.05) in T2DM patients in comparison with healthy controls. There was no significant difference in them between nonobese and obese diabetics. However, RBP-4 and IGF/IGFBP-3 molar ratio were higher in uncontrolled than in controlled diabetic patients at P<0.001 and P<0.01, respectively. Moreover, RBP-4, LCN-2, and IGF-I/IGFBP-3 molar ratio were negatively correlated with β-cell function. In conclusion, serum RBP-4 and IGF-I/IGFBP-3 molar ratio but not LCN-2 were prominently elevated with poor glycemic control rather than obesity in T2DM patients. Whereas, declining β-cell function is associated with elevation of serum RBP-4, LCN-2 as well as IGF-I/IGFBP-3 molar ratio.

Serum insulin‐like growth factor I and its binding protein 3 in their relation to intima–media thickness: results of the study of health in Pomerania (SHIP)

Previous studies detected associations between lower insulin-like growth factor I (IGF-I) levels and increased risk of congestive heart failure or ischaemic heart disease. The aim of the present study was to assess the association of IGF-I and its binding protein 3 (IGFBP-3) with the carotid intima-media thickness (IMT) as marker of asymptomatic cardiovascular disease. From the population-based Study of Health in Pomerania (SHIP), a total of 2286 participants aged 45 years or older with readable ultrasound of the carotid arteries were available for the present analyses. Serum IGF-I and IGFBP-3 levels were categorized into three groups (low, moderate, high) according to the sex-specific 10th and 90th percentile. Analyses of variance (anova) and logistic regression analyses adjusted for age, waist circumference, diabetes, hypertension and creatinine clearance were performed. After adjusting for confounding factors, IGF-I and the IGF-I/IGFBP-3 ratio were positively related to IMT in anova. Logistic regression analyses confirmed these findings and showed that high IGF-I levels, a high IGF-I/IGFBP-3 ratio and low IGFBP-3 levels were associated to higher odds of increased IMT. In conclusion, high IGF-I or high IGF-I/IGFBP-3 ratio values and low IGFBP-3 levels are associated with increased IMT. Therefore, systemic levels of the IGF axis or alterations in the balance of its components are associated with subclinical atherosclerotic disease.

Diagnostic markers in combination improve the identification of growth-restricted neonates

Background The identification of growth-restricted neonates is hampered by the lack of an appropriate diagnostic tool. Aim To determine the value of combining diagnostic markers in detecting growth-restricted neonates. Methods A set of anthropometric indices, nutritional status and placental weight were assessed in the study population soon after birth. Insulin-like growth factor I (IGF-I) and its binding protein 3 (IGFBP-3) were assayed in cord blood. Babies having low values (≤25th centile for gestational age) in 0, 1 or more of four anthropometric indices were classified as Group 250, Group 251 and Group 252, respectively. For statistical evaluation the Mann–Whitney test and a multiple regression analysis were performed. Results One hundred-eighty (180) singleton babies of over 36 weeks of gestational age (GA) were studied. IGF-I, IGFBP-3 levels and placental weight were significantly lower in Group 252 than both Group 250 (P < 0.0001) and Group 251 (p < 0.0001 to p = 0.03). Group 251 and Group 250 did not differ significantly regarding IGF-I and IGFBP-3 levels (p values 0.09 and 0.13, respectively). The combination of anthropometric indices enhanced their ability to predict IGF-I, IGFBP-3 levels and placental weight; the nutritional status of the babies added power to all individual models in predicting the three outcome variables. Analogous results were obtained when the 10th (instead of the 25th) centile for GA was used for the anthropometric indices. Conclusion The combination of simple diagnostic markers of growth restriction can define a reference test with enhanced diagnostic potential compared to the potential of the same markers in isolated use.

Association of circulating IGF-I and IGFBP-3 concentrations and exercise capacity in healthy volunteers: Results of the Study of Health in Pomerania

Background Insulin-like growth factor I (IGF-I) and its binding protein 3 (IGFBP-3) are central mediators of endocrine effects of growth hormone and there is increasing evidence for an association with muscle strength and exercise capacity. The aim of the present study was to clarify the possible association of circulating IGF-I and IGFBP-3 concentrations and exercise capacity in a general adult population. Materials and methods From the Study of Health in Pomerania (SHIP) 1332 subjects aged 25 to 85 years participated in a standardised symptom limited cardiopulmonary exercise test on a bicycle. Exercise capacity was characterized by oxygen uptake at anaerobic threshold (VO 2@AT), peak exercise (peakVO 2), oxygen pulse and maximum power output at peak exertion. Multivariable linear regression analyses adjusted for age, sex, body mass index, physical activity and smoking were performed. Results At peak exercise performance, in women IGF-I showed significant associations to peakVO 2 and maximum power output, IGF-I/IGFBP-3 ratio was associated with maximum power output. In men, this association was not consistently reproducible. Neither IGF-I nor IGFBP-3 did reveal any association to VO 2@AT in both genders. Conclusion Serum IGF-I concentrations are associated with peak exercise capacity in healthy women, but not in men over a wide range in ages, body sizes and activity scores.

The role of insulin‐like growth factor‐I and its binding proteins in glucose homeostasis and type 2 diabetes

This review addresses the possible role of the insulin-like growth factor (IGF)-axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF-I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin-like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre-diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross-sectionally with altered circulating levels of IGF-I and its binding proteins (IGFBPs). Administration of recombinant human IGF-I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF-I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic beta-cell mass and function. There is considerable inter-individual heterogeneity in endogenous levels of IGF-I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association.

Diabetic osteopathy and the IGF system in the Goto–Kakizaki rat

Objective Diabetes mellitus is associated with an increased risk of osteopenia, fracture and Charcot arthropathy. Abnormalities of the IGF system commonly observed in diabetes may underlie this “diabetic osteopathy” as IGF-I and its binding proteins (IGFBPs) have been shown to affect osteoblast and osteoclast activity. Design In type-2 diabetic and control rats we analyzed IGF-I and IGFBP-1 and -4 levels in serum, and notably, also the IGF-I levels in cortical bone, ankles and vertebrae by immunoassays. Osteopathy was assessed by radiography and dual energy X-ray absorptiometry. Results In the diabetic rats IGF-I was significantly reduced in serum and diaphyseal bone while IGFBP-1 and IGFBP-4 were increased in serum. The periosteal and endosteal diameters were increased in the diaphysis of humerus and tibia (changes similar to those in elderly humans) while bone mineral density was reduced in long bone metaphyses and vertebrae. Conclusions Our study demonstrates both systemic and local disturbances of the IGF-system in rats with type-2 diabetes, consistent with the observed enhanced endosteal erosion in long bone diaphyses, and osteopenia in metaphyses and vertebrae. Whether similar IGF-system changes contribute to osteopathy in patients with diabetes and if treatment of diabetes can reverse the osteopathy has yet to be explored.

Energy flux, more so than energy balance, protein intake, or fitness level, influences insulin-like growth factor-I system responses during 7 days of increased physical activity

The purpose of this study was to determine the impact of dietary factors and exercise-associated factors on the response of IGF-I and its binding proteins (IGFBPs) during a period of increased physical activity. Twenty-nine men completed a 4-day (days 1-4) baseline period of a controlled energy balanced diet while maintaining their normal physical activity level followed by 7 days (days 5-11) of a 1,000 kcal/day increase in physical activity above their normal activity levels. Two subject groups, one sedentary (Sed, mean Vo(2peak): 39 mlxkg(-1)xmin(-1), n = 7) and one fit (FIT1, mean Vo(2peak): 56 ml.kg(-1)xmin(-1), n = 8) increased energy intake to maintain energy balance throughout the 7-day intervention. In two other fit subject groups (FIT2, n = 7 and FIT3, n = 7), energy intake remained at baseline resulting in a 1,000 kcal/day exercise-induced energy deficit. Of these, FIT2 received an adequate protein diet (0.9 g/kg), and FIT3 received a high-protein diet (1.8 g/kg). For all four groups, IGF-I, IGFBP-3, and the acid labile subunit (ALS) were significantly decreased by day 11 (27 +/- 4%, 10 +/- 2%, and 19 +/- 4%, respectively) and IGFBP-2 significantly increased by 49 +/- 21% following day 3. IGFBP-1 significantly increased only in the two negative energy balance groups, FIT2 (38 +/- 6%) and FIT3 (46 +/- 8%). Differences in initial fitness level and dietary protein intake did not alter the IGF-I system response to an acute increase in physical activity. Decreases in IGF-I were observed during a moderate increase in physical activity despite maintaining energy balance, suggesting that currently unexplained exercise-associated mechanisms, such as increased energy flux, regulate IGF-I independent of energy deficit.

Insulin-like growth factor-I and mineral metabolism markers in children with idiopathic decrease in bone mass

Objective The aim of the study was to determine whether the serum concentration of insulin-like growth factor-I (IGF-I) and its binding protein-3 (IGFBP-3) correlates with the mineral metabolism markers in children with idiopathic decrease in bone mass. Patients and methods The study comprised 62 patients aged 6–18 years, including 42 with idiopathic decrease in bone mineral density (20 with osteoporosis and 22 with osteopenia) and 20 control children. Osteoporosis and osteopenia were diagnosed on the basis of complex clinical, densitometric and biochemical examinations (in all patients secondary causes of the decreased bone mass were excluded). Serum concentration of IGF-I was determined with radioimmunoassay and IGFBP-3 using immunoradiometry. Results The children with osteoporosis and osteopenia were found to have mean IGF-I concentration statistically significantly lower than the controls (548 and 645 v. 819 ng/ml, respectively; p < 0.05). Moreover, IGF-I correlated positively with total and spinal bone mineral density. In children with osteoporosis there was also a significant relationship between IGF-I and pyridinoline and deoxypyridinoline in urine. Conclusions Lower serum IGF-I concentration together with higher bone resorption and low bone mineral density reveal involvement of this growth factor in the development of idiopathic decrease of bone mass in children.

A Prospective Study of Plasma C-Peptide and Colorectal Cancer Risk in Men

Colorectal cancer and type 2 diabetes share many risk factors, and hyperinsulinemia appears to be associated with an increased risk of colorectal cancer. We used the concentration of plasma C-peptide (an indicator of insulin production) to determine whether insulin and insulin resistance are associated with the risk of developing colorectal cancer. We conducted a nested case-control study in the Physicians' Health Study. Plasma samples were collected from 14 916 cancer-free men from August 1982 through December 1984. Plasma C-peptide concentration, measured with an enzyme-linked immunosorbent assay, was available for 176 case patients who developed incident colorectal cancer through December 31, 1995, and 294 age- and smoking status-matched control subjects. Information on four other insulin resistance-related factors at baseline was obtained. We used conditional logistic regression models to investigate associations. All statistical tests were two-sided. Plasma C-peptide concentration was positively associated with age, body mass index (BMI), and number of insulin resistance-related factors, and it was inversely associated with fasting time before the blood draw, alcohol consumption, and vigorous exercise. An increased concentration of plasma C-peptide was statistically significantly associated with an increased risk of colorectal cancer (relative risk [RR] for the highest versus lowest quintile of plasma C-peptide = 2.7, 95% confidence interval [CI] = 1.2 to 6.2; P(trend) =.047), after adjusting for age, smoking status, fasting, BMI, alcohol consumption, vigorous exercise, and aspirin assignment in the Physicians' Health Study. The association became even stronger when the analysis was further adjusted for factors related to insulin resistance other than insulin levels (RR for the highest versus lowest quintile = 3.4, 95% CI = 1.4 to 8.3; P(trend) =.02) or when data from case patients who were diagnosed during the first 5 years of follow-up were excluded (RR for the highest versus the lowest quintile = 3.4, 95% CI = 1.3 to 8.8; P(trend) =.03). Adjusting for plasma levels of insulin-like growth factor I (IGF-I) and its binding protein 3 (IGFBP-3) did not materially change the results. There was no apparent modification of risk by BMI, insulin resistance-related factors, or vigorous exercise. Elevated insulin production, as reflected by elevated concentrations of plasma C-peptide, may predict the risk of developing colorectal cancer, independently of BMI, factors related to insulin resistance, or levels of IGF-I and IGFBP-3.

Biochemical markers of bone metabolism in infants and children under intravenous corticosteroid therapy.

The short-term effects of corticosteroids (CS) administered intravenously (IV) on biochemical parameters of bone metabolism were followed in infants and children. Forty-nine patients from 2 months to 10 years of age, admitted to Pediatrics Department for bronchiolitis, viral-associated wheezing and croup, were treated with IV hydrocortisone or methylprednisolone (10 or 2 mg/Kg/day, respectively) for 3 days. Blood and fasting urine were collected on admission (day 1), 2 days later (day 3) and 12 days after the end of therapy (day 15). Fifty-one children of similar age and gender without respiratory problems or bone diseases were used as controls. On day 3, suppression of the bone formation markers osteocalcin (OC) (P < 0.001) and total alkaline phosphatase (ALP) (P < 0.05) was observed, but not of the bone resorption markers of hydroxyproline, pyridinoline and calcium excretion (UHyp/UCr, UPYD/UCr and UDPD/UCr, UCa/UCr). Significant decreases were indicated in serum phosphate (Pi) and the maximum renal tubular Pi reabsorption (TmP/GFR) compared to basal (P < 0.001). No significant changes were noticed in the circulating levels of calcium (Ca), parathyroid hormone (iPTH), 25OHD, 24,25(OH)2D, 1,25(OH)2D, the insulin-like growth factor-I (IGF-I) and its binding protein-3 (IGFBP-3). Two weeks after therapy, the increase of OC to higher than basal (P < 0.01) indicated a probable activation of the osteoblasts. Serum Pi and the TmP/GFR index values that had significantly decreased by day 3 returned to pretreatment levels by day 15. When assessing the effects of the CS in relation to age, no changes were detected in the levels of OC and total ALP in the <12-month-old children, but a fall of OC was observed in the >1-year-old group (P < 0.001). In contrast to the OC, the effects on serum and renal tubular reabsorption of phosphate were similar for both groups. In conclusion, short-term IV administered CS led to significant but reversible inhibition of bone formation markers, especially detectable in the >1-year-old children, without affecting the bone resorption ones. The adverse effects on phosphate metabolism were also significant, but temporal and irrespective of age.

EFFECTS OF STRENGTH TRAINING ON BODY COMPOSITION, FASTING INSULIN, AND INSULIN-LIKE GROWTH FACTOR-I

Physically active individuals may have decreased risk for cancers of hormonally related etiology, such as breast and colon. Exercise may decrease incidence of these cancers by lowering total and/or bioavailable serum insulin-like growth factor one (IGF-I). IGF-I and its binding proteins (IGFBPs) have been associated with increased risk for breast and colon cancers. PURPOSE: To investigate exercise-induced changes in: IGF-I and IGF-I/IGFBP-3 (as surrogate for bioavailable IGF-I). We compared changes of these variables in women who were lean (n = 28) to those who were overweight (n = 27) at baseline (DEXA assessed body fat %: lean < 39% < overweight). METHODS: 55 healthy women, 30–50 years old, completed this randomized controlled trial, which involved 15 weeks of supervised progressive strength training (2/week, 27 sets/session, 8 to 10 rep. max.), and 24 additional weeks unsupervised. Subjects refrained from change in diet and other activity regardless of group assignment. Measurements were taken at baseline, 15 and 39 weeks. RESULTS: See table 1. By 15 weeks, the overweight subjects also had significant increases in lean mass, no change in fat mass, and significant decreases of fasting insulin. By 39 weeks, levels of IGF-I and IGF-I/IGFBP-3 rose to match controls in overweight subjects, despite further improvements in lean mass and fasting insulin as well as significant fat mass losses. In lean subjects, IGF-I and IGF-I/IGFBP-3 returned to baseline levels by 39 weeks.Table 1: Change at 15 weeks, *p < 0.03 compared to control groupCONCLUSION: 15 weeks of supervised strength training produced significant improvements IGF-I and IGF-I/IGFBP-3 in overweight women, concurrent with improvements in lean mass and fasting insulin. The IGF-I changes were not maintained an additional 24 weeks. Supported by: MNOC, NIH grant 1 P30-DK50456 and UMN GCRC, NIH grant # M01-RR00400

Effects of two oral contraceptives on plasma levels of insulin-like growth factor I (IGF-I) and growth hormone (hGH)

In 18 healthy women, the effect of two oral contraceptives (OCs) on insulin-like growth factor (IGF-I) and its binding protein-3 (IGFBP-3) and growth hormone (hGH) plasma level were studied before and after intake of either of two OC formulations over 21 days, one containing 2 mg dienogest and 0.03 mg ethinylestradiol (group A) and the other 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol (group B). There was a reduction of the mean IGF-I concentration of 30% (p = 0.008) in the women receiving dienogest-containing pills and 12% (p = 0.006) in women taking the levonogestrel-containing preparation. This difference between drug groups was statistically significant (p = 0.002). A correlation between the control values and the basal-treatment difference (r = 0.945; p = 0.000) was observed only in women of group A. Between basal and treatment cycles the mean plasma levels of hGH remained unchanged in both groups tested, but the 23.5-h integrated mean hGH plasma concentrations (AUC 0–23.5h) were significantly elevated by 36% (p = 0.016) in comparison to basal values before treatment only in women receiving the levonorgestrel-containing pills. Also, in the women who received the dienogest-containing preparation, the changes of integrated mean plasma level were inversely associated with the control values (r = −0.723; p = 0.025). Neither in group A nor in group B was the mean plasma level of IGFB-3 changed. In conclusion: the results of the present analysis indicate that hormonal contraceptives can modulate the GH and IGF-I-axis in the reproductive age. Probably the androgenic progestogen levonorgestrel (0.125 mg/day) opposes the estrogen-induced action. In the women who took the dienogest-containing formulations (anti-androgenic progestogen—group A), the extent of individual changes (hGh and IGF-I) depends on the basal level prior to pill intake. Further studies, especially of long-term intake of OCs, are necessary to confirm these results and to assess the practical relevance for possible effects on connective tissue and bone.

Serum Insulin-like Growth Factors IGF-I and IGFBP-3 in Children With Slipped Capital Femoral Epiphysis

Hormonal imbalance in puberty and biomechanical overload due to obesity have been implied in the still unknown cause of slipped capital femoral epiphysis (SCFE). Local mediators of growth hormone (GH) action, such as insulin-like growth factor I (IGF-I), play a crucial role in the development of the growth plate cartilage. Concentrations of IGF-I and its binding protein 3 (IGFBP-3) were measured in the serum of 19 SCFE children without endocrine disorders. Standing height and body weight were determined. The results were related to the bone age. Concentrations for IGF-I and IGFBP-3 were predominantly within the normal ranges for chronologic age and bone age. The correlation of IGF-I and IGFBP-3 serum levels was high. Standing height and body weight showed a tendency toward the higher percentile ranges. Ten of 19 patients were above the 97th percentile concerning their weight for height. Bone age did not differ significantly from chronologic age. Serum concentrations of IGF-I and IGFBP-3 provided no evidence of a disturbance of the somatotropic axis in SCFE children. Increased body weight associated with normal skeletal maturation implies a mechanical stress factor in the cause of SCFE in these children.

Serum Insulin-like Growth Factors IGF-I and IGFBP-3 in Children With Slipped Capital Femoral Epiphysis

Hormonal imbalance in puberty and biomechanical overload due to obesity have been implied in the still unknown cause of slipped capital femoral epiphysis (SCFE). Local mediators of growth hormone (GH) action, such as insulinlike growth factor I (IGF-I), play a crucial role in the development of the growth plate cartilage. Concentrations of IGF-I and its binding protein 3 (IGFBP-3) were measured in the serum of 19 SCFE children without endocrine disorders. Standing height and body weight were determined. The results were related to the bone age. Concentrations for IGF-I and IGFBP-3 were predominantly within the normal ranges for chronologic age and bone age. The correlation of IGF-I and IGFBP-3 serum levels was high. Standing height and body weight showed a tendency toward the higher percentile ranges. Ten of 19 patients were above the 97th percentile concerning their weight for height. Bone age did not differ significantly from chronologic age. Serum concentrations of IGF-I and IGFBP-3 provided no evidence of a disturbance of the somatotropic axis in SCFE children. Increased body weight associated with normal skeletal maturation implies a mechanical stress factor in the cause of SCFE in these children.

Plasma growth hormone-binding protein activity, insulin-like growth factor I, and its binding protein levels in patients with Turner's syndrome: effect of short- and long-term recombinant human growth hormone administration.

Plasma growth hormone-binding protein (GH-BP) activity and the levels of IGF-I and its binding proteins (IGFBP) were studied in eight girls with Turner's syndrome before and during recombinant-hGH (r-hGH) administration. Growth hormone and GH-BP activity were assayed at baseline and hourly, over a 12-h period, after an intramuscular bolus of 0.09 mg/kg of the hormone. After 7 d, each patient received r-hGH at 0.33 mg/kg/weekly s.c. every day at nighttime; plasma growth hormone-binding protein activity, blood IGF-I, and IGFBP were evaluated before and on d 7, 30, 180, and 360. Baseline reference values were obtained from 10 bone age-matched healthy girls. Basal GH-BP activity, IGF-I, and IGFBP levels were similar in patients and controls. Four h after the intramuscular injection, GH-BP activity maximally increased and returned to baseline 6-7 h later; during long-term r-hGH administration GH-BP activity peaked at +180 d but declined to pretreatment at +360 d. IGF-I, IGFBP-3, and IGFBP-4 increased under r-hGH and, in contrast to GH-BP activity, remained high throughout the study. In conclusion, in girls with Turner's syndrome, GH-BP activity, IGF-I, IGFBP-3, and IGFBP-4 are induced by r-hGH. However, the increase of IGF-I and IGFBP-3 does not require an increased level of the cellular growth hormone receptors, as suggested by the unchanged +360 d values of plasma GH-BP activity compared with baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

ACTH and angiotensin II regulation of insulin-like growth factor-I and its binding proteins in cultured bovine adrenal cells

Insulin-like growth factor-I (IGF-I) is required for the maintenance of differentiated functions of bovine adrenal fasciculata cells in culture. We have investigated, by immunocytochemistry, the presence of IGF-I in cells cultured in the absence or presence of ACTH and angiotensin II (AII), as well as the secretion of IGF-I and its binding proteins (IGFBPs). In control cultures, very few cells were specifically stained with the anti-IGF-I serum. Following 2 days of treatment with AII (1 microM) or ACTH (10 nM) the number of stained cells increased by 5- and 14-fold respectively. In all cases the staining was specific, since it was abolished when non-immune rabbit serum replaced the anti-IGF serum or when the anti-IGF-I serum was preincubated with saturating concentrations of the peptide. Under the same experimental conditions the secretion of IGF-I into the medium, evaluated by a specific radioimmunoassay, was increased two- and sevenfold by AII and ACTH respectively. Using the method of Western ligand blotting, the major form of IGFBP secreted by control adrenal cells was found to be a 38-42 kDa doublet protein. Two minor forms with apparent molecular weights of 28-31 kDa and 24 kDa have also been identified. Following acid-ethanol extraction of the conditioned medium, all the IGFBPs were recovered in the pellet, whereas most of the IGF-I was in the supernatant. ACTH and, to a lesser extent, AII pretreatment increased the 38-42 kDa IGFBP by several fold, decreased the 28-31 kDa IGFBP and had no effect on the 24 kDa IGFBP. In conclusion, these results demonstrate (i) that bovine adrenal cells contain IGF-I-like immunoreactive material, (ii) that the stimulatory effects of ACTH and AII on IGF-I secretion by bovine adrenal cells are due mainly to an increase in the number of IGF-I-producing cells and (iii) that ACTH and AII modulate the secretion of IGFBP by adrenal cells. Although the roles of IGFBPs have not been defined in adrenal cells, they are capable of modulating the biological action of IGFs in other cell cultures. Regulation of both IGF-I and its binding proteins by the two specific hormones ACTH and AII suggests important roles for these binding proteins in modulating the action of IGF-I in bovine adrenal cell function.