IGF-I and IGFBP-3 polymorphisms and risk of prostate cancer

BACKGROUND: Insulin-like growth factor-I (IGF-I) is a potent mitogen for both normal and malignant prostate epithelial cells. The majority of circulating IGF-I is bound in a complex with IGF binding protein-3 (IGFBP-3), which in turn limits IGF-I bioavailability. Multiple studies suggest that higher IGF-I and/or lower IGFBP-3 serum levels are positively associated with prostate cancer risk. Several polymorphisms within the IGF-I and IGFBP-3 coding regions have been associated with increased serum protein levels. METHODS: To ascertain the potential relationship between serum levels and polymorphism, and prostate cancer risk, we investigated the role of two polymorphisms the IGF-I cytosine-adenosine (CA)-repeat and the IGFBP-3 Ala32Gly, and prostate cancer in a population-based, case-control, study of middle-aged men. RESULTS: We found no significant association between the IGFBP-3 Ala32Gly polymorphism and prostate cancer risk, even though the presence of at least one Gly allele did correlate with increased serum levels of IGFBP-3. For IGF-I, more controls (42%) than cases (38%) were homozygous for 19-CA-repeats (odds ratio, OR = 0.85; 95% confidence interval (CI) = 0.66-1.09). After stratifying by disease characteristics, 19-CA-repeat homozygous men displayed a decreased risk of low-grade disease (OR = 0.50; 95% CI = 0.27-0.93), but no associations were observed with more aggressive features of disease. Additionally, there was no correlation between mean serum IGF-I protein levels and IGF-I genotype in controls. CONCLUSIONS: Further evaluation of the IGF-I CA-repeat polymorphism and prostate cancer is necessary to determine if the modest risk reduction associated with the 19-CA-repeat homozygous state is observed in other study populations.     

Association of IGF-1 and IGFBP-3 with lower urinary tract symptoms in the third national health and nutrition examination survey

BACKGROUND: Benign growth of the prostate is thought to contribute to lower urinary tract symptoms (LUTS) in older men. It is, however, unclear which factors induce prostate growth in these men. We examined the association of insulin-like growth factor (IGF)-1 and its major binding protein IGFBP-3 with LUTS in a representative US study. METHODS: We included men 60 years and older who participated in the morning session of the Third National Health and Examination Survey (NHANES III) between 1988 and 1994. Men were classified as cases (n = 91) if they reported at least three of four LUTS (nocturia, incomplete emptying, hesitancy, or weak stream) but had not had non-cancer prostate surgery in the past. Controls were men without symptoms and surgery (n = 220). All results were weighted to account for sampling probability in NHANES III. IGF-1 and IGFBP-3 were measured by ELISA and IRMA, respectively. RESULTS: After mutual adjustment, men in the highest tertile of serum IGF-1 concentration had a non-significantly higher odds of LUTS than men in the lowest tertile (odds ratio (OR) = 3.20; 95% confidence interval (CI) 0.89-11.4; p-trend = 0.09]. A high concentration of IGFBP-3 was inversely related to the odds of LUTS (OR = 0.25; 95% CI 0.08-0.81; p-trend = 0.02). CONCLUSION: A high IGFBP-3 level might affect LUTS by decreasing the bioavailability of IGF-1 or independent of IGF-1 by up-regulating apoptosis, and, thus, limiting its growth promoting effects on the prostate.     

The insulin-like growth factor system in the prostate

Summary The insulin-like growth factor (IGF) system is involved in the regulation of cell growth. The system involves a network of molecules that includes the IGFs themselves (IGF-I and -II), IGF receptors (types I and II), IGF-binding proteins (IGFBP-1 through -6), and IGFBP proteases. Characterization of this complex system in the prostate has recently been initiated. Prostatic cell lines as well as primary cultures of prostatic epithelial and stromal cells have been analyzed for expression of IGFs, receptors, and IGFBPs. Prostatic epithelial cells and, quite likely, stromal cells as well respond to the mitogenic activity of IGFs via the type I IGF receptor. Prostatic stromal cells synthesize and secrete IGF-II; there is evidence that prostatic cell lines also synthesize IGFs, but this has not been confirmed in primary cultures of prostatic epithelial cells. Prostatic stromal and epithelial cells secrete a number of IGFBPs. The biological impact of some of these IGFBPs on the growth of prostatic cells has been examined, and proteolytic cleavage of IGFBP-3 by prostate-specific antigen (PSA) has been demonstrated. Aberrations in several elements of the IGF system have been observed in stromal cells derived from benign prostatic hyperplasia (BPH). The IGF system may therefore have a part in the etiology of BPH as well as in normal and malignant processes in the prostate.     

Insulin-like growth factor axis and risk of type 2 diabetes in women

IGF-I shares structural homology and in vitro metabolic activity with insulin. Laboratory models suggest that IGF-I and its binding proteins IGFBP-1 and IGFBP-2 have potentially beneficial effects on diabetes risk, whereas IGFBP-3 may have adverse effects. We therefore conducted a prospective nested case-control investigation of incident diabetes (n = 742 case subjects matched 1:1 to control subjects) and its associations with IGF-axis protein levels in the Nurses' Health Study, a cohort of middle-aged women. The median time to diabetes was 9 years. Statistical analyses were adjusted for multiple risk factors, including insulin and C-reactive protein. Diabetes risk was fivefold lower among women with baseline IGFBP-2 levels in the top versus bottom quintile (odds ratio [OR](q5-q1) = 0.17 [95% CI 0.08-0.35]; P trend < 0.0001) and was also negatively associated with IGFBP-1 levels (OR(q5-q1) = 0.37 [0.18-0.73]; P trend = 0.0009). IGFBP-3 was positively associated with diabetes (OR(q5-q1) = 2.05 [1.20-3.51]; P trend = 0.002). Diabetes was not associated with total IGF-I levels, but free IGF-I and diabetes had a significant association that varied (P interaction = 0.003) by insulin levels above the median (OR(q5-q1) = 0.48 [0.26-0.90]; P trend = 0.0001) versus below the median (OR(q5-q1) = 2.52 [1.05-6.06]; P trend < 0.05). Thus, this prospective study found strong associations of incident diabetes with baseline levels of three IGFBPs and free IGF-I, consistent with hypotheses that the IGF axis might influence diabetes risk.     

Circulating insulin-like growth factor-I and benign prostatic hyperplasia--a prospective study.

OBJECTIVE: The aim of this study was to investigate the role of insulin-like growth factor-I (IGF-I), a strongly mitogenic and anti-apoptotic factor, in the development of benign prostatic hyperplasia (BPH). The bioactivity of IGF-I within tissues depends on circulating levels, as well as on the local production of IGF-I and the presence of IGF-binding proteins (IGFBPs). The IGFBPs regulate the efflux of IGF-I to the extravascular space and the bioavailability of IGF-I within tissues. MATERIAL AND METHODS: Within the Northern Sweden Health and Disease Study, 60 cases of BPH defined by a history of prostate resection were identified, and two controls per case were selected. IGF-I, IGFBP-1, IGFBP-3 and insulin were measured by immuno-radiometric assays in stored plasma samples drawn a mean of 3.2 years before surgery. RESULTS: The risk of BPH increased with increasing quartile levels of IGF-I adjusted for IGFBP-3 (p(trend) = 0.10) up to a relative risk of 2.16 (95% confidence interval 0.83-5.64) for the highest quartile. The risk decreased with increasing levels of IGFBP-1 (p(trend) = 0.10). CONCLUSIONS: Our results suggest that elevated IGF-I bioactivity may stimulate the development of BPH; however, they were not statistically significant and require confirmation from larger studies.     

Serum insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in localized, metastasized prostate cancer and benign prostatic hyperplasia

OBJECTIVE: Insulin-like growth factors (IGF-I and IGF-II) are important mitogenic peptides and are thought to be significant factors involved in normal and malignant cellular proliferation including benign prostatic hyperplasia (BPH) and prostate cancer (PC). In particular, the association between IGF-I and PC has received much attention. Insulin-like growth factor binding protein-3 (IGFBP-3) is the major carrier protein in serum for the IGF-I, thus is an important functional modulator of it. On the other hand, one of the functions of prostate-specific antigen (PSA) is to cleave IGFBP-3. Epidemiological studies have shown that decreased levels of serum IGFBP-3 are associated with increased PC risk. Controversial results have also been reported on the value of serum IGF-I and/or IGFBP-3 in the detection of PC, especially of metastatic PC; as increased, decreased or unchanged when compared to BPH. The aim of the present study was to investigate whether serum IGF-I and IGFBP-3 levels change in localized and metastasized PC cases compared with BPH as the control cases. METHOD: The study included 45 BPH, 24 localized PC and 19 metastasized PC cases. Serum IGF-I and IGFBP-3 levels were measured by two-site immunoradiometric assay kits, and serum total and free PSA levels were assayed by chemiluminescence method. RESULTS: Serum IGF-I levels in both localized and metastasized PC cases were similar to BPH cases (138.3 +/- 58.2, 137.7 +/- 39.0 and 147.7 +/- 44.2 ng/ml, respectively), whereas serum IGFBP-3 levels were lower in metastasized PC group than in BPH group (1,795.6 +/- 305.6 and 2,196.0 +/- 505.7 ng/ml; p = 0.005). In localized PC, serum IGFBP-3 levels (1,911.00 +/- 349.58 ng/ml) were similar to metastasized PC. There were significant correlations between serum IGFBP-3 and serum free PSA in three groups (r = -0.46, p = 0.02 for localized PC; r = -0.56, p = 0.01 for metastasized PC, and r = -0.31, p = 0.03 for BPH). CONCLUSION: These data reveal that serum IGF-I levels may not change either in localized or metastasized PC, and that decreased serum IGFBP-3 levels may be attributed to its proteolysis by PSA which is increased in PC.     

SERUM LEVELS OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-3 IN BENIGN AND MALIGNANT BREAST DISEASE

Background : The insulin-like growth factors IGF-I and IGF-II and their major binding protein IGFBP-3 influence the growth of breast cancer cells in vitro. Some benign non-breast tumours appear to be associated with increased serum IGFBP-3 levels which would tend to reduce bioactive-free IGF concentrations. The present study investigates whether this pattern also occurs in neoplastic breast disease. Methods : Serum IGF-I, IGF-II and IGFBP-3 were measured by specific radioassay in 12 women with benign breast disease, 31 patients with breast cancer and in age-matched controls. Results : The mean (± SD) serum IGFBP-3 concentration was higher in benign breast disease (3.6 ± 0.7 mg/L) than in controls (2.7 ± 0.6 mg/L) or in breast cancer patients (2.7 ± 0.5 mg/L) (P = 0.001). Serum IGF-I and IGF-II levels were not significantly different among the groups. However, the index of free unbound IGF measured as the molar ratio of IGF-I plus IGF-II divided by IGFBP-3 was significantly lower in benign breast disease than in the other subjects. Conclusions : Either the production or clearance of IGFBP-3 is altered in benign breast disease so that there is less free IGF available to cells. This may serve to protect against malignant transformation in patients with benign breast disorders.     

Serum levels of insulin-like growth factor binding protein-3 in benign and malignant breast disease.

BACKGROUND: The insulin-like growth factors IGF-I and IGF-II and their major binding protein IGFBP-3 influence the growth of breast cancer cells in vitro. Some benign non-breast tumours appear to be associated with increased serum IGFBP-3 levels which would tend to reduce bioactive-free IGF concentrations. The present study investigates whether this pattern also occurs in neoplastic breast disease. METHODS: Serum IGF-I, IGF-II and IGFBP-3 were measured by specific radioassay in 12 women with benign breast disease, 31 patients with breast cancer and in age-matched controls. RESULTS: The mean (+/-SD) serum IGFBP-3 concentration was higher in benign breast disease (3.6+/-0.7 mg/L) than in controls (2.7+/-0.6 mg/L) or in breast cancer patients (2.7+/-0.5 mg/L) (P = 0.001). Serum IGF-I and IGF-II levels were not significantly different among the groups. However, the index of free unbound IGF measured as the molar ratio of IGF-I plus IGF-II divided by IGFBP-3 was significantly lower in benign breast disease than in the other subjects. CONCLUSIONS: Either the production or clearance of IGFBP-3 is altered in benign breast disease so that there is less free IGF available to cells. This may serve to protect against malignant transformation in patients with benign breast disorders.     

Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyperplasia and prostate cancer

The prostate gland is an androgen-dependent, and polymorphisms in androgen synthesis gene steroid 5-alpha reductase type II (SRD5A2) may be associated with benign prostatic hyperplasia (BPH) and prostate cancer. We evaluated the association between 3 polymorphisms in the SRD5A2 gene (2 single nucleotide polymorphism: alanine-49 to threonine [A49T] and valine-89 to leucine [V89L], and a (TA)n dinucleotide repeat in the 3' untranslated region), and BPH and prostate cancer within a multiethnic population. Men between 60 and 86 years of age were recruited from annual prostate cancer screening programs and from a large urology clinic. Unconditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (95% CI). We genotyped 606 men (412 Hispanic, 98 Caucasian, 73 African-American, and 23 Asian), of whom 100 had prostate cancer, 393 had BPH (280 symptomatic and 113 asymptomatic), and 113 had normal prostates. Overall, the V89L variant was associated with prostate cancer; the OR for men with the leucine-leucine (LL) genotype compared to men with the valine-valine (VV) genotype was 4.47 (95% CI, 1.24-16.18). This association was stronger in Hispanics (OR=7.26; 95% CI: 1.49-35.47). Although V89L was nonsignificantly associated with BPH in overall population, BPH risk increased significantly with the number of L alleles in Hispanics (P for trend=0.03). Prostate cancer and BPH were not associated with the alanine-49 to threonine single nucleotide polymorphism and the (TA)n repeat. These results suggest that the SRD5A2 gene may play an important role in both BPH and prostate cancer.     

A potentially deleterious role of IGFBP-2 on bone density in aging men and women.

The role of the IGFs and IGFBPs on age-related changes in BMD in adult men and women is not well understood. Studying an age-stratified community based sample of 344 men and 276 women, we found higher IGFBP-2 levels to be associated with lower BMD. IGFBP-2, which increases with age in both men and women, was the strongest, most consistent predictor of BMD among the IGF/IGFBPs studied. INTRODUCTION: Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are important regulators of tissue growth and metabolism, but their association with BMD in adult men and women is controversial. MATERIALS AND METHODS: In an age-stratified, random sample of the community population, we examined the role of serum levels of IGF-I, IGF-II, and IGFBP-1, -2, and -3 on BMD of the proximal femur (total hip), lateral spine, midshaft, and ultradistal radius as measured by DXA. We explored the association before and after adjustment for potential confounders, including age, bioavailable estradiol and testosterone, sex hormone binding globulin (SHBG), and measures of total fat and skeletal muscle mass. RESULTS: We studied 344 men (age, 23-90 years) and 276 women (age, 21-93 years; 166 postmenopausal) not on hormone replacement or oral contraceptives. In both men and women, IGF-I and IGFBP-3 levels fell with advancing age, whereas IGFBP-2 levels tended to rise with age. There was an inverse association of IGFBP-2 with BMD at most skeletal sites in men and both premenopausal and postmenopausal women, whereas lower IGF-I and IGFBP-3 were associated with lower BMD in men and postmenopausal women only. Lower IGF-II was associated with lower BMD in men only. There were no associations between IGFBP-1 and BMD in either sex. After adjustment for age, in most cases, we found no further associations between IGF-I, IGF-II, or IGFBP-3 and BMD. In contrast, after age adjustment, higher IGFBP-2 remained a predictor of lower BMD in men and postmenopausal women at all sites except for the lateral spine (for men: r = -0.21, -0.20, and -0.19, all p < 0.001; and for postmenopausal women: r = -0.34, -0.24, and -0.25, all p < 0.01, for the total hip, midshaft, and ultradistal radius, respectively). IGFBP-2 remained an independent negative predictor of BMD in men, postmenopausal women, and all women combined after additional adjustment for bioavailable sex steroids, but not at all sites after adjustment for SHBG and muscle mass. In premenopausal women, IGFBP-2 had similar associations as seen in postmenopausal women, but they were weaker and not statistically robust. CONCLUSIONS: Among the IGF/IGFBPs in our study, IGFBP-2 was a key negative predictor of BMD among men and women, particularly postmenopausal women. Our findings suggest a potential role of the IGF/IGFBP system in regulating bone loss in aging men and women and identify a previously under-recognized, potentially deleterious role for IGFBP-2, a known inhibitor of IGF action that increases with age in both sexes. Whether the action of the IGF/IGFBP system on bone metabolism is mediated partly through its effects on muscle mass or SHBG deserves further study.     

The association between benign prostatic hyperplasia and chronic kidney disease in community-dwelling men

BACKGROUND: Benign prostatic hyperplasia (BPH) and chronic kidney disease are important public health problems in older men. Previous referral-based studies disagree on whether BPH is associated with chronic kidney disease. The objective of this study was to determine the community-based association between clinical measures of BPH and chronic kidney disease. METHODS: A community-based sample of 2115 white men (ages 40-79 years) was randomly selected from the Olmsted County, Minnesota population (55% participation rate) in 1990. A random subsample (N= 476) had a detailed clinical evaluation. This evaluation included a questionnaire with similar queries to the International Prostate Symptom Score (IPSS), peak urinary flow rates (uroflowmeter), postvoid residual urine volume (ultrasound), prostate volume (ultrasound), serum prostate specific antigen (PSA), and serum creatinine. RESULTS: After adjustment for age, hypertension, diabetes, leukocyte esterase positive (possible urinary tract infection), and smoking, chronic kidney disease [serum creatinine > or =133 micromol/L (1.5 mg/dL)] was associated with diminished peak urinary flow rate (<15 mL/sec) by an odds ratio (OR) = 2.96 (95% CI 1.30-7.01), moderate-severe lower urinary tract symptoms (IPSS >7) by an OR = 2.91 (95% CI 1.32-6.62), and chronic urinary retention (postvoid residual >100 mL) by an OR = 2.28 (95% CI 0.66-6.68). There was no association with a prostate volume >30 mL by an OR = 0.56 (95% CI 0.22-1.37) or PSA >1.4 ng/mL by an OR = 1.17 (95% CI 0.47-2.81). CONCLUSION: There was a cross-sectional association between signs and symptoms of bladder outlet obstruction and chronic kidney disease in community-dwelling men. Prostatic enlargement was not associated with chronic kidney disease.     

Polymorphisms in genes involved in sex hormone metabolism may increase risk of benign prostatic hyperplasia

BACKGROUND: This study investigates associations between polymorphisms in genes involved in sex hormone metabolism and measures of benign prostatic hyperplasia (BPH). METHODS: Community-dwelling Caucasian men (n=510, median age 60 years in 2000) from the Olmsted County, MN, participated in a longitudinal study of BPH. From 1990 through 2000, urologic measures of BPH were assessed biennially from lower urinary tract symptom severity, peak flow rates, prostate volume, serum prostate specific antigen (PSA) level, acute urinary retention, and treatment for BPH. Men were genotyped for polymorphisms in genes involved in sex hormone metabolism. RESULTS: With the wildtype genotype as reference, men with HSD3B1 (c.1100 A/C) heterozygous genotype (hazard ratio (HR)=0.7, 95% confidence intervals (CI)=0.6, 0.9) were at decreased risk of an enlarged prostate and men with CYP19 (TTTA)(n) genotype homozygous for >or=175 TTTA repeats (HR=1.5, 95% CI=1.1, 2.1), and CYP19 (c.1531 C/T) homozygous T variant (HR=1.6, 95% CI=1.1, 2.2) were at increased risk of an enlarged prostate. The homozygous A variant of the PSA gene (g.-252 G/A), was associated with treatment for BPH (HR=2.3, 95% CI=1.2, 4.4). In multivariate analyses, the homozygous variant genotypes of AKR1C3 (c.15 G/A and c.90 G/A) were associated with a decreased risk of an enlarged prostate (HR=0.56, 95% CI=0.35, 0.90 and HR=0.57, 95% CI=0.33, 0.98). CONCLUSIONS: Polymorphisms in HSD3B1, CYP19, AKR1C3 genes may be associated with an enlarged prostate in older men. These data provide insights into genes that should be examined further for their potential role in the pathogenesis of BPH.     

Insulin-like growth factors and their binding proteins in prostate cancer: Cause or consequence?☆

Insulin-like growth factors (IGFs) promote growth and survival of many types of tumor cells. Epidemiologic studies have implicated carcinogenesis with high levels of IGFs in circulation or in tissues. The levels of IGF binding proteins (IGFBPs) have been associated with reduced risk for prostate and other cancers. Experimental studies have implicated high levels of IGF-I directly and IGFBP-3 inversely in prostate cancer growth, survival, and progression. However, recent evidence suggests a much weaker association of IGF-I with prostate cancer development and a stronger antagonistic association of IGFBP-3 with prostate cancer progression. Considering the clonal heterogeneity and unpredictable progression pattern of prostate cancer, the role of any single growth factor or its regulator (IGFBP) as a single determining factor is limited. This review is a critical appraisal of the role of IGFs, IGFBP, and IGF-I receptor (the IGF axis) in both experimental and clinical prostate cancer genesis and progression.     

Bone Mineral Density in Femoral Neck is Positively Correlated to Circulating Insulin-Like Growth Factor (IGF)-I and IGF-Binding Protein (IGFBP)-3 in Swedish Men

Studies on the hormonal regulation of bone metabolism in men have indicated covariation between insulin-like growth factor-I (IGF-I) and sex hormones with bone mineral density (BMD). In this study the relationships between BMD in total body, lumbar spine, femoral neck, distal and ultradistal (UD) radius and circulating levels of IGFs, IGF binding proteins (IGFBPs), and sex steroids were investigated in 55 Swedish men between 22 and 85 (52 +/- 18, mean +/- SD) years of age. BMD in total body, distal and UD radius, and femoral neck was positively correlated with serum IGF-I (r = 0.31 to 0.49), IGF-II (r = 0.32 to 0.48), IGFBP-3 (r = 0.37 to 0.53), and free androgen index (FAI) (r = 0.32 to 0.40), and negatively with IGFBP-1 (r = -0.37 to -0.41) and IGFBP-2 (r = -0.29 to -0.41) levels. A positive correlation was observed between BMD in femoral neck and estradiol/SHBG ratio (r = 0.34, P = 0.01). Age correlated negatively with serum IGF-I, IGF-II, IGFBP-3, FAI, estradiol/SHBG ratio, and BMD in total body, distal and UD radius, and femoral neck, and positively with IGFBP-1, IGFBP-2, and SHBG levels. According to stepwise multiple regression analyses, a combination of weight, IGFBP-3, and testosterone accounted for 43% of the variation in BMD in femoral neck, 34% in ultradistal radius and 48% in total body (P < 0.0001). These findings indicate that sex hormones and the different components of the IGF system are associated with BMD in Swedish men, suggesting that age-related changes in these systems could contribute to the development of osteoporosis in elderly men.     

Insulin-like growth factor (IgF)-I,IgF binding protein-3, and prostate cancer: correlation with gleason score

Introduction

Non-androgenic growth factors are involved in the growth regulation of prostate cancer (PCa).

Objective

This is the first Brazilian study to correlate, in a population of patients operated for PCa, PSA, total testosterone, insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) with Gleason score and to compare with a control group with benign prostate hyperplasia (BPH).

Materials and Methods

This retrospective single-center study included 49 men with previously diagnosed PCa and 45 with previously diagnosed BPH. PSA, testosterone, IGF-I, IGFBP-3 were determined in both groups.

Results

PSA and IGFBP-3 levels were significantly higher in the PCa group as compared to the BPH group (p<0.001 and p=0.004, respectively). There was a significant difference when we compared the PSA before surgery (p<0.001) and at the inclusion in the study (p<0.001) and IGFBP3 (0.016) among patients with Gleason <7, ≥7 and BPH. In the PCa group, PSA, testosterone, IGF-I and IGFBP-3 levels were comparable between Gleason <7 and ≥7.

Conclusions

Our data suggest that in localized PCa, the quantification of PSA and, not of IGF-1, may provide independent significant information in the aggressiveness. IGFBP-3 could be a biochemical marker of disease control in PCa patients.     

Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy

BACKGROUND: The insulin-like growth factor (IGF) system plays a key role in regulation of bone formation. In patients with renal osteodystrophy, an elevation of some IGF binding proteins (IGFBPs) has been described, but there is no study measuring serum levels of both IGF-I and IGF-II as well as IGFBP-1 to -6 in different forms of renal osteodystrophy and hyperparathyroidism. METHODS: In a cross-sectional study, we investigated 319 patients with mild (N = 29), moderate (N = 48), preuremic (N = 37), and end-stage renal failure (ESRF; N = 205). The ESRF group was treated by hemodialysis (HD; N = 148), peritoneal dialysis (PD; N = 27), or renal transplantation (RTX; N = 30). As controls without renal failure, we recruited age-matched healthy subjects (N = 87) and patients with primary hyperparathyroidism (pHPT; N = 25). Serum levels of total and free IGF-I, IGF-II, IGFBP-1 to -6, and biochemical bone markers including intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), and osteocalcin (OSC) were measured by specific immunometric assays. IGF system components and bone markers were correlated with clinical and bone histologic findings. Mean values +/- SEM are given. RESULTS: With declining renal function a significant increase was measured for IGFBP-1 (range 7- to 14-fold), IGFBP-2 (3- to 8-fold), IGFBP-3 (1.5- to 3-fold), IGFBP-4 (3- to 19-fold), and IGFBP-6 (8- to 25-fold), whereas IGFBP-5 levels tended to decrease (1.3- to 1. 6-fold). In contrast, serum levels of IGF-I, free IGF-I, and IGF-II remained constant in most patients. Compared with renal failure patients, pHPT patients showed a similar decline in IGFBP-5 levels and less elevated levels of IGFBP-1 (3.5-fold), IGFBP-2 (2-fold), IGFBP-3 (1.2-fold), and IGFBP-6 (4-fold) but no elevation of IGFBP-4 levels. In all subjects, free and total IGF-I levels showed significant negative correlations with IGFBP-1, IGFBP-2, and IGFBP-4 (that is, inhibitory IGF system components) and significant positive correlations with IGFBP-3 and IGFBP-5 (that is, stimulatory IGF system components). A positive correlation was observed between IGF-II and IGFBP-6. ESRF patients with mixed uremic bone disease and histologic evidence for osteopenia revealed significantly (P < 0.05) higher levels of IGFBP-2 and IGFBP-4 but lower IGFBP-5 levels. Histologic parameters of bone formation showed significant positive correlations with serum levels of IGF-I, IGF-II, and IGFBP-5. In contrast, IGFBP-2 and IGFBP-4 correlated positively with indices of bone loss. Moreover, dialysis patients with low bone turnover (N = 24) showed significantly (P < 0.05) lower levels of IGFBP-5, PTH, B-ALP, and OSC than patients with high bone turnover. CONCLUSION: Patients with primary and secondary hyperparathyroidism showed lower levels of the putative stimulatory IGFBP-5 but higher levels of IGFBP-1, -2, -3, and -6, whereas total IGF-I and IGF-II levels were not or only moderately increased. The marked increase in serum levels of IGFBP-4 appeared to be characteristic for chronic renal failure. IGFBP-5 correlated with biochemical markers and histologic indices of bone formation in renal osteodystrophy patients and was not influenced by renal function. Therefore, IGFBP-5 may gain significance as a serological marker for osteopenia and low bone turnover in long-term dialysis patients.     

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

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

良性前列腺增生病人血清IGF-1、IGFBP-3水平分析

目的 :检测良性前列腺增生 (BPH)病人血清胰岛素生长因子 Ⅰ(IGF 1 )及其结合蛋白 3 (IGFBP 3)的水平 ,探讨IGF 1、IGFBP 3对揭示BPH病因及治疗方面的价值。　方法 :采用免疫放射分析法 (IRMA)测定 64例BPH病人血清中IGF 1、IGFBP 3水平 ,并以 30例健康男性作对照。BPH病人按照其前列腺总体积 (PV)的大小分为 3组 :A组PV≤ 30ml,1 8例 ;B组　PV 31～ 50ml,2 4例 ;C组　PV≥ 50ml,2 2例。　结果 :BPH组血清IGF 1、IGFBP 3含量与对照组比较 ,差异均无显著性。BPH组中 ,C组与A组比较 ,IGF 1、IGFBP 3水平均显著升高 (P<0 .0 5) ,C组与B组比较 ,IGF 1水平显著增高 (P =0 .0 0 3) ,IGFBP 3水平无统计学差异。IGF 1、IGFBP 3的水平随PV的增加而升高 ,均呈正相关 (r =0 .58,r =0 .48)。　结论 :IGF 1、IGFBP 3水平的高低与前列腺增生的程度有关 ,对BPH病因的揭示及BPH的非手术治疗均有一定的临床价值