Insulin-Like Growth Factor I (IGF-I) and IGF-Binding Protein-3 in Benign Prostatic Hyperplasia and Prostate Cancer

Abstract

In view of evidence indicating significant involvement of the insulin-like growth factor (IGF) system in the pathogenesis of prostate cancer, we measured serum IGF-I and IGF-binding protein-3 (IGFBP-3) in men with benign prostatic hyperplasia (BPH; n = 75) or prostatic carcinoma (CaP; n = 84). The age-matched patient populations were selected to have circulating prostate-specific antigen (PSA), the most reliable predictor of CaP, in the overlapping diagnostic gray zone range of approximately 4--10 microg/L. Of particular interest was investigation of intact, fragment, and total IGFBP-3 levels in relation to PSA, which is also a well established IGFBP-3 protease. Among the key findings were significantly higher IGF-I and intact IGFBP-3 levels in CaP vs. BPH (P < 0.001), whereas changes in fragment and total IGFBP-3 were statistically insignificant. As expected, total PSA levels were similar in the two groups of patients (P = 0.173), whereas free PSA levels were significantly lower in those with CaP (P < 0.001). IGF-I and IGFBP-3 (intact and total) correlated significantly (P = 0.024 to <0.001) and inversely (r = -0.26 to -0.35) with free PSA in BPH, but not in CaP, and no correlations were found in comparisons involving total PSA. Statistical analysis of the various markers and their combinations indicated enhanced performance of IGF-I/free PSA [receiver operating characteristics area under the curve (AUC) = 0.728] and intact IGFBP-3/free PSA (AUC = 0.737) ratios in discriminating between BPH and CaP compared with the currently used free/total PSA ratio (AUC = 0.689). Multivariate logistic regression models confirmed the observed relationships and identified IGF-I/free PSA and intact IGFBP-3/free PSA as independent factors in predicting the presence of CaP. We conclude that increases in IGF-I and intact IGFBP-3 levels are positively associated with the presence of CaP in this group of patients with low to moderately elevated PSA, and that their measurements in relation to PSA may help improve diagnostic discrimination between BPH and prostate cancer.

Insulin-like growth factor-I and prostate cancer: a meta-analysis

“…When 3 studies that used patients with benign prostatic hyperplasia as controls (Djavan et al, 1999;Finne et al, 2000, Khosravi et al, 2001 were excluded from the OR estimation, the overall OR declined from 1.47 to 1.36, but remained statistically significant (P < 0.01). The homogeneity test showed that the remaining 11 studies were still not homogeneous with regard to the effect size (chi-square = 71.03, df = 10, P < 0.01).…”

“…Of the 9 studies, 2 studies used patients with BPH as controls (Finne et al, 2000;Khosravi et al, 2001) and when these were excluded, the overall OR increased from 1.25 to 1.28, remaining statistically significant (P = 0.015).…”

“…Studies in which the controls consisted entirely of healthy males and in which sample size was > 50 in both case and control groups were categorized as a high-score group. Based on these criteria, seven studies (Cohen et al, 1993;Kanety et al, 1993;Ho and Baxter, 1997;Baffa et al, 2000;Djavan et al, 1999;Finne et al, 2000;Khosravi et al, 2001) were classified as low score and the other 7 as high score.…”

Putative role of serum insulin-like growth factor–1 (IGF-1) and IGF binding protein-3 (IGFBP-3) levels in the development of prostate cancer in Arab men

“…The results, to date, have not been conclusive. Some studies (mostly prospective or meta analyses) show increased risk for prostate cancer with increasing IGF levels, [4][5][6][7][8] while others (mostly nonprospective, small number of patients, etc) have found no relationship between serum IGF-1 and risk for prostate cancer. [9][10][11][12] Since IGF itself is influenced by many other factors, to assess its role accurately in prostate carcinogenesis, a number of authors have looked at serum IGF-1 as well as IGF-binding protein 3 (IGFBP-3)-one of its binding proteins.…”

“…2,4,17,18 Furthermore, plasma IGFBP-3 levels are reported to be highest in healthy subjects, followed by patients with localized prostate cancer, while levels are lowest in those with skeletal metastases. 8,15 Most of the previous epidemiological studies on IGF1 and IGFBP3 (except that by Chokkalingam et al 7 conducted on the Chinese) were in Caucasians with known high risk for prostate cancer. To further understand the role of IGFs in prostate cancer, its study in a community with low incidence of prostate cancer as in Arabs is warranted.…”