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Regional Variations of Insulin-Like Growth Factor I (IGF-I), IGF-II, and Receptor Type 1 in Benign Prostatic Hyperplasia Tissue and Their Correlation with Intraprostatic Androgens¹

Department of Fisiopatologia Medica, II Endocrinologia (S.M., R.I., C.M., S.L., P.F., M.P., A.S., F.S., V.T.), and Department of Urologia (F.D.S.), University La Sapienza of Rome, 00161 Rome, Italy

Address all correspondence and requests for reprints to: Dr. Vincenzo Toscano, II Endocrinologia, Dip Fisiopatologia Medica, Università La Sapienza, 00161 Rome, Italy. E-mail: i.s.g.s.h{at}agora.stm.it

Benign prostatic hyperplasia (BPH) is an androgen-dependent disease; it originates exclusively in the inner prostate, which includes tissue surrounding the urethra. Stromal-epithelial interaction has a pivotal role in the regulation of the development and growth of the prostate, and locally produced peptide growth factors are considered important mediators of this interaction. Insulin-like growth factor I (IGF-I) and IGF-II, acting mainly through type 1 IGF receptor (IGFR1), have mitogenic and antiapoptotic effects on epithelial and stromal prostatic cells. In this study the expression of IGF-I, IGF-II, and IGFR1 messenger ribonucleic acid (mRNA), the immunoreactive content of IGF-I (irIGF-I) and IGF-II (irIGF-II) were determined in periurethral, intermediate, and subcapsular regions of BPH tissue to verify their possible regional variation; a correlation to the tissue levels of dihydrotestosterone (DHT) and 3-androstanediol (3Diol) was also determined to verify their possible androgen dependence.

Prostates were removed by suprapubic prostatectomy from 14 BPH patients and sectioned in the periurethral, intermediate, and subcapsular regions. Gene expression of IGF-I, IGF-II, and IGFR1 was evaluated by semiquantitative RT-PCR, using ß-actin as a control. irIGF-I was measured by RIA, and irIGF-II was measured by IRMA after acidification and chromatography on Sep-Pak C₁₈ cartridges. DHT and 3Diol concentrations were evaluated by RIA after extraction and purification on Celite microcolumns.

IGF-II and IGFR1, but not IGF-I, mRNA was higher in the periurethral than in the intermediate (P < 0.05) and subcapsular (P < 0.01) region. Also, prostatic levels of irIGF-II, expressed as picomoles per g tissue, were higher in the periurethral (20.84 ± 1.84) than in the intermediate (14.81 ± 2.11; P < 0.05) and subcapsular (10.88 ± 1.21; P < 0.001) region. No significant differences were found in irIGF-I content. Considering prostatic androgen levels, DHT and 3Diol presented a regional variation, with the highest concentrations in the periurethral region. IGF-II mRNA and irIGF-II levels were positively correlated with both DHT and 3Diol content.

These results demonstrate that in BPH tissue a greater IGF-II activity is present in the periurethral region, the site of origin of BPH. Moreover, we can hypothesize that the tissue androgen content may modulate prostatic production of IGF-II, acting at the transcriptional and probably the posttranscriptional level. Therefore, even though further studies will need to confirm this hypothesis, DHT may increase IGF-II activity, mainly in the periurethral region, which, in turn, induces, through IGFR1, benign proliferation of both epithelial and stromal cells, characteristic of BPH.

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