Background and Aim. It is well known that androgen deprivation relates to penile fibrosis, so we hypothesize that long-term treatment with 5-alphareductase inhibitors (5ARIs) may increase the risk of fibrosis of prostate. Patients and Methods. Thirty-two BPH patients who underwent transurethral resection of the prostate were enrolled. The patients were divided into two groups: group one, 16 patients underwent TURP who had been treated with tamsulosin for 2 years; group two, 16 patients underwent TURP who had been treated with combination of tamsulosin and dutasteride for at least 1 year. We evaluated the expressions of nNOS, iNOS, eNOS, TGF-β1, TGF-β2, phosphorylated-Smad2/3 (p-Smad2/3), E-cadherin, N-cadherin, and α-smooth muscle actin in the resected prostate tissues by western blotting, and the TGF-β concentration was determined by ELISA kit. Results. The expressions of 3 isoforms of NOS were significantly increased in group 2 except of eNOS in lateral prostate, and the expressions of TGF-β1, TGF-β2, and p-Smad2/3 increased about 2-fold compared with group 1. In group 2, the E-cadherin expression decreased while N-cadherin expression increased significantly. Conclusions. The overexpression of nNOS may contribute to prostate smooth muscle relaxation; however, long-time treatment with 5？ARI increases the risk of fibrosis of prostate. 1. Introduction The 5-alpha reductase (5？AR) inhibitor (5？ARI) was developed to treat the patients with symptomatic benign prostatic hyperplasia (BPH) and decrease the frequency and risk of BPH-related morbidities [1, 2]. Presently available orally administered 5？ARIs, finasteride and dutasteride, inhibit 5？AR, an enzyme that catalyzes the irreversible reduction of testosterone (T) to dihydrotestosterone (DHT), with NADPH as the hydrogen donor [3]. Dutasteride is a selective inhibitor of 5？AR type 1 (5？AR1) and 5？AR type 2 (5？AR2). Finasteride is considered mainly an inhibitor of 5？AR2 and is approximately 50 times weaker in inhibiting 5？AR1 than 5？AR2 [4]. The development of BPH is an androgen-dependent process, and androgen suppression causes regression primarily of the epithelial elements of the prostate, resulting in a reduction in the size of the gland and improvement in symptoms [5, 6]. As we know, androgen deprivation by surgical or medical castration is associated with penile cavernosal fibrosis resulting in penile tissue atrophy, alterations in dorsal nerve structure, alterations in endothelial morphology, reductions in trabecular smooth muscle content, increases in deposition of extracellular matrix, and
References
[1]
J. D. McConnell, R. Bruskewitz, P. Walsh et al., “The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia,” The New England Journal of Medicine, vol. 338, no. 9, pp. 557–563, 1998.
[2]
C. G. Roehrborn, P. Boyle, J. C. Nickel, K. Hoefner, and G. Andriole, “Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia,” Urology, vol. 60, no. 3, pp. 434–441, 2002.
[3]
D. W. Russell and J. D. Wilson, “Steroid 5α-reductase: two genes/two enzymes,” Annual Review of Biochemistry, vol. 63, pp. 25–61, 1994.
[4]
S. Aggarwal, S. Thareja, A. Verma, T. R. Bhardwaj, and M. Kumar, “An overview on 5α-reductase inhibitors,” Steroids, vol. 75, no. 2, pp. 109–153, 2010.
[5]
D. S. Coffey and P. C. Walsh, “Clinical and experimental studies of benign prostatic hyperplasia,” Urologic Clinics of North America, vol. 17, no. 3, pp. 461–475, 1990.
[6]
C. A. Peters and P. C. Walsh, “The effect of nafarelin, acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatic hyperplasia,” The New England Journal of Medicine, vol. 317, no. 10, pp. 599–604, 1987.
[7]
A. I. El-Sakka and A. A. Yassin, “Review: amelioration of penile fibrosis: myth or reality,” Journal of Andrology, vol. 31, no. 4, pp. 324–335, 2010.
[8]
A. Leask and D. J. Abraham, “TGF-β signaling and the fibrotic response,” The FASEB Journal, vol. 18, no. 7, pp. 816–827, 2004.
[9]
F. Verrecchia and A. Mauviel, “Transforming growth factor-β signaling through the Smad pathway: role in extracellular matrix gene expression and regulation,” Journal of Investigative Dermatology, vol. 118, no. 2, pp. 211–215, 2002.
[10]
J. Massagué, J. Seoane, and D. Wotton, “Smad transcription factors,” Genes and Development, vol. 19, no. 23, pp. 2783–2810, 2005.
[11]
D. Javelaud and A. Mauviel, “Mammalian transforming growth factor-βs: smad signaling and physio-pathological roles,” International Journal of Biochemistry and Cell Biology, vol. 36, no. 7, pp. 1161–1165, 2004.
[12]
A. Moustakas, K. Pardali, A. Gaal, and C.-H. Heldin, “Mechanisms of TGF-β signaling in regulation of cell growth and differentiation,” Immunology Letters, vol. 82, no. 1-2, pp. 85–91, 2002.
[13]
X. Huang and C. Lee, “Regulation of stromal proliferation, growth arrest, differentiation and apoptosis in benign prostatic hyperplasia by TGF-β,” Frontiers in Bioscience, vol. 8, pp. s740–s749, 2003.
[14]
T. L. Timme, L. D. Truong, K. M. Slawin, D. Kadmon, S. H. P. Sang Hee Park, and T. C. Thompson, “Mesenchymal-epithelial interactions and transforming growth factor-β1 expression during normal and abnormal prostatic growth,” Microscopy Research and Technique, vol. 30, no. 4, pp. 333–341, 1995.
[15]
S.-F. Wu, H.-Z. Sun, X.-D. Qi, and Z.-H. Tu, “Effect of epristeride on the expression of IGF-1 and TGF-β receptors in androgen-induced castrated rat prostate,” Experimental Biology and Medicine, vol. 226, no. 10, pp. 954–960, 2001.
[16]
M. Ruiz-Ortega, M. Ruperez, V. Esteban, and J. Egido, “Molecular mechanisms of angiotensin II-induced vascular injury,” Current Hypertension Reports, vol. 5, no. 1, pp. 73–79, 2003.
[17]
J. H. Li, X. R. Huang, H.-J. Zhu, R. Johnson, and H. Y. Lan, “Role of TGF-β signaling in extracellular matrix production under high glucose conditions,” Kidney International, vol. 63, no. 6, pp. 2010–2019, 2003.
[18]
J. H. Li, X. R. Huang, H.-J. Zhu et al., “Advanced glycation end products activate Smad signaling via TGF-beta-dependent and independent mechanisms: implications for diabetic renal and vascular disease,” The FASEB Journal, vol. 18, no. 1, pp. 176–178, 2004.
[19]
N. F. Gonzalez-Cadavid and J. Rajfer, “Mechanisms of disease: new insights into the cellular and molecular pathology of Peyronie's disease,” Nature Clinical Practice Urology, vol. 2, no. 6, pp. 291–297, 2005.
[20]
A. I. El-Sakka, H. M. Hassoba, R. J. Pillarisetty, R. Dahiya, and T. F. Lue, “Peyronie's disease is associated with an increase in transforming growth factor-β protein expression,” Journal of Urology, vol. 158, no. 4, pp. 1391–1394, 1997.
[21]
T. J. Bivalacqua, E. K. Diner, T. E. Novak et al., “A rat model of Peyronie's disease associated with a decrease in erectile activity and an increase in inducible nitric oxide synthase protein expression,” Journal of Urology, vol. 163, no. 6, pp. 1992–1998, 2000.
[22]
H. H. Davila, T. R. Magee, D. Vernet, J. Rajfer, and N. F. Gonzalez-Cadavid, “Gene transfer of inducible nitric oxide synthase complementary DNA regresses the fibrotic plaque in an animal model of Peyronie's disease,” Biology of Reproduction, vol. 71, no. 5, pp. 1568–1577, 2004.
[23]
A. L. Burnett, M. P. Maguire, S. L. Chamness et al., “Characterization and localization of nitric oxide synthase in the human prostate,” Urology, vol. 45, no. 3, pp. 435–439, 1995.
[24]
R. Gradini, M. Realacci, A. Ginepri, et al., “Nitric oxide synthases in normal and benign hyperplastic human prostate: immunohistochemistry and molecular biology,” The Journal of Pathology, vol. 189, pp. 224–229, 1999.
[25]
T. Klotz, W. Bloch, C. Volberg, U. Engelmann, and K. Addicks, “Selective expression of inducible nitric oxide synthase in human prostate carcinoma,” Cancer, vol. 82, pp. 1897–1903, 1998.
[26]
S. Baltaci, D. Orhan, ？. G？güs, K. Türk？lmez, ？. Tulunay, and O. G？güs, “Inducible nitric oxide synthase expression in benign prostatic hyperplasia, low- and high-grade prostatic intraepithelial neoplasia and prostatic carcinoma,” BJU International, vol. 88, no. 1, pp. 100–103, 2001.
[27]
L. S. Marks, A. W. Partin, F. J. Dorey et al., “Long-term effects of finasteride on prostate tissue composition,” Urology, vol. 53, no. 3, pp. 574–580, 1999.
