Review: Amelioration of penile fibrosis: Myth or reality

Journal of Andrology

Volumn 31, Issue 4, 2010, Pages 324-335

  El Sakka, Ahmed I ^a   Yassin, Aksam A ^b  

^a Suez Canal University Faculty of Medicine   (Egypt)

^b Institute of Urology and Andrology at Segeberger Kliniken   (Germany)

Author keywords

Aging; Corpora cavernosa; Tunica albuginea

Indexed keywords

ANDROSTANOLONE; ANTIFIBROTIC AGENT; COLLAGEN FIBER; CYCLIC AMP; CYCLIC GMP; ENDOTHELIAL NITRIC OXIDE SYNTHASE; HYPOXIA INDUCIBLE FACTOR 1ALPHA; INDUCIBLE NITRIC OXIDE SYNTHASE; MESSENGER RNA; METALLOPROTEINASE; MYOSTATIN; PENTOXIFYLLINE; PHOSPHODIESTERASE V INHIBITOR; PLASMINOGEN ACTIVATOR INHIBITOR; SILDENAFIL; TADALAFIL; TESTOSTERONE; TRANSFORMING GROWTH FACTOR BETA1; VARDENAFIL; ANDROGEN;

AGING; CORONARY ARTERY DISEASE; CORPUS CAVERNOSUM; DIABETES MELLITUS; DISEASE ASSOCIATION; ENDOTHELIAL DYSFUNCTION; ERECTILE DYSFUNCTION; EXTRACELLULAR MATRIX; FIBROSIS; HEART FAILURE; HUMAN; ISCHEMIA; MALE SEXUAL DYSFUNCTION; NERVE INJURY; PENILE FIBROSIS; PENIS INJURY; PEYRONIE DISEASE; PRIORITY JOURNAL; PROSTATECTOMY; PROTEIN EXPRESSION; PULMONARY HYPERTENSION; REVIEW; SMOKING; SMOOTH MUSCLE FIBER; TESTOSTERONE BLOOD LEVEL; TISSUE INJURY; TUNICA ALBUGINEA; ANIMAL; MALE; PATHOLOGY; PENIS;

AGING; ANDROGENS; ANIMALS; DIABETES MELLITUS; FIBROSIS; HUMANS; MALE; PENILE INDURATION; PENIS;

EID: 77957842891     PISSN: 01963635     EISSN: 19394640     Source Type: Journal    
DOI: 10.2164/jandrol.109.008730     Document Type: Review

References (114)

1. Akkus E, Carrier S, Baba K, Hsu GL, Padma-Nathan H, Nunes L, Lue TF. Structural alterations in the tunica albuginea of the penis: impact of Peyronie's disease, ageing and impotence. Br J Urol. 1997;79:47-53. (Pubitemid 28318844)
2. Armagan A, Kim NN, Goldstein I, Traish AM. Dose-response relationship between testosterone and erectile function: evidence for the existence of a critical threshold. J Androl. 2006;27:517-526. (Pubitemid 44126263)
3. Atkinson JJ, Senior RM. Matrix metalloproteinase-9 in lung remodeling. Am J Respir Cell Mol Biol. 2003;28:12-24.
4. Aversa A, Greco E, Bruzziches R, Pili M, Rosano G, Spera G. Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study. Int J Impot Res. 2007;19(2):200-207. (Pubitemid 46340840)
5. Baba K, Yajima M, Carrier S, Akkus E, Reman J, Nunes L, Lue TF, Iwamoto T. Effect of testosterone on the number of NADPH diaphorase-stained nerve fibers in the rat corpus cavernosum and dorsal nerve. Urology. 2000;56:533-538. (Pubitemid 30658203)
6. Behr-Roussel D, Gorny D, Mevel K, Caisey S, Bernabe J, Burgess G, Wayman C, Alexandre L, Giuliano F. Chronic sildenafil improves erectile function and endothelium dependent cavernosal relaxations in rats: lack of tachyphylaxis. Eur Urol. 2005;47:87-91. (Pubitemid 39575722)
7. Bélanger C, Luu-The V, Dupont P, Tchernof A. Adipose tissue intracrinology: potential importance of local androgen/estrogen metabolism in the regulation of adiposity. Horm Metab Res. 2002;34:737-745. (Pubitemid 36398717)
8. Bivalacqua TJ, Champion HC, Leungwattanakij S, Yang DY, Hyun JS, Abdel-Mageed AB, Sikka SC, Kadowitz PJ, Hellstrom WJ. Evaluation of nitric oxide synthase and arginase in the induction of a Peyronie's-like condition in the rat. J Androl. 2001;22(3):497-506. (Pubitemid 32322142)
9. Bivalacqua TJ, Champion HC, Usta MF, Cellek S, Chitaley K, Webb RC, Lewis RL, Mills TM, Hellstrom WJ, Kadowitz PJ. RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. Proc Natl Acad Sci U S A. 2004;101(24):9121-9126. (Pubitemid 38781621)
10. Bivalacqua TJ, DengW, KendirciM, UstaMF, Robinson C, Taylor BK, Murthy SN, Champion HC, Hellstrom WJ, Kadowitz PJ. Mesenchymal stem cells alone or ex vivo gene modified with endothelial nitric oxide synthase reverse age associated erectile dysfunction. Am J Physiol Heart Circ Physiol. 2007;292:H1278-H1290.
11. Bivalacqua TJ, Diner EK, Novak TE, Vohra Y, Sikka SC, Champion HC, Kadowitz PJ, Hellstrom WJ. A rat model of Peyronie's disease associated with a decrease in erectile activity and an increase in inducible nitric oxide synthase protein expression. J Urol. 2000;163(6):1992-1998. (Pubitemid 30366800)
12. Bonniaud P, Margetts PJ, Kolb M, Schroeder JA, Kapoun AM, Damm D, Murphy A, Chakravarty S, Dugar S, Higgins L, Protter AA, Gauldie J. Progressive transforming growth factor beta1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. Am J Respir Crit Care Med. 2005;171(8):889-898. (Pubitemid 40562720)
13. Border WA, Ruoslahti E. Transforming growth factor-β in disease: the dark side of tissue repair. J Clin Invest. 1992;90:1-7.
14. Brant WO, Dean RC, Lue TF. Treatment of Peyronie's disease with oral pentoxifylline. Nat Clin Pract Urol. 2006;3(2):111-115. (Pubitemid 43239268)
15. Brock G, Hsu GL, Nunes L, von Heyden B, Lue TF. The anatomy of the tunica albuginea in the normal penis and Peyronie's disease. J Urol. 1997;157(1):276-281. (Pubitemid 26414973)
16. Cantini LP, Ferrini MG, Vernet D, Magee TR, Qian A, Gelfand RA, Rajfer J, Gonzalez-Cadavid NF. Profibrotic role of myostatin in Peyronie's disease. J Sex Med. 2008;5(7):1607-1622. (Pubitemid 352044418)
17. Carrier S, Nagaraju P, Morgan DM, Baba K, Nunes L, Lue TF. Age decreases nitric oxide synthase-containing nerve fibers in the rat penis. J Urol. 1997;157:1088-1092. (Pubitemid 27066323)
18. Catalona WJ, Bigg SW. Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. J Urol. 1990;143:538-543. (Pubitemid 20108146)
19. Chang Y, Ceacareanu B, Dixit M, Sreejayan N, Hassid A. Nitric oxide induced motility in aortic smooth muscle cells: role of protein tyrosine phosphatase SHP-2 and GTP-binding protein Rho. Circ Res. 2002;91:390-397. (Pubitemid 35034206)
20. Chen Y, Hozawa S, Sawamura S, Sato S, Fukuyama N, Tsuji C, Mine T, Okada Y, Tanino R, Ogushi Y, Nakazawa H. Deficiency of inducible nitric oxide synthase exacerbates hepatic fibrosis in mice fed high-fat diet. Biochem Biophys Res Commun. 2005;326:45-51. (Pubitemid 39573198)
21. Craven PA, Studer RK, Felder J, Phillips S, DeRubertis FR. Nitric oxide inhibition of transforming growth factor-beta and collagen synthesis in mesangial cells. Diabetes. 1997;46:671-681. (Pubitemid 27143386)
22. Dahiya R, Chui R, Perinchery G, Nakajima K, Oh BR, Lue TF. Differential gene expression of growth factors in young and old rat penile tissues is associated with erectile dysfunction. Int J Impot Res. 1999;11:201-206. (Pubitemid 29392825)
23. Daley JT, Brown ML, Watkins MT, Traish AM, Huang YH, Moreland RB, Saenz de Tejada I. Prostanoid production in rabbit corpus cavernosum: I. regulation by oxygen tension. J Urol. 1996;155(4):1482-1487. (Pubitemid 26081275)
24. Davila HH, Magee TR, Rajfer J, Gonzalez-Cadavid NF. Gene therapy with the inducible nitric oxide synthase (iNOS) cDNA regresses the fibrotic plaque in an animal model of Peyronie's disease. Biol Reprod. 2004;71:1568-1577. (Pubitemid 39403252)
25. Davila HH, Magee TR, Zuniga FI, Rajfer J, Gonzalez-Cadavid NF. Peyronie's disease associated with increase in plasminogen activator inhibitor in fibrotic plaque. Urology. 2005;65(4):645-648. (Pubitemid 40522991)
26. de Gouville AC, Boullay V, Krysa G, Pilot J, Brusq JM, Loriolle F, Gauthier J, Papworth SA, Laroze A, Gellibert F, Huet S. Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis. Br J Pharmacol. 2005;145(2):166-167. (Pubitemid 40756521)
27. Diegelmann RF. Cellular and biochemical aspects of normal and abnormal wound healing: an overview. J Urol. 1997;157:298-302.
28. El-Sakka AI, Hassan MU, Nunes L, Bhatanagar RS, Yen TSB, Lue TF. Histological and ultrastructural alterations in an animal model of Peyronie's disease. Br J Urol. 1998a;81:445-452. (Pubitemid 28316555)
29. El-Sakka AI, Hassoba HM. Age-related testosterone depletion in patients with erectile dysfunction. J Urol. 2006;176:2589-2593. (Pubitemid 44665993)
30. El-Sakka AI, Hassoba HM, Chui RM, Bhatnagar RS, Dahiya R, Lue TF. An animal model of Peyronie's-like condition associated with an increase of transforming growth factor beta mRNA and protein expression. J Urol. 1997a;158(4):2284-2290. (Pubitemid 27481391)
31. El-Sakka AI, Hassoba HM, Pillarisetty RJ, Nunes L, Dahiya R, Lue TF. Peyronie's disease is associated with an increase in transforming growth factor beta protein expression. J Urol. 1997b;158(4):1391-1394.
32. El-Sakka AI, Selph CA, Yen TSB, Dahiya R, Lue TF. The effect of surgical trauma on rat tunica albuginea. J Urol. 1998b;159:1700-1707. (Pubitemid 29117387)
33. El-Sakka AI, Tayeb KA. Peyronie's disease in diabetic patients being screened for erectile dysfunction. J Urol. 2005;174:1026-1030. (Pubitemid 41140670)
34. El-Sakka AI, Tayeb KA. Vascular impairment of erection in patients with diabetes and Peyronie's disease: is that an accumulative? J Sex Med. 2009;6(6):1736-1742.
35. Ferrini MG, Davila H, Kovanecz I, Sanchez S, Gonzalez-Cadavid NF, Rajfer J. Long-term continuous treatment with vardenafil prevents fibrosis and preserves smooth muscle content in the rat corpora cavernosa after bilateral cavernosal nerve transection. Urology. 2006a;68:429-435.
36. Ferrini MG, Davila H, Valente EG, Gonzalez-Cadavid NF, Rajfer J. Aging-related induction of inducible nitric oxide synthase (NOS2A) is vasculo-protective in the arterial media. Cardiovasc Res. 2004;61:796-805. (Pubitemid 38249479)
37. Ferrini MG, Kovanecz I, Nolazco G, Rajfer J, Gonzalez-Cadavid NF. Effects of long-term treatment with vardenafil on the development of the fibrotic plaque in a rat model of Peyronie's disease. BJU Int. 2006b;97:625-633.
38. Ferrini MG, Kovanecz I, Sanchez S, Umeh C, Rajfer J, Gonzalez-Cadavid NF. Fibrosis and loss of smooth muscle in the corpora cavernosa precede corporal veno-occlusive dysfunction (CVOD) induced by experimental cavernosal nerve damage in the rat. J Sex Med. 2009;6(2):415-428.
39. Ferrini MG, Kovanecz I, Sanchez S, Vernet D, Davila HH, Rajfer J, Gonzalez-Cadavid NF. Long-term continuous treatment with sildenafil ameliorates aging-related erectile dysfunction and the underlying corporal fibrosis in the rat. Biol Reprod. 2007;76(5):915-923. (Pubitemid 46651233)
40. Ferrini M, Magee TR, Vernet D, Rajfer J, Gonzalez-Cadavid NF. Aging related expression of inducible nitric oxide synthase (iNOS) and markers of tissue damage in the rat penis. Biol Reprod. 2001;64:974-982. (Pubitemid 32174071)
41. Foresta C, Caretta N, Lana A, De Toni L, Biagioli A, Ferlin A, Garolla A. Reduced number of circulating endothelial progenitor cells in hypogonadal men. J Clin Endocrinol Metab. 2006;91:4599-4602. (Pubitemid 44833444)
42. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Grimminger F, Kurzyna M, Simonneau G; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148-2157.
43. Garbán H, Vernet D, Freedman A, Rajfer J, González-Cadavid N. Effect of aging on nitric oxide-mediated penile erection in rats. Am J Physiol. 1995;268:467-475.
44. Giuliano F, Rampin O, Schirar A, Jardin A, Rousseau JP. Autonomic control of penile erection: modulation by testosterone in the rat. J Neuroendocrinol. 1993;5:677-683. (Pubitemid 24013372)
45. Goldstein AM, Padma-Nathan H. The microarchitecture of the intracavernosal smooth muscle and the cavernosal fibrous skeleton. J Urol. 1990;144:1144-1146. (Pubitemid 20388053)
46. Gonzalez-Cadavid NF. Mechanisms of penile fibrosis. J Sex Med. 2009;6(suppl 3):353-362.
47. Gonzalez-Cadavid NF, Rajfer J. Molecular pathophysiology and gene therapy of aging-related erectile dysfunction. Exp Gerontol. 2004;39:1705-1712. (Pubitemid 39576140)
48. Gonzalez-Cadavid NF, Rajfer J. Mechanisms of disease: new insights into the cellular and molecular pathology of Peyronie's disease. Nat Clin Pract Urol. 2005;2:291-298. (Pubitemid 40903186)
49. Gori T, Sicuro S, Dragoni S, Donati G, Forconi S, Parker JD. Sildenafil prevents endothelial dysfunction induced by ischemia and reperfusion via opening of adenosine triphosphate-sensitive potassium channels: a human in vivo study. Circulation. 2005;111:742-746.
50. Gralnek D, Wessells H, Cui H, Dalkin BL. Differences in sexual function and quality of life after nerve sparing and nonnerve sparing radical retropubic prostatectomy. J Urol. 2000;163:1166-1169.
51. Hakenjos L, Bamberg M, Rodemann HP. TGF-beta1-mediated alterations of rat lung fibroblast differentiation resulting in the radiation-induced fibrotic phenotype. Int J Radiat Biol. 2000;76:503-509. (Pubitemid 30232449)
52. Hatzimouratidis K, Hatzichristou D. Phosphodiesterase type 5 inhibitors: the day after. Eur Urol. 2007;51:75-89.
53. Hochberg D, Johnson CW, Chen J, Cohen D, Stern J, Vaughan ED Jr, Poppas D, Felsen D. Interstitial fibrosis of unilateral ureteral obstruction is exacerbated in kidneys of mice lacking the gene for inducible nitric oxide synthase. Lab Invest. 2000;80:1721-1728.
54. Hong EK, Lepor H, McCullough AR. Time dependent patient satisfaction with sildenafil for erectile dysfunction (ED) after nerve-sparing radical retropubic prostatectomy (RRP). Int J Impot Res. 1999;11(suppl 1):S15-S22.
55. Hsu GL, Brock G, von Heyden B, Nunes L, Lue TF, Tanagho EA. The distribution of elastic fibrous elements within the human penis. Br J Urol. 1994;37:566-571. (Pubitemid 24190164)
56. Iacono F, Giannella R, Somma P, Manno G, Fusco F, Mirone V. Histological alterations in cavernous tissue after radical prostatectomy. J Urol. 2005;173:1673-1676. (Pubitemid 40524802)
57. Jiaan DB, Seftel AD, Fogarty J, Hampel N, Cruz W, Pomerantz J, Zuik M, Monnier VM. Age-related increase in an advanced glycation end product in penile tissue. World J Urol. 1995;13:369-375.
58. Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S. Acute type 5 phosphodiesterase inhibition with sildenafil enhances flow-mediated vasodilation in patients with chronic heart failure. J Am Coll Cardiol. 2000;36:845-851.
59. Keast JR, Gleeson RJ, Shulkes A, Morris MJ. Maturational and maintenance effects of testosterone on terminal axon density and neuropeptide expression in the rat vas deferens. Neuroscience. 2002;112:391-398. (Pubitemid 34607022)
60. Korenman SG, Viosca SP. Treatment of vasculogenic sexual dysfunction with pentoxifylline. J Am Geriatr Soc. 1993;41:363-366. (Pubitemid 23110730)
61. Kovanecz I, Ferrini MG, Vernet D, Nolazco G, Rajfer J, Gonzalez-Cadavid NF. Pioglitazone prevents corporal veno-occlusive dysfunction (CVOD) in a rat model of type 2 diabetes mellitus. BJU Int. 2006;98:116-124. (Pubitemid 43885518)
62. Kovanecz I, Nolazco G, Ferrini MG, Toblli JE, Heydarkhan S, Vernet D, Rajfer J, Gonzalez-Cadavid NF. Early onset of fibrosis within the arterial media in a rat model of type 2 diabetes mellitus exhibiting erectile dysfunction. BJU Int. 2009;103(10):1396-1404.
63. Kukreja RC, Salloum F, Das A, Ockaili R, Yin C, Bremer YA, Fisher PW, Wittkamp M, Hawkins J, Chou E, Kukreja AK, Wang X, Marwaha VR, Xi L. Pharmacological preconditioning with sildenafil: basic mechanisms and clinical implications. Vascul Pharmacol. 2005;42:219-232. (Pubitemid 40726325)
64. Lau DHW, Kommu SS, Siddiqui EJ, Thompson CS, Morgan RJ, Mikhailidis DP, Mumtaz FH. Gene therapy and erectile dysfunction: the current status. Asian J Androl. 2007;9:8-15. (Pubitemid 46050213)
65. Leungwattanakij S, Bivalacqua TJ, Usta MF, Yang DY, Hyun JS, Champion HC, Abdel-Mageed AB, Hellstrom WJ. Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum. J Androl. 2003;24(2):239-245.
66. Li P, Oparil S, Novak L, Cao X, Shi W, Lucas J, Chen YF. ANP signaling inhibits TGF-b-induced Smad2 and Smad3 nuclear translocation and extracellular matrix expression in rat pulmonary arterial smooth muscle cells. J Appl Physiol. 2007;102:390-398. (Pubitemid 46089790)
67. Luangkhot R, Rutchik S, Agarwal V, Puglia K, Bhargava G, Melman A. Collagen alterations in the corpus cavernosum of men with sexual dysfunction. J Urol. 1992;148:467-471.
68. Marin R, Escrig A, Abreu P, Mas M. Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes. Biol Reprod. 1999;61:1012-1016. (Pubitemid 29455639)
69. Martin M, Lefaix J, Delanian S. TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys. 2000;47:277-290.
70. Martinez-Pineiro L, Dahiya R, Brock GB, Hsu GL, von Heyden B, Lue TF. Chronic penile denervation in the rat: effect on cavernous tissue morphology and function. Int J Impot Res. 1995;7:165-174.
71. McCullough A. Penile change following radical prostatectomy: size, smooth muscle atrophy, and curve. Curr Urol Rep. 2008;9(6):492-499.
72. McVary KT, Polepalle S, Riggi S, Pelham RW. Topical prostaglandin E1 SEPA gel for the treatment of erectile dysfunction. J Urol. 1999;162:726-730.
73. Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol. 1999;161:5-11.
74. Mills TM, Lewis RW, Wingard CJ, Linder AE, Jin L, Webb RC. Vasoconstriction, RhoA/Rho-kinase and the erectile response. Int J Impot Res. 2003;15:S20-S24.
75. Moncada S, Higgs EA. The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol. 2006;1147:S193-S201. (Pubitemid 43077277)
76. Montorsi F, Guazzoni G, Strambi LF, Da Pozzo LF, Nava L, Barbieri L, Rigatti P, Pizzini G, Miani A. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol. 1997;158:1408-1410.
77. Montorsi F, McCullough A. Efficacy of sildenafil citrate in men with erectile dysfunction following radical prostatectomy: a systematic review of clinical data. J Sex Med. 2005;2:658-667. (Pubitemid 41742926)
78. Morales A. An integral view of the neuroendocrine aspects of male sexual dysfunction and aging. Can J Urol. 2003;10(2):1777-1779.
79. Moreland RB. Is there a role of hypoxemia in penile fibrosis: a viewpoint presented to the Society for the Study of Impotence. Int J Impot Res. 1998;10:113-120.
80. Moreland RB, Traish A, McMillin MA, Smith B, Goldstein I, Saenz de Tejada I. PGE1 suppresses the induction of collagen synthesis by transforming growth factor-beta 1 in human corpus cavernosum smooth muscle. J Urol. 1995;153:826-834.
81. Mulhall JP, Land S, Parker M, Waters WB, Flanigan RC. The use of an erectogenic pharmacotherapy regimen following radical prostatectomy improves recovery of spontaneous erectile function. J Sex Med. 2005;2:532-542. (Pubitemid 40975838)
82. Mulhall JP, Müller A, Donohue JF, Mullerad M, Kobylarz K, Paduch DA, Tal R, Li PS, Cohen-Gould L, Scardino PT. The functional and structural consequences of cavernous nerve injury are ameliorated by sildenafil citrate. J Sex Med. 2008;5(5):1126-1136. (Pubitemid 351606701)
83. Mulhall JP, Slovick R, Hotaling J, Aviv N, Valenzuela R, Waters WB, Flanigan RC. Erectile dysfunction after radical prostatectomy: hemodynamic profiles and their correlation with the recovery of erectile function. J Urol. 2002;167:1371-1375. (Pubitemid 34132096)
84. Musicki B, Champion HC, Becker RE, Liu T, Kramer MF, Burnett AL. Erection capability is potentiated by long-term sildenafil treatment: role of blood flow-induced endothelial nitric-oxide synthase phosphorylation. Mol Pharmacol. 2005;68:226-232. (Pubitemid 41002962)
85. Nolazco G, Kovanecz I, Vernet D, Ferrini M, Gelfand B, Tsao J, Magee T, Rajfer J, Gonzalez-Cadavid NF. Effect of muscle derived stem cells on the restoration of corpora cavernosa smooth muscle and erectile function in the aged rat. BJU Int. 2008;101:1156-1164. (Pubitemid 351502662)
86. Padma-Nathan H, McCullough AR, Levine LA, Lipshultz LI, Siegel R, Montorsi F, Giuliano F, Brock G; Study Group. Randomized, double-blind, placebo-controlled study of post-operative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve sparing radical prostatectomy. Int J Impot Res. 2008;20:479-486.
87. Park KH, Kim SW, Kim KD, Paick JS. Effects of androgens on the expression of nitric oxide synthase mRNAs in rat corpus cavernosum. BJU Int. 1999;83:327-333. (Pubitemid 29151537)
88. Perinchery G, El-Sakka AI, Angan A, Nakajima K, Dharia A, Tanaka Y, Lue TF, Dahiya R. Microsatellite alterations and loss of heterozygosity in Peyronie's disease. J Urol. 2000;164(3):842-846. (Pubitemid 30637643)
89. Rajfer J, Gore JL, Kaufman J, Gonzalez-Cadavid N. Case report: avoidance of palpable corporal fibrosis due to priapism with upregulators of nitric oxide. J Sex Med. 2006;3(1):173-176.
90. Rogers RS, Graziottin TM, Lin CS, Kan YW, Lue TF. Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno-associated virus-mediated VEGF gene therapy prevent and reverse venogenic erectile dysfunction in rats. Int J Impot Res. 2003;15:26-37.
91. Rosanio S, Ye Y, Atar S, Rahman AM, Freeberg SY, Huang MH, Uretsky BF, Birnbaum Y. Enhanced cardioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvastatin. Cardiovasc Drugs Ther. 2006;20:27-36.
92. Rosano GM, Aversa A, Vitale C, Fabbri A, Fini M, Spera G. Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol. 2005;47:214-220.
93. Rosen ED, Hsu CH, Wang X, Sakai S, Freeman MW, Gonzalez FJ, Spiegelman BM. C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev. 2002;16:22-26. (Pubitemid 34049634)
94. Sattar AA, Salpigides G, Vanderhaeghen JJ, Schulman CC, Wespes E. Cavernous oxygen tension and smooth muscle fibers: relation and function. J Urol. 1995;154:1736-1739.
95. Saura M, Zaragoza C, Herranz B, Griera M, Diez-Marques L, Rodriguez-Puyol D, Rodriguez-Puyol M. Nitric oxide regulates transforming growth factor-beta signaling in endothelial cells. Circ Res. 2005;97:1115-1123.
96. Schwartz EJ, Wong P, Graydon RJ. Sildenafil preserves intracorporeal smooth muscle after radical prostatectomy. J Urol. 2004;171:771-774. (Pubitemid 38090480)
97. Shen ZJ, Zhou XL, Lu YL, Chen ZD. Effect of androgen deprivation on penile ultrastructure. Asian J Androl. 2003;5:33-36.
98. Sighinolfi MC, Mofferdin A, De Stefani S, Celia A, Micali S, Cicero AF, Bianchi G. Changes in peak systolic velocity induced by chronic therapy with phosphodiesterase type-5 inhibitor. Andrologia. 2006;38(3):84-86.
99. Singh R, Artaza JN, Taylor WE, Braga M, Yuan X, Gonzalez-Cadavid NF, Bhasin S. Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with betacatenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. Endocrinology. 2006;147:141-154. (Pubitemid 43004269)
100. Smith BH. Peyronie's disease. Am J Clin Pathol. 1966;45:670-678.
101. Song YS, Lee HJ, Park IH, Kim WK, Ku JH, Kim SU. Potential differentiation of human mesenchymal stem cells transplanted in rat corpus cavernosum toward endothelial or smooth muscle cells. Int J Impot Res. 2007;19:378-385. (Pubitemid 47026078)
102. Sporn MB, Roberts AB, Wakefield LM, de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol. 1987;105:1039-1045.
103. Traish AM, Goldstein I, Kim NN. Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol. 2007;52(1):54-70. (Pubitemid 46803026)
104. Traish AM, Munarriz R, O'Connell L, Choi S, Kim SW, Kim NN, Huang YH, Goldstein I. Effects of medical or surgical castration on erectile function in an animal model. J Androl. 2003;24:381-387. (Pubitemid 39571794)
105. Traish AM, Toselli P, Jeong SJ, Kim NN. Adipocyte accumulation in penile corpus cavernosum of the orchiectomized rabbit: a potential mechanism for venoocclusive dysfunction in androgen deficiency. J Androl. 2005;26:242-248. (Pubitemid 40293710)
106. Vignozzi L, Filippi S, Morelli A, Ambrosini S, Luconi M, Vannelli GB, Donati S, Crescioli C, Zhang XH, Mirone V, Forti G, Maggi M. Effect of chronic tadalafil administration on penile hypoxia induced by cavernous neurotomy in the rat. J Sex Med. 2006;3(3):419-431.
107. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol. 1982;128:492-497.
108. Wang T, Liu Y, Chen L, Wang X, Hu XR, Feng YL, Liu DS, Xu D, Duan YP, Lin J, Ou XM, Wen FQ. Effect of sildenafil on acroleininduced airway inflammation and mucus production in rats. Eur Respir J. 2009;33(5):1122-1132.
109. Wespes E, Sattar AA, Golzarian J, Wery D, Daoud N, Schulman CC. Corporeal veno-occlusive dysfunction predominantly intracavernous muscular pathology. J Urol. 1997;157:1678-1680. (Pubitemid 27171752)
110. Yaman O, Yilmaz E, Bozlu M, Anafarta K. Alterations of intracorporeal structures in patients with erectile dysfunction. Urol Int. 2003;71:87-90. (Pubitemid 36829138)
111. Yassin A, Saad F. Dramatic improvement of penile venous leakage upon testosterone administration. A case report and review of literature. Andrologia. 2006;38:34-37.
112. Yassin A, Saad F, Traish AM. Testosterone undecanoate restores erectile function in a subset of patients with venous leakage: a series of case reports. J Sex Med. 2006;3:727-735.
113. Zhang LW, Piao S, Choi MJ, ShinHY, JinHR, Kim WJ, Song SU, Han JY, Park SH, Mamura M, Kim SJ, Ryu JK, Suh JK. Role of increased penile expression of transforming growth factor-beta1 and activation of the smad signaling pathway in erectile dysfunction in streptozotocin-induced diabetic rats. J Sex Med. 2008;10:2318-2329.
114. Zvara P, Sioufi R, Schipper HM, Begin LR, Brock GB. Nitric oxide mediated erectile activity is a testosterone dependent event: a rat erection model. Int J Impot Res. 1995;7:209-219. (Pubitemid 3008688)