The Future of Erectile Dysfunction Therapy I: Implementation of Translational Research

  • Michael Pan
  • Jason R. KovacEmail author


The treatment of erectile dysfunction (ED) was radically altered following the introduction of oral phosphodiesterase type 5 inhibitors and direct penile injections of vasoactive compounds. However, a large number of men have a poor response to these traditional treatments and require additional management strategies. Currently, novel, minimally invasive strategies are being developed with the hope of delaying placement of an inflatable penile prosthesis, which represents the final phase of ED treatment. This chapter examines the development and role of nanoparticles, the use of stem cells, tissue engineering, and gene therapy for the treatment of ED.


Erectile dysfunction Shockwave therapy Nanoparticles Stem cells Tissue engineering 



JRK is an NIH K12 Scholar supported by a Male Reproductive Health Research Career (MRHR) Development Physician-Scientist Award (HD073917-01) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Program.


  1. 1.
    Saigal CS, Wessells H, Pace J, Schonlau M, Wilt TJ, Urologic Diseases in America Project. Predictors and prevalence of erectile dysfunction in a racially diverse population. Arch Intern Med. 2006;166(2):207–12. PubMed PMID: 16432090.CrossRefPubMedGoogle Scholar
  2. 2.
    Guay AT, Perez JB, Jacobson J, Newton RA. Efficacy and safety of sildenafil citrate for treatment of erectile dysfunction in a population with associated organic risk factors. J Androl. 2001;22(5):793–7. PubMed PMID: 11545291.PubMedGoogle Scholar
  3. 3.
    Friedman AJ, Han G, Navati MS, Chacko M, Gunther L, Alfieri A, et al. Sustained release nitric oxide releasing nanoparticles: characterization of a novel delivery platform based on nitrite containing hydrogel/glass composites. Nitric Oxide Biol Chem. 2008;19(1):12–20. PubMed PMID: 18457680.CrossRefGoogle Scholar
  4. 4.
    Han G, Tar M, Kuppam DS, Friedman A, Melman A, Friedman J, et al. Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction. J Sex Med. 2010;7(1 Pt 1):224–33. PubMed PMID: 19765204. Pubmed Central PMCID: 2864537.CrossRefPubMedGoogle Scholar
  5. 5.
    Kawashita M, Tsuneyama S, Miyaji F, Kokubo T, Kozuka H, Yamamoto K. Antibacterial silver-containing silica glass prepared by sol-gel method. Biomaterials. 2000;21(4):393–8. PubMed PMID: 10656321.CrossRefPubMedGoogle Scholar
  6. 6.
    Hakim L, Van der Aa F, Bivalacqua TJ, Hedlund P, Albersen M. Emerging tools for erectile dysfunction: a role for regenerative medicine. Nat Rev Urol. 2012;9(9):520–36. PubMed PMID: 22824778.CrossRefPubMedGoogle Scholar
  7. 7.
    Tong Y, Tar M, Davelman F, Christ G, Melman A, Davies KP. Variable coding sequence protein A1 as a marker for erectile dysfunction. BJU Int. 2006;98(2):396–401. PubMed PMID: 16879685. Pubmed Central PMCID: 2034203.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Tong Y, Tar M, Melman A, Davies K. The opiorphin gene (ProL1) and its homologues function in erectile physiology. BJU Int. 2008;102(6):736–40. PubMed PMID: 18410445. Pubmed Central PMCID: 2872073.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Soni SD, Song W, West JL, Khera M. Nitric oxide-releasing polymeric microspheres improve diabetes-related erectile dysfunction. J Sex Med. 2013;10(8):1915–25. PubMed PMID: 23751157.CrossRefPubMedGoogle Scholar
  10. 10.
    Alpert JS. Nanette K. Wenger: a woman’s life in cardiology. Clin Cardiol. 2004;27(2):114–5. PubMed PMID: 14979635.CrossRefPubMedGoogle Scholar
  11. 11.
    Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, Hering U, Bulitta J, Schreiner P, et al. Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther. 2002;71(1):21–9. PubMed PMID: 11823754.CrossRefPubMedGoogle Scholar
  12. 12.
    Skolarikos A, Alargof E, Rigas A, Deliveliotis C, Konstantinidis E. Shockwave therapy as first-line treatment for Peyronie’s disease: a prospective study. J Endourol. 2005;19(1):11–4. PubMed PMID: 15735375.CrossRefPubMedGoogle Scholar
  13. 13.
    Liu J, Zhou F, Li GY, Wang L, Li HX, Bai GY, et al. Evaluation of the effect of different doses of low energy shock wave therapy on the erectile function of streptozotocin (STZ)-induced diabetic rats. Int J Mol Sci. 2013;14(5):10661–73. PubMed PMID: 23698784. Pubmed Central PMCID: 3676859.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gruenwald I, Appel B, Kitrey ND, Vardi Y. Shockwave treatment of erectile dysfunction. Ther Adv Urol. 2013;5(2):95–9. PubMed PMID: 23554844. Pubmed Central PMCID: 3607492.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Holfeld J, Tepekoylu C, Kozaryn R, Urbschat A, Zacharowski K, Grimm M, et al. Shockwave therapy differentially stimulates endothelial cells: implications on the control of inflammation via toll-like receptor 3. Inflammation. 2014;37(1):65–70. PubMed PMID: 23948864.CrossRefPubMedGoogle Scholar
  16. 16.
    Wang CJ, Yang YJ, Huang CC. The effects of shockwave on systemic concentrations of nitric oxide level, angiogenesis and osteogenesis factors in hip necrosis. Rheumatol Int. 2011;31(7):871–7. PubMed PMID: 20232068.CrossRefPubMedGoogle Scholar
  17. 17.
    Zuoziene G, Laucevicius A, Leibowitz D. Extracorporeal shockwave myocardial revascularization improves clinical symptoms and left ventricular function in patients with refractory angina. Coron Artery Dis. 2012;23(1):62–7. PubMed PMID: 22107803.CrossRefPubMedGoogle Scholar
  18. 18.
    Ciccone MM, Notarnicola A, Scicchitano P, Sassara M, Carbonara S, Maiorano M, et al. Shockwave therapy in patients with peripheral artery disease. Adv Ther. 2012;29(8):698–707. PubMed PMID: 22869515.CrossRefPubMedGoogle Scholar
  19. 19.
    Qiu X, Lin G, Xin Z, Ferretti L, Zhang H, Lue TF, et al. Effects of low-energy shockwave therapy on the erectile function and tissue of a diabetic rat model. J Sex Med. 2013;10(3):738–46. PubMed PMID: 23253086. Pubmed Central PMCID: 3593747.CrossRefPubMedGoogle Scholar
  20. 20.
    Vardi Y, Appel B, Kilchevsky A, Gruenwald I. Does low intensity extracorporeal shock wave therapy have a physiological effect on erectile function? Short-term results of a randomized, double-blind, sham controlled study. J Urol. 2012;187(5):1769–75. PubMed PMID: 22425129.CrossRefPubMedGoogle Scholar
  21. 21.
    Condorelli RA, Calogero AE, Vicari E, Favilla V, Morgia G, Cimino S, et al. Vascular regenerative therapies for the treatment of erectile dysfunction: current approaches. Andrology. 2013;1(4):533–40. PubMed PMID: 23658196.CrossRefPubMedGoogle Scholar
  22. 22.
    Zhang H, Yang R, Wang Z, Lin G, Lue TF, Lin CS. Adipose tissue-derived stem cells secrete CXCL5 cytokine with neurotrophic effects on cavernous nerve regeneration. J Sex Med. 2011;8(2):437–46. PubMed PMID: 21114767. Pubmed Central PMCID: 3176296.CrossRefPubMedGoogle Scholar
  23. 23.
    Lin G, Banie L, Ning H, Bella AJ, Lin CS, Lue TF. Potential of adipose-derived stem cells for treatment of erectile dysfunction. J Sex Med. 2009;6 Suppl 3:320–7. PubMed PMID: 19267855. Pubmed Central PMCID: 2895916.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Xu LJ, Xue BX, Chen D, Gao J, Yang DR, Sun CY, et al. Isolation and passage of muscle-derived stem cells from the rat penile corpora cavernosa and induction of differentiation into smooth muscle cells. Cytotechnology. 2013;66:987–94. PubMed PMID: 24242826.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ryu JK, Kim DH, Song KM, Yi T, Suh JK, Song SU. Intracavernous delivery of clonal mesenchymal stem cells restores erectile function in a mouse model of cavernous nerve injury. J Sex Med. 2014;11(2):411–23. PubMed PMID: 24251583.CrossRefPubMedGoogle Scholar
  26. 26.
    Ouyang B, Sun X, Han D, Chen S, Yao B, Gao Y, et al. Human urine-derived stem cells alone or genetically-modified with FGF2 Improve type 2 diabetic erectile dysfunction in a rat model. PLoS One. 2014;9(3):e92825. PubMed PMID: 24663037. Pubmed Central PMCID: 3963968.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Huang YC, Ning H, Shindel AW, Fandel TM, Lin G, Harraz AM, et al. The effect of intracavernous injection of adipose tissue-derived stem cells on hyperlipidemia-associated erectile dysfunction in a rat model. J Sex Med. 2010;7(4 Pt 1):1391–400. PubMed PMID: 20141586. Pubmed Central PMCID: 3163604.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Qiu X, Villalta J, Ferretti L, Fandel TM, Albersen M, Lin G, et al. Effects of intravenous injection of adipose-derived stem cells in a rat model of radiation therapy-induced erectile dysfunction. J Sex Med. 2012;9(7):1834–41. PubMed PMID: 22548750. Pubmed Central PMCID: 3389585.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Piao S, Kim IG, Lee JY, Hong SH, Kim SW, Hwang TK, et al. Therapeutic effect of adipose-derived stem cells and BDNF-immobilized PLGA membrane in a rat model of cavernous nerve injury. J Sex Med. 2012;9(8):1968–79. PubMed PMID: 22642440.CrossRefPubMedGoogle Scholar
  30. 30.
    Ying C, Hu W, Cheng B, Yang M, Zheng X, Wang X. Erectile function restoration after repair of resected cavernous nerves by adipose-derived stem cells combined with autologous vein graft in rats. Cell Mol Neurobiol. 2014;34(3):393–402. PubMed PMID: 24398902.CrossRefPubMedGoogle Scholar
  31. 31.
    Lee SH, Kim IG, Jung AR, Shrestha KR, Lee JH, Park KD, et al. Combined effects of brain-derived neurotrophic factor immobilized poly-lactic-co-glycolic acid membrane with human adipose-derived stem cells and basic fibroblast growth factor hydrogel on recovery of erectile dysfunction. Tissue Eng A. 2014;20:2446–54. PubMed PMID: 24673637.CrossRefGoogle Scholar
  32. 32.
    Jeong HH, Piao S, Ha JN, Kim IG, Oh SH, Lee JH, et al. Combined therapeutic effect of udenafil and adipose-derived stem cell (ADSC)/brain-derived neurotrophic factor (BDNF)-membrane system in a rat model of cavernous nerve injury. Urology. 2013;81(5):1108 e7–14. PubMed PMID: 23522997.CrossRefPubMedGoogle Scholar
  33. 33.
    Daly WT, Knight AM, Wang H, de Boer R, Giusti G, Dadsetan M, et al. Comparison and characterization of multiple biomaterial conduits for peripheral nerve repair. Biomaterials. 2013;34(34):8630–9. PubMed PMID: 23937914.CrossRefPubMedGoogle Scholar
  34. 34.
    May F, Weidner N, Matiasek K, Caspers C, Mrva T, Vroemen M, et al. Schwann cell seeded guidance tubes restore erectile function after ablation of cavernous nerves in rats. J Urol. 2004;172(1):374–7. PubMed PMID: 15201814.CrossRefPubMedGoogle Scholar
  35. 35.
    Bhatheja K, Field J. Schwann cells: origins and role in axonal maintenance and regeneration. Int J Biochem Cell Biol. 2006;38(12):1995–9. PubMed PMID: 16807057.CrossRefPubMedGoogle Scholar
  36. 36.
    Angeloni NL, Bond CW, Tang Y, Harrington DA, Zhang S, Stupp SI, et al. Regeneration of the cavernous nerve by Sonic hedgehog using aligned peptide amphiphile nanofibers. Biomaterials. 2011;32(4):1091–101. PubMed PMID: 20971506. Pubmed Central PMCID: 2993249.CrossRefPubMedGoogle Scholar
  37. 37.
    Bond CW, Angeloni N, Harrington D, Stupp S, Podlasek CA. Sonic Hedgehog regulates brain-derived neurotrophic factor in normal and regenerating cavernous nerves. J Sex Med. 2013;10(3):730–7. PubMed PMID: 23237228. Pubmed Central PMCID: 3593960.CrossRefPubMedGoogle Scholar
  38. 38.
    Bella AJ, Lin G, Tantiwongse K, Garcia M, Lin CS, Brant W, et al. Brain-derived neurotrophic factor (BDNF) acts primarily via the JAK/STAT pathway to promote neurite growth in the major pelvic ganglion of the rat: part I. J Sex Med. 2006;3(5):815–20. PubMed PMID: 16942526.CrossRefPubMedGoogle Scholar
  39. 39.
    Lin G, Bella AJ, Lue TF, Lin CS. Brain-derived neurotrophic factor (BDNF) acts primarily via the JAK/STAT pathway to promote neurite growth in the major pelvic ganglion of the rat: part 2. J Sex Med. 2006;3(5):821–7, discussion 8–9. PubMed PMID: 16942527.Google Scholar
  40. 40.
    Song LJ, Xu YM, Li C, Fu Q, Cui L, Hu XY. Construction of cavernosum smooth muscle using umbilical artery smooth muscle cells seeded on acellular corporal collagen matrices. Int J Androl. 2009;32(5):514–23. PubMed PMID: 18399980.CrossRefPubMedGoogle Scholar
  41. 41.
    Chen KL, Eberli D, Yoo JJ, Atala A. Bioengineered corporal tissue for structural and functional restoration of the penis. Proc Natl Acad Sci U S A. 2010;107(8):3346–50. PubMed PMID: 19915140. Pubmed Central PMCID: 2840474.CrossRefPubMedGoogle Scholar
  42. 42.
    Ji C, Min F, Liang W, Chen Y, Pan S, Bin L, et al. Construction of tissue-engineered corpus cavernosum with muscle-derived stem cells and transplantation in vivo. BJU Int. 2011;107(10):1638–46. PubMed PMID: 20868390.CrossRefPubMedGoogle Scholar
  43. 43.
    Imbeault A, Bernard G, Ouellet G, Bouhout S, Carrier S, Bolduc S. Surgical option for the correction of Peyronie’s disease: an autologous tissue-engineered endothelialized graft. J Sex Med. 2011;8(11):3227–35. PubMed PMID: 21718447.CrossRefPubMedGoogle Scholar
  44. 44.
    Ma L, Yang Y, Sikka SC, Kadowitz PJ, Ignarro LJ, Abdel-Mageed AB, et al. Adipose tissue-derived stem cell-seeded small intestinal submucosa for tunica albuginea grafting and reconstruction. Proc Natl Acad Sci U S A. 2012;109(6):2090–5. PubMed PMID: 22308363. Pubmed Central PMCID: 3277542.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Burnett AL. Erectile dysfunction management for the future. J Androl. 2009;30(4):391–6. PubMed PMID: 18802198.CrossRefPubMedGoogle Scholar
  46. 46.
    Hatzimouratidis K. Editorial comment on: smooth-muscle-specific gene transfer with the human maxi-K channel improves erectile function and enhances sexual behavior in atherosclerotic cynomolgus monkeys. Eur Urol. 2009;56(6):1066. PubMed PMID: 19167151.CrossRefPubMedGoogle Scholar
  47. 47.
    Bivalacqua TJ, Champion HC, Mehta YS, Abdel-Mageed AB, Sikka SC, Ignarro LJ, et al. Adenoviral gene transfer of endothelial nitric oxide synthase (eNOS) to the penis improves age-related erectile dysfunction in the rat. Int J Impot Res. 2000;12 Suppl 3:S8–17. PubMed PMID: 11002394.CrossRefPubMedGoogle Scholar
  48. 48.
    Magee TR, Ferrini MG, Davila HH, Zeller CB, Vernet D, Sun J, et al. Protein inhibitor of nitric oxide synthase (NOS) and the N-methyl-D-aspartate receptor are expressed in the rat and mouse penile nerves and colocalize with penile neuronal NOS. Biol Reprod. 2003;68(2):478–88. PubMed PMID: 12533411.CrossRefPubMedGoogle Scholar
  49. 49.
    Magee TR, Kovanecz I, Davila HH, Ferrini MG, Cantini L, Vernet D, et al. Antisense and short hairpin RNA (shRNA) constructs targeting PIN (protein inhibitor of NOS) ameliorate aging-related erectile dysfunction in the rat. J Sex Med. 2007;4(3):633–43. PubMed PMID: 17433082.CrossRefPubMedGoogle Scholar
  50. 50.
    Bivalacqua TJ, Kendirci M, Champion HC, Hellstrom WJ, Andersson KE, Hedlund P. Dysregulation of cGMP-dependent protein kinase 1 (PKG-1) impairs erectile function in diabetic rats: influence of in vivo gene therapy of PKG1alpha. BJU Int. 2007;99(6):1488–94. PubMed PMID: 17355372.CrossRefPubMedGoogle Scholar
  51. 51.
    Chang S, Hypolite JA, Velez M, Changolkar A, Wein AJ, Chacko S, et al. Downregulation of cGMP-dependent protein kinase-1 activity in the corpus cavernosum smooth muscle of diabetic rabbits. Am J Physiol Regul Integr Comp Physiol. 2004;287(4):R950–60. PubMed PMID: 15205187.CrossRefPubMedGoogle Scholar
  52. 52.
    Bivalacqua TJ, Deng W, Kendirci M, Usta MF, Robinson C, Taylor BK, et al. 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(3):H1278–90. PubMed PMID: 17071732.CrossRefPubMedGoogle Scholar
  53. 53.
    Chancellor MB, Tirney S, Mattes CE, Tzeng E, Birder LA, Kanai AJ, et al. Nitric oxide synthase gene transfer for erectile dysfunction in a rat model. BJU Int. 2003;91(7):691–6. PubMed PMID: 12699487.CrossRefPubMedGoogle Scholar
  54. 54.
    Tirney S, Mattes CE, Yoshimura N, Yokayama T, Ozawa H, Tzeng E, et al. Nitric oxide synthase gene therapy for erectile dysfunction: comparison of plasmid, adenovirus, and adenovirus-transduced myoblast vectors. Mol Urol. 2001;5(1):37–43. PubMed PMID: 11689150.CrossRefPubMedGoogle Scholar
  55. 55.
    Bakircioglu ME, Lin CS, Fan P, Sievert KD, Kan YW, Lue TF. The effect of adeno-associated virus mediated brain derived neurotrophic factor in an animal model of neurogenic impotence. J Urol. 2001;165(6 Pt 1):2103–9. PubMed PMID: 11371936.CrossRefPubMedGoogle Scholar
  56. 56.
    Gholami SS, Rogers R, Chang J, Ho HC, Grazziottin T, Lin CS, et al. The effect of vascular endothelial growth factor and adeno-associated virus mediated brain derived neurotrophic factor on neurogenic and vasculogenic erectile dysfunction induced by hyperlipidemia. J Urol. 2003;169(4):1577–81. PubMed PMID: 12629419.CrossRefPubMedGoogle Scholar
  57. 57.
    Kato R, Wolfe D, Coyle CH, Huang S, Wechuck JB, Goins WF, et al. Herpes simplex virus vector-mediated delivery of glial cell line-derived neurotrophic factor rescues erectile dysfunction following cavernous nerve injury. Gene Ther. 2007;14(18):1344–52. PubMed PMID: 17611585.PubMedGoogle Scholar
  58. 58.
    Kato R, Wolfe D, Coyle CH, Wechuck JB, Tyagi P, Tsukamoto T, et al. Herpes simplex virus vector-mediated delivery of neurturin rescues erectile dysfunction of cavernous nerve injury. Gene Ther. 2009;16(1):26–33. PubMed PMID: 18668142. Pubmed Central PMCID: 2615792.CrossRefPubMedGoogle Scholar
  59. 59.
    Dall’Era JE, Meacham RB, Mills JN, Koul S, Carlsen SN, Myers JB, et al. Vascular endothelial growth factor (VEGF) gene therapy using a nonviral gene delivery system improves erectile function in a diabetic rat model. Int J Impot Res. 2008;20(3):307–14. PubMed PMID: 18273028.CrossRefPubMedGoogle Scholar
  60. 60.
    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(1):26–37. PubMed PMID: 12605238.CrossRefPubMedGoogle Scholar
  61. 61.
    Song KM, Chung JS, Choi MJ, Jin HR, Yin GN, Kwon MH, et al. Effectiveness of intracavernous delivery of adenovirus encoding Smad7 gene on erectile function in a mouse model of cavernous nerve injury. J Sex Med. 2014;11(1):51–63. PubMed PMID: 24433558.CrossRefPubMedGoogle Scholar
  62. 62.
    Bivalacqua TJ, Usta MF, Kendirci M, Pradhan L, Alvarez X, Champion HC, et al. Superoxide anion production in the rat penis impairs erectile function in diabetes: influence of in vivo extracellular superoxide dismutase gene therapy. J Sex Med. 2005;2(2):187–97, discussion 97–8. PubMed PMID: 16422885.Google Scholar
  63. 63.
    Chitaley K, Bivalacqua TJ, Champion HC, Usta MF, Hellstrom WJ, Mills TM, et al. Adeno-associated viral gene transfer of dominant negative RhoA enhances erectile function in rats. Biochem Biophys Res Commun. 2002;298(3):427–32. PubMed PMID: 12413959.CrossRefPubMedGoogle Scholar
  64. 64.
    Christ GJ, Day N, Santizo C, Sato Y, Zhao W, Sclafani T, et al. Intracorporal injection of hSlo cDNA restores erectile capacity in STZ-diabetic F-344 rats in vivo. Am J Physiol Heart Circ Physiol. 2004;287(4):H1544–53. PubMed PMID: 15371262.CrossRefPubMedGoogle Scholar
  65. 65.
    Christ GJ, Rehman J, Day N, Salkoff L, Valcic M, Melman A, et al. Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in penile function. Am J Physiol. 1998;275(2 Pt 2):H600–8. PubMed PMID: 9683449.PubMedGoogle Scholar
  66. 66.
    Melman A, Biggs G, Davies K, Zhao W, Tar MT, Christ GJ. Gene transfer with a vector expressing Maxi-K from a smooth muscle-specific promoter restores erectile function in the aging rat. Gene Ther. 2008;15(5):364–70. PubMed PMID: 18200069.CrossRefPubMedGoogle Scholar
  67. 67.
    Drago F, Busa L. Acute low doses of melatonin restore full sexual activity in impotent male rats. Brain Res. 2000;878(1–2):98–104. PubMed PMID: 10996140.CrossRefPubMedGoogle Scholar
  68. 68.
    Qiu XF, Li XX, Chen Y, Lin HC, Yu W, Wang R, et al. Mobilisation of endothelial progenitor cells: one of the possible mechanisms involved in the chronic administration of melatonin preventing erectile dysfunction in diabetic rats. Asian J Androl. 2012;14(3):481–6. PubMed MID: 22367180. Pubmed Central PMCID: 3720169.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Tijmes M, Pedraza R, Valladares L. Melatonin in the rat testis: evidence for local synthesis. Steroids. 1996;61(2):65–8. PubMed PMID: 8750434.CrossRefPubMedGoogle Scholar
  70. 70.
    Yamada K, Maruyama K, Mogami S, Miyagawa N, Tsuboi M. Influence of melatonin on reproductive behavior in male rats. Chem Pharm Bull. 1992;40(8):2222–3. PubMed PMID: 1423787.CrossRefPubMedGoogle Scholar
  71. 71.
    Tavukcu HH, Sener TE, Tinay I, Akbal C, Ersahin M, Cevik O, et al. Melatonin and tadalafil treatment improves erectile dysfunction after spinal cord injury in rats. Clin Exp Pharmacol Physiol. 2014;41(4):309–16. PubMed PMID: 24552354.CrossRefPubMedGoogle Scholar
  72. 72.
    Hannan JL, Albersen M, Kutlu O, Gratzke C, Stief CG, Burnett AL, et al. Inhibition of Rho-kinase improves erectile function, increases nitric oxide signaling and decreases penile apoptosis in a rat model of cavernous nerve injury. J Urol. 2013;189(3):1155–61. PubMed PMID: 23021998. Pubmed Central PMCID: 4007006.CrossRefPubMedGoogle Scholar
  73. 73.
    Hannan JL, Kutlu O, Stopak BL, Liu X, Castiglione F, Hedlund P, et al. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats. J Sex Med. 2014;11:1442–51. PubMed PMID: 24636283.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Scott Department of UrologyBaylor College of MedicineHoustonUSA
  2. 2.Urology of IndianaCarmelUSA

Personalised recommendations