A Comprehensive Review of Erectile Dysfunction in Men with Diabetes

Abstract

Erectile dysfunction (ED) is more common in men with diabetes (DM). Dependent on the selected population, age, DM type and duration, the prevalence of diabetic ED (DED) varies from 32 to 90%. In 12–30% of men ED is the first sign of diabetes, diagnosed later. Today men with diabetes live longer than ever, and develop more late diabetic complications. Having in mind also the global ageing of the world population all this data suggests an increasing number of men with DED in the future. The main factors playing in the complex pathogenesis of DED are diabetic neuropathy (oxidative stress, polyol pathway, advanced glycation end-products, nerve growth factor deficiency, dysfunction of protein kinase C, tissue remodeling, etc.), macrovascular arterial disease (endothelial dysfunction, abnormal collagen deposition and smooth muscle degeneration, dyslipidemia, arterial hypertension, veno-occlusive dysfunction, etc.), hypogonadism, structural remodeling of the corporeal tissue, psychogenic components and adverse drug reactions. The diagnostic process is based on the results of questionnaires, neurological, vascular (Doppler) and other more rarely used investigations.

Because of the complex pathogenesis of DED diabetic men represent a “difficult” treatment group. The difficulties are from the “beginning”, because patients do not talk about their problem spontaneously, and doctors do not ask about it. The treatment of DED should be team work, preferably including also specialists in sexual medicine. Psychological support and counseling of the couple is necessary in most cases. The general measures include implementation of a healthier lifestyle, improved glycemic-, lipids-, and arterial pressure control, and careful re-evaluation of the concomitant medications. The specific treatment includes as first line therapy the inhibitors of phosphodiesterase type 5 (PDE-5) with lesser effectiveness compared to non-DM men. There are rare studies with selected diabetic populations and even less with head-to-head comparisons between the PDE-5 inhibitors. Men with DM have a higher prevalence of hypogonadism. Testosterone replacement therapy should be started in symptomatic men with proven hypogonadism and no contraindications. Vacuum constriction devices and intracavernous or intraurethral applications of vasoactive drugs are the second line therapy. Vascular surgery rarely comes into consideration. The penile implant is the last and effective option in men with severe DED.

Key words

erectile dysfunction - diabetes - diabetic neuropathy - PDE-5 inhibitor - intracavernosal injection - penile implant

• References

• 1 Aaberg ML, Burch DM, Hud ZR et al. Gender differences in the onset of diabetic neuropathy. J Diabetes Complications 2008; 22: 83-87
• 2 Adegite A, Aniekwensi E, Ohihoin A et al. Perception about aetiology of sexual problems, health seeking behavior and treatment for sexual problems among type 2 diabetic men. 20^th IDF World Congress, 18–22.10.2009, Montreal, Canada; P-1370, Book of abstracts p.462
• 3 Al-Amran FG, Zwain AA, Hadi NR et al. Autonomic cerebral vascular response to sildenafil in diabetic patient. Diabetol Metab Syndr 2012; 27; 4: 2
• 4 Angelopoulos N, Papanikolaou G, Noutsou M et al. Glucose Metabolism, Insulin Secretion and Insulin Sensitivity in Juvenile Hemochromatosis. A Case Report and Review of the Literature. Exp Clin Endocrinol Diabetes 2007; 115: 192-197
• 5 Angulo J, González-Corrochano R, Cuevas P et al. Diabetes exacerbates the functional deficiency of NO/cGMP pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries. J Sex Med 2010; 7 (2 Pt 1) 758-768
• 6 Arafa M, Eid H, El-Badry A et al. The prevalence of Peyronie’s disease in diabetic patients with erectile dysfunction. Int J Impot Res 2007; 19: 213-217
• 7 Avasthi A, Grover S, Bhansali A et al. Erectile dysfunction in diabetes mellitus contributes to poor quality of life. Int Rev Psychiatry 2011; 23: 93-99
• 8 Baba K, Yajima M, Carrier S et al. 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
• 9 Bacon CG, Hu FB, Giovannucci E et al. Association of type and duration of diabetes with erectile dysfunction in a large cohort of men. Diabetes Care 2002; 25: 1458
• 10 Bartolini M, Giommi R, Forti G et al. Organic, relational and psychological factors in erectiledys function in men with diabetes mellitus. Eur Urol 2004; 46: 222-228
• 11 Basu A, Ryder RE. New treatment options for erectile dysfunction in patients with diabetes mellitus. Drugs 2004; 64: 2667-2688
• 12 Belkoff LH, McCullough A, Goldstein I et al. An open-label, long-term evaluation of the safety, efficacy and tolerability of avanafil in male patients with mild to severe erectile dysfunction. Int J Clin Pract 2013; 67: 333-341
• 13 Berardis GD, Franciosi M, Belfigli M et al. Erectile dysfunction and quality of life in type 2 diabetic patients: A serious problem too often overlooked. Diabetes Care 2002; 25: 284-291
• 14 Bivalacqua TJ, Champion HC, Usta MF et al. RhoA/Rhokinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. Proc Natl Acad Sci USA 2004; 101: 9121-9126
• 15 Bivalacqua TJ, Usta MF, Champion HC et al. Endothelial dysfunction in erectile dysfunction: role of the endothelium in erectile physiology and disease. J Androl 2003; 24 (Suppl. 06) S17-S37
• 16 Bivalacqua TJ, Usta MF, Kendirci M et al. Superoxide anion production in the rat penis impairs EF in diabetes: influence of in vivo extracellular superoxide dismutase gene therapy. J Sex Med 2005; 2: 187-197
• 17 Boulton AJ, Kempler P, Ametov A et al. Whither pathogenetic treatments for diabetic polyneuropathy?. Diabetes Metab Res Rev 2013; 29: 327-333
• 18 Brock G, Nehra A, Lipshultz LI et al. Safety and efficacy of vardenafil for the treatment of men with erectile dysfunction after radical retropubic prostatectomy. J Urol 2003; 170 (4, pt 1) 1278-1283
• 19 Brock GB, McMahon CG, Chen KK et al. Efficacy and safety of tadalafi l for the treatment of erectile dysfunction: results of integrated analyses. J Urol 2002; 168: 1332-1336
• 20 Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilation in experimental diabetes. J Clin Invest 1991; 87: 432-438
• 21 Burchardt T, Burchardt M, Karden J et al. Reduction of endothelial and smooth muscle density in the corpora cavernosa of the streptozotocin induced diabetic rat. J Urol 2000; 164: 1807-1811
• 22 Burke FP, Jacobson DF, McGree ME et al. Diabetes and sexual dysfunction in Olmsted County, Minnesota. J Sex Med 2006; 3 (Suppl. 01) 19
• 23 Burke JP, Jacobson DJ, McGree ME et al. Diabetes and sexual dysfunction: Result from Olmsted county study of urinary symptoms and health status among men. The journal of urology 2007; 177: 1438-1442
• 24 Burke RM, Evans JD. Avanafil for treatment of erectile dysfunction: review of its potential. Vasc Health Risk Manag 2012; 8: 517-523
• 25 Burnett AL, Strong TD, Trock BJ et al. Serum biomarker measurements of endothelial function and oxidative stress after daily dosing of sildenafil in type 2 diabetic men with erectile dysfunction. J Urol 2009; 181: 245-251
• 26 Buvat J, van Ahlen H, Schmitt H et al. Efficacy and safety of two dosing regimens of tadalafil and patterns of sexual activity in men with diabetes mellitus and erectile dysfunction: Scheduled use vs. on-demand regimen evaluation (SURE) study in 14 European countries. J Sex Med 2006; 3: 512-520
• 27 Buyukafsar K, Un I. Effects of the Rho-kinase inhibitors, Y-27632 and fasudil, on the corpus cavernosum from diabetic mice. Eur J Pharmacol 2003; 472: 235-238
• 28 Carson 3rd CC, Mulcahy JJ, Harsch MR. Long-term infection outcomes after original antibiotic impregnated inflatable penile prosthesis implants: up to 7.7 years of follow-up. J Urol 2011; 185: 614-618
• 29 Carson CC, Rajfer J, Eardley I et al. The efficacy and safety of tadalafi l: an update. BJU Int 2004; 93: 1276-1281
• 30 Carson CC, Shabsigh R, Segal S et al. Efficacy, safety, and treatment satisfaction of tadalafi l versus placebo in patients with erectile dysfunction evaluated at tertiary-care academic centers. Urology 2005; 65: 353-359
• 31 Cartledge JJ, Eardley I, Morrison JF. Advanced glycation end-products are responsible for the impairment of corpus cavernosal smooth muscle relaxation seen in diabetes. B J U Int 2001; 87: 402-407
• 32 Chitaley K, Kupelian V, Subak L et al. Diabetes, obesity and erectile dysfunction: field overview and research priorities. J Urol 2009; 182 (6 Suppl) S45-S50
• 33 Chitaley K. Type 1 and type 2 diabetic-erectile dysfunction: same diagnosis (ICD-9), different disease?. J Sex Med 2009; 6 (suppl) 262
• 34 Christ GJ, Lerner SE, Kim DC et al. Endothelin-1 as a putative modulator of erectile dysfunction: I. Characteristics of contraction of isolated corporal tissue strips. J Urol 1995; 153: 1998-2003
• 35 Chrysant SG. Effectiveness and safety of phosphodiesterase 5 inhibitors in patients with cardiovascular disease and hypertension. Curr Hypertens Rep 2013; 15: 475-483
• 36 Chua R, Tar M, Melman A et al. Streptozotocin-induced diabetes results in time-dependent upregulation of the endothelin/rho-kinase pathway in rat corpus cavernosum smooth muscle. J Sex Med 2006; 3 (Suppl. 01) 25
• 37 Chung E, Van CT, Wilson I et al. Penile prosthesis implantation for the treatment for male erectile dysfunction: clinical outcomes and lessons learnt after 955 procedures. World J Urol 2013; 31: 591-595
• 38 Clozel M, Gray GA, Breu V et al. The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo. Biochem Biophys Res Commun 1992; 186: 867-873
• 39 Coombs PG, Heck M, Guhring P et al. A review of outcomes of an intracavernosal injection therapy programme. BJU Int 2012; 110: 1787-1791
• 40 Corona G, Giorda CB, Cucinotta D et al . Gruppo di studio SUBITODE . Sexual dysfunction at the onset of type 2 diabetes: The interplay of depression, hormonal and cardiovascular factors. J Sex Med 2014; 11: 2065-2073
• 41 Corona G, Mannucci E, Petrone L et al. NCEP-ATPIII-defined metabolic syndrome, type 2 diabetes mellitus, and prevalence of hypogonadism in male patients with sexual dysfunction. J Sex Med 2007; 4: 1038-1045
• 42 Corrales JJ, Burgo RM, Garca-Berrocal B et al. Partial androgen deficiency in aging type 2 diabetic men and its relationship to glycemic control. Metabolism 2004; 53: 666-672
• 43 Dean J, Hackett GI, Gentile V et al. Psychosocial outcomes and drug attributes affecting treatment choice in men receiving sildenafil citrate and tadalafil for the treatment of erectile dysfunction: results of a multicenter, randomized, open-label, crossover study. J Sex Med 2006; 3: 650-661
• 44 Deyoung L, Chung E, Kovac JR et al. Daily use of sildenafil improves endothelial function in men with type 2 diabetes. J Androl 2012; 33: 176-180
• 45 Diemont W, Meuleman E. Neurological testing in erectile dysfunction. J Androl 1997; 18: 345-350
• 46 Dimmeler S, Zeiher AM. Endothelial cell apoptosis in angiogenesis and vessel regression. Circulation Research 2000; 87: 434-439
• 47 Drivsholm T, de Fine Olivarius N, Nielsen AB et al. Symptoms, signs and complications in newly diagnosed type 2 diabetic patients, and their relationship to glycaemia, blood pressure and weight. Diabetologia 2005; 48: 210-214
• 48 Dyck PJ, Kratz KM, Karnes JL et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993; 43: 817-824
• 49 Eardley I, Fisher W, Rosen RC et al. The multinational Men's Attitudes to Life Events and Sexuality study: the influence of diabetes on self-reported erectile function, attitudes and treatment-seeking patterns in men with erectile dysfunction. Int J Clin Pract 2007; 61: 1446-1453
• 50 Eardley I, Rosen R, Fisher WA et al. Attitudes toward treatment of erectile dysfunction: results from the MALES study. Eur Urol Suppl 2003; 2: 97 Abstract 377
• 51 Eid JF, Wilson SK, Cleves M et al. Coated implants and "no touch" surgical technique decreases risk of infection in inflatable penile prosthesis implantation to 0.46%. Urology 2012; 79: 1310-1315
• 52 El-Sakka AI, Tayeb KA. Peyronie’s disease in diabetic patients being screened for erectile dysfunction. J Urol 2005; 174: 1026-1030
• 53 Fakjian N, Hunter S, Cole GW et al. An argument for circumcision.Prevention of balanitis in the adult. Arch Dermatol 1990; 126: 1046-1047
• 54 Fedele D, Coscelli C, Santeusanio F et al. Erectile dysfunction in diabetic subjects in Italy. Gruppo Italiano Studio Deficit Erettile nei Diabetici. Diabetes Care 1998; 21: 1973-1977
• 55 Feldman HA, Goldstein I, Hatzichristou DG et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54-61
• 56 Frøkjær JB, Brock C, Søfteland E et al. Macrostructural Brain Changes in Patients with Longstanding Type 1 Diabetes Mellitus – a Cortical Thickness Analysis Study. Exp Clin Endocrinol Diabetes 2013; 121: 354-360
• 57 Fonseca V, Seftel A, Denne J et al Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: analysis of data from tadalafil clinical trials. Diabetologia 2004; 47: 1914-1923
• 58 Gareri P, Castagna A, Francomano D et al. Erectile dysfunction in the elderly: an old widespread issue with novel treatment perspectives. Int J Endocrinol 2014; 17 Article ID 878670 15 pages
• 59 Giagulli VA, Moghetti P, Kaufman JM et al. Managing erectile dysfunction in heart failure. Endocr Metab Immune Disord Drug Targets 2013; 13: 125-134
• 60 Giugliano F, Maiorino MI, Bellastella G et al. Adherence to Mediterranean diet and erectile dysfunction in men with type 2 Diabetes. J Sex Med 2010; 7: 1911-1917
• 61 Gluckman E. Hemochromatosis in heterozygotes. N Engl J Med 1996; 24: 1837-1838
• 62 Goldstein I, Young JM, Fischer J et al. Vardenafil Diabetes Study Group . Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 2003; 26: 777-783
• 63 Goldstein I, Jones LA, Belkoff LH et al. Avanafil for the treatment of erectile dysfunction: a multicenter, randomized, double-blind study in men with diabetes mellitus. Mayo Clin Proc 2012; 87: 843-852
• 64 Grover-Páez F, Villegas Rivera G, Guillén Ortíz R. Sildenafil citrate diminishes microalbuminuria and the percentage of A1c in male patients with type 2 diabetes. Diabetes Res Clin Pract 2007; 78: 136-140
• 65 Hakim LS, Goldstein I. Diabetic sexual dysfunction. Endocrinol Metab Clin North Am 1996; 25: 379-400
• 66 Hatzichristou D, Montorsi F, Buvat J et al. European Vardenafil Study Group . The efficacy and safety of flexible-dose vardenafil (levitra) in a broad population of European men. Eur Urol 2004; 45: 634-641
• 67 Hatzimouratidis K, Hatzichristou DG. A comparative review of the options for treatment of erectile dysfunction: which treatment for which patient?. Drugs 2005; 65: 1621-1650
• 68 Hecht MJ, Neundorfer B, Kiesewetter F et al. Neuropathy is a major contributing factor to diabetic erectile dysfunction. Neurol Res 2001; 23: 651-654
• 69 Hellstrom WJ, Gittelman M, Karlin G et al. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, doubleblind, placebo-controlled trial. J Androl 2002; 23: 763-771
• 70 Hidalgo-Tamola J, Chitaley K. Type 2 diabetes mellitus and erectile dysfunction. J Sex Med 2009; 6: 916-926
• 71 Hidmark A, Fleming T, Vittas S et al. A New Paradigm to Understand and Treat Diabetic Neuropathy. Exp Clin Endocrinol Diabetes 2014; 122: 201-207
• 72 Incrocci L, Slob AK, Hop WC. Tadalafi l (Cialis) and erectile dysfunction after radiotherapy for prostate cancer: an open-label extension of a blinded trial. Urology 2007; 70: 1190-1193
• 73 International Diabetes Federation, IDF Diabetes atlas 6^th edition 2013
• 74 Jarow JP. Risk factors for penile prosthetic infection. J Urol 1996; 156 (2 Pt 1) 402-404
• 75 Jesmin S, Sakuma I, Salah-Eldin A et al. Diminished penile expression of vascular endothelial growth factor and its receptors at the insulin-resistant stage of a type II diabetic rat model: a possible cause for erectile dysfunction in diabetes. J Mol Endocrinol 2003; 31: 401-418
• 76 Jevtich MJ, Khawand NY, Vidic B. Clinical significance of ultrastructural findings in the corpora cavernosa of normal and impotent men. J Urol 1990; 143: 289-293
• 77 Johannes CB, Araujo AB, Feldman HA et al. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts Male Aging Study. J Urol 2000; 163: 460
• 78 Kadioglu A, Oktar T, Kandirali E et al. Incidentally diagnosed Peyronie’s disease in men presenting with erectile dysfunction. Int J Impot Res 2004; 16: 540-543
• 79 Kamenov Z, Christov V, Yankova T. Erectile dysfunction in diabetic men – linked more to microangiopathic complications and neuropathy than to macroangiopathic disturbances. Journal of Men’s Health and Gender 2007; 4: 64-73
• 80 Kamenov Z, Higashino H, Todorova M et al. Physiological characteristics of diabetic neuropathy in sucrose-fed Otsuka Long-Evans Tokushima fatty rats. Methods Find Exp Clin Pharmacol 2006; 28: 13-18
• 81 Kamenov Z. Comparison of the first intake of vardenafil and tadalafil in patients with diabetic neuropathy and diabetic erectile dysfunction. JSM 2011; 8: 851-864
• 82 Kamenov Z. Erectile dysfunction in diabetic men. In: Sexual dysfunctions. Risk factors, psychological impact, and treatment. (ed.). Frederique Courtois . Nova Science Publishers, Inc.; New York: 2013. ISBN: 978-1-62808-768-0
• 83 Kamenov ZA, Parapunova RA, Georgieva RT. Earlier development of diabetic neuropathy in men than in women with type 2 diabetes mellitus. Gend Med 2010; 7: 600-615
• 84 Kamenov ZA, Petrova JJ, Christov VG. Diagnosis of diabetic neuropathy using simple somatic and a new autonomic (neuropad) tests in the clinical practice. Exp Clin Endocrinol Diabetes 2010; 118: 226-233
• 85 Kamenov ZA, Traykov LD. Diabetic autonomic neuropathy. Adv Exp Med Biol 2012; 771: 176-193
• 86 Kamenov ZA, Traykov LD. Diabetic somatic neuropathy. Adv Exp Med Biol 2012; 771: 155-175
• 87 Kang SG, Kim JJ. Udenafil: efficacy and tolerability in the management of erectile dysfunction. Ther Adv Urol 2013; 5: 101-110
• 88 Kawano K, Hirashima T, Mori S et al. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 1992; 41: 1422-1428
• 89 Khan MA, Thompson CS, Jeremy JY et al. The effect of superoxide dismutase on nitric oxide-mediated and electrical field-stimulated diabetic rabbit cavernosal smooth muscle relaxation. BJU Int 2001; 87: 98-103
• 90 Klein R, Klein BE, Moss SE. Ten-year incidence of self-reported erectile dysfunction in people with long-term type 1 diabetes. J Diabetes Compl 2005; 19: 35
• 91 Levine LA, Dimitriou RJ. Vacuum constriction and external erection devices in erectile dysfunction. Urol Clin North Am 2001; 28: 335-341
• 92 Lewis RW. Epidemiology of erectile dysfunction. Urol Clin North Am 2001; 28: 209-216
• 93 Lin C-S, Ho H-C, Chen K-C et al. Intracavernosal injection of vascular endothelial growth factor induces nitric oxide synthase isoforms. BJU International 2002; 89: 955-960
• 94 Lu C-C, Jiann B-P, Sun C-C et al. Association of glycemic control with risk of erectile dysfunction in men with type 2 diabetes. J Sex Med 2009; 6: 1719-1728
• 95 Lu YL, Shen ZJ, Wang H et al. Ultrastructural changes of penile tunica albuginea in diabetic rats. Asian J Androl 2004; 6: 365-368
• 96 Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009; 6: 1232-1247
• 97 Malavige LS, Jayaratne SD, Kathriarachchi ST et al. Erectile dysfunction among men with diabetes is strongly associated with premature ejaculation and reduced libido. J Sex Med 2008; 5: 2125-2134
• 98 Manes C, Papanas N, Exiara T et al. The Indicator Test Neuropad in the Assessment of Small and Overall Nerve Fibre Dysfunction in Patients with Type 2 Diabetes: a Large Multicentre Study. Exp Clin Endocrinol Diabetes 2014; 122: 195-199
• 99 Martin-Morales A, Sanchez-Cruz JJ, Saenz de Tejada I et al. Prevalence and independent risk factors for erectile dysfunction in Spain: results of the Epidemiologia de la Disfuncion Erectil Masculina Study. J Urol 2001; 166: 569-574
• 100 McMahon C. Efficacy and safety of daily tadalafil in men with erectile dysfunction previously unresponsive to on-demand tadalafil. J Sex Med 2004; 1: 292-300
• 101 Meuleman EJ, Eardley I, Rosen R et al. Attitudes toward treatment of erectile dysfunction: results from the MALES (Men’s Attitudes toward Life Events and Sexuality) study. Presented at: Annual Meeting of the Asian Pacific Society of Sexual and Impotence Research; Cebu, Philippines 2003
• 102 Ming XF, Viswambharan H, Barandier C et al. Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells. Mol Cell Biol 2002; 22: 8467-8477
• 103 Montague DK, Angermeier KW, Lakin MM. Penile prosthesis infections. Int J Impot Res 2001; 13: 326-328
• 104 Montorsi F, Hellstrom WJ, Valiquette L et al. North American and European Vardenafil Groups . Vardenafil provides reliable efficacy over time in men with erectile dysfunction. Urology 2004; 64: 1187-1195
• 105 Montorsi P, Montorsi F, Schulman CC. Is erectile dysfunction the “tip of the iceberg” of a systemic vascular disorder?. Eur Urol 2003; 44: 352-354
• 106 Moon du G, Yang DY, Lee CH et al. A therapeutic confirmatory study to assess the safety and efficacy of Zydena (udenafil) for the treatment of erectile dysfunction in male patients with diabetes mellitus. J Sex Med 2011; 8: 2048-2061
• 107 Moore CR, Wang R. Pathophysiology and treatment of diabetic erectile dysfunction. Asian J Androl 2006; 8: 675-684
• 108 Mulligan T, Frick MF, Zuraw QC et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006; 60: 762-769
• 109 Musicki B, Palese MA, Crone JK et al. Phosphorylated endothelial nitric oxide synthase mediates vascular endothelial growth factor-induced penile erection. Biol Reprod 2004; 70: 282-289
• 110 National Intelligence Council Global trends 2025: A Transformed World 2008
• 111 Ng KK, Lim HC, Ng FC et al. The use of sildenafil in patients with erectile dysfunction in relation to diabetes mellitus – a study of 1,511 patients. Singapore Med J 2002; 43: 387-390
• 112 Nieschlag E, Swerdloff R, Behre HM et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. J Androl 2006; 27: 135-137
• 113 Nofzinger EA. Sexual Dysfunction in Patients with Diabetes Mellitus: The Role of a "Central" Neuropathy. Semin Clin Neuropsychiatry 1997; 2: 31-39
• 114 Padma-Nathan H. Efficacy and tolerability of tadalafil, a novel phosphodiesterase 5 inhibitor, in treatment of erectile dysfunction. Am J Cardiol 2003; 92: 19M-25M
• 115 Papapetropoulos A, García-Cardeña G, Madri JA et al. Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. Journal of Clinical Investigation 1997; 100: 3131-3139
• 116 Park HJ, Choi HK, Ahn TY et al. Efficacy and safety of oral mirodenafil in the treatment of erectile dysfunction in diabetic men in Korea: a multicenter, randomized, double-blind, placebo-controlled clinical trial. J Sex Med 2010; 7: 2842-2850
• 117 Park JK, Lee SO, Kim YG et al. Role of rho-kinase activity in angiotensin II-induced contraction of rabbit clitoral cavernosum smooth muscle. Int J Impot Res 2002; 14: 472-477
• 118 Park SH, Park SW, Cha BY et al. Comparison of the efficacy and safety of once-daily dosing and on-demand use of udenafil for type 2 diabetic patients with erectile dysfunction. Asian J Androl 2014;
• 119 Penson DF, Latini DM, Lubeck DP et al. Do impotent men with diabetes have more severe erectile dysfunction and worse quality of life than the general population of impotent patients? Results from the Exploratory Comprehensive Evaluation of Erectile Dysfunction (ExCEED) database. Diabetes Care 2003; 26: 1093-1099
• 120 Phé V, Rouprêt M. Erectile dysfunction and diabetes: a review of the current evidence-based medicine and a synthesis of the main available therapies. Diabetes Metab 2012; 38: 1-13
• 121 Porst H, Oelke M, Goldfischer ER et al. Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia: subgroup analyses of pooled data from 4 multinational, randomized, placebo-controlled clinical studies. Urology 2013; 82: 667-673
• 122 Porst H, Rajfer J, Casabй A et al. Long-term safety and efficacy of tadalafil 5 mg dosed once daily in men with erectile dysfunction. J Sex Med 2008; 5: 2160-2169
• 123 Porst H, Rosen R, Padma-Nathan H et al. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int J Impot Res 2001; 13: 192-199
• 124 Porst HJB. (ed.). Standard practice in sexual medicine. 1^st edition. Oxford: Blackwell; 2007
• 125 Potempa AJ, Ulbrich E, Bernard I et al. Vardenafil Study Group . Efficacy of vardenafil in men with erectile dysfunction: a flexible-dose community practice study. Eur Urol 2004; 46: 73-79
• 126 Price D, Hackett G. Management of erectile dysfunction in diabetes: an update for 2008. Curr Diab Rep 2008; 8: 437-443
• 127 Price DE, Cooksey G, Jehu D et al. The management of impotence in diabetic men by vacuum tumescence therapy. Diabet Med 1991; 8: 964-967
• 128 Redrow GP, Thompson CM, Wang R. Treatment strategies for diabetic patients suffering from erectile dysfunction: an update. Expert Opin Pharmacother 2014; 15: 1827-1836
• 129 Rees RW, Ziessen T, Ralph DJ et al. Human and rabbit cavernosal smooth muscle cells express Rho-kinase. Int J Impot Res 2002; 14: 1-7
• 130 Reinhardt W, Darwiche K, Wiemann J et al. Sleep apnoe syndrome is associated with low serum testosterone levels and reversible by cpap- treatment. Exp Clin Endocrinol Diabetes 2004; 112-P12
• 131 Rendell MS, Rajfer J, Wicker PA et al. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. Sildenafil Diabetes Study Group. JAMA 1999; 281: 421-426
• 132 Rhoden EL, Teloken C, Ting HY et al. Prevalence of Peyronie’s disease in men over 50-year-old from Southern Brazil. Int J Impot Res 2001; 13: 291-293
• 133 Rosen RC, Riley A, Wagner G et al. The international index of erectile function (IIEF): а multidimensional scale for assessment of erectile function. Urology 1997; 49: 822-830
• 134 Ryan JG. Cost and policy implications from the increasing prevalence of obesity and diabetes mellitus. Gender Medicine 2009; 6: 86-108
• 135 Ryu JK, Cho KS, Kim SJ et al. Korean Society for Sexual Medicine and Andrology (KSSMA) Guideline on Erectile Dysfunction. World J Mens Health 2013; 31: 83-102
• 136 Saenz de Tejada I, Anglin G, Knight JR et al. Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care 2002; 25: 2159-2164
• 137 Saenz de Tejada I, Emmick J, Anglin G et al. The effect of IC351 taken as needed for treatment of erectile dysfunction in men with diabetes. Eur Urol 2001; 39: 16 abs.55
• 138 Safarinejad MR. Oral sildenafil in the treatment of erectile dysfunction in diabetic men: a randomized double-blind and placebo-controlled study. J Diabetes Complications 2004; 18: 205-210
• 139 Schulman CC, Shen W, Stothard DR et al. Integrated analysis examining first-dose success, success by dose, and maintenance of success among men taking tadalafil for erectile dysfunction. Urology 2004; 64: 783-788
• 140 Schwarzer U, Sommer F, Klotz T et al. The prevalence of Peyronie’s disease: Results of a large survey. BJU Int 2001; 88: 727-730
• 141 Seftel AD, Vaziri ND, Ni Z et al. Advanced glycation end products in human penis: elevation in diabetic tissue, site of deposition, and possible effect through iNOS or eNOS. Urology 1997; 50: 1016-1026
• 142 Segal RL, Camper SB, Ma L et al. Prediction model for penile prosthesis implantation for erectile dysfunction management. Curr Med Res Opin 2014; 1: 1-7
• 143 Selvarajah D, Wilkinson ID, Maxwell M et al. Magnetic resonance neuroimaging study of brain structural differences in diabetic peripheral neuropathy. Diabetes Care 2014; 37: 1681-1688
• 144 Sheehy AM, Phung YT, Riemer RK et al. Growth factor induction of nitric oxide synthase in rat pheochromocytoma cells. Molecular Brain Research 1997; 52: 71-77
• 145 Siddiqui MA, Ahmed Z, Khan AA. Psychological Impact on Sexual Health among Diabetic Patients: A Review. International Journal of Diabetes Research 2012; 1: 28-31
• 146 Sidi AA, Becher EF, Zhang G et al. Patient acceptance of and satisfaction with an external negative pressure device for impotence. J Urol 1990; 144: 1154-1156
• 147 Siemons LJ, Mahler CH. Hypogonadotrophic hypogonadism in hemochromatosis: recovery of reproductive function after iron depletion. J Clin Endocrinol Metab 1987; 65: 585-587
• 148 Sima AAF, Ristic H, Merry A et al. The primary preventional and secondary interventative effects of acetyl-L-carnitine on diabetic neuropathy in the BB/W-rat. J Clin Invest 1996; 97: 1900-1907
• 149 Singh R, Barden A, Mori T et al. Advanced glycation end-products: a review. Diabetologia 2001; 44: 129-146
• 150 Smith AD. Causes and classification of impotence. Urol Clin North Am 1981; 8: 79-89
• 151 Song WD, Yuan YM, Cui WS et al. Penile prosthesis implantation in Chinese patients with severe erectile dysfunction: 10-year experience. Asian J Androl 2013; 15: 658-661
• 152 Stoian DI, Craciunescu M, Anastasiu DD et al. Sustained life style changes – impact on sexual quality, metabolic parameters and QoL in overweight men with metabolic syndrome. Exp Clin Endocrinol Diabetes 2014; 122-P172
• 153 Stracke H, Gaus W, Achenbach U et al. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes 2008; 116: 600-605
• 154 Stuckey BG, Jadzinsky MN, Murphy LJ et al. Sildenafil citrate for treatment of erectile dysfunction in men with type 1 diabetes: results of a randomized controlled trial. Diabetes Care 2003; 26: 279-284
• 155 Sun L, Peng FL, Yu ZL et al. Combined sildenafil with vacuum erection device therapy in the management of diabetic men with erectile dysfunction after failure of first-line sildenafil monotherapy. Int J Urol 2014;
• 156 Teerlink JR, Breu V, Sprecher U et al. Potent vasoconstriction mediated by endothelin ETB receptors in canine coronary arteries. Circ Res 1994; 74: 105-114
• 157 Tefekli A, Kandirali E, Erol B et al. Peyronie’s disease: A silent consequence of diabetes mellitus. Asian J Androl 2006; 8: 75-79
• 158 Tesfaye S, Stevens LK, Stephenson JM et al. Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study. Diabetologia 1996; 39: 1377-1384
• 159 Traish A, Kim N. The physiological role of androgens in penile erection: regulation of corpus cavernosum structure and function. J Sex Med 2005; 2: 759-770
• 160 Tsertsvadze A, Fink HA, Yazdi F et al. Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Ann Intern Med 2009; 151: 650-661
• 161 Usta MF, Bivalacqua TJ, Yang DY et al. The protective effect of aminoguanidine on erectile function in streptozotocin diabetic rats. J Urol 2003; 170: 1437-1442
• 162 Valiquette L, Young JM, Moncada I et al. Sustained efficacy and safety of vardenafil for treatment of erectile dysfunction: a randomized, double-blind, placebo-controlled study. Mayo Clin Proc 2005; 80: 1291-1297
• 163 Vardi M, Nini A. Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus. Cochrane Database Syst Rev 2007; 24 CD002187
• 164 Vardi Y, Sprecher E, Gruenwald I. Logistic regression and survival analysis of 450 impotent patients treated with injection therapy: long-term dropout parameters. J Urol 2000; 163: 467-470
• 165 Vickers MA, Wright EA. Erectile dysfunction in the patient with diabetes mellitus. Am J Manag Care 2004; 10 (1 Suppl) S3-S11
• 166 Vinik A, Richardson D. Erectile dysfunction in diabetes. Diabetes Rev 1998; 6: 16-33
• 167 Vinik AI, Holland MT, Le Beau JM et al. Diabetic neuropathies. Diabetes Care 1992; 15: 1926-1975
• 168 Wallis RM, Corbin JD, Francis SH et al. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 1999; 83: 3C-12C
• 169 Walsh TJ, Hotaling JM, Smith A et al. Men with diabetes may require more aggressive treatment for erectile dysfunction. Int J Impot Res 2014; 26: 112-115
• 170 Wang C, Nieschlag E, Swerdloff R et al. International Society of Andrology (ISA); International Society for the Study of Aging Male (ISSAM); European Association of Urology (EAU); European Academy of Andrology (EAA); American Society of Andrology (ASA) . Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl 2009; 30: 1-9
• 171 Wang H, Eto M, Steers WD et al. RhoA-mediated Ca2+ sensitization in erectile function. J Biol Chem 2002; 277: 30614-30621
• 172 Wilkinson ID, Selvarajah D, Greig M et al. Magnetic resonance imaging of the central nervous system in diabetic neuropathy. Curr Diab Rep 2013; 13: 509-516
• 173 Wilson SK, Carson CC, Cleves MA et al. Quantifying risk of penile prosthesis infection with elevated glycosylated haemoglobin. J Urol 1998; 159: 1537-1539 [discussion 1539–1540]
• 174 Wilson SK, Delk 2nd JR. Inflatable penile implant infection: predisposing factors and treatment suggestions. J Urol 1995; 153 (3 Pt 1) 659-661
• 175 Wing RR, Rosen RC, Fava JL et al. Effects of weight loss intervention on erectile function in older men with type 2 diabetes in the look AHEAD trial. J Sex Med 2010; 7: 156-165
• 176 Yagihashi S, Yamagishi S, Wada R. Pathology and pathogenetic mechanisms of diabetic neuropathy: Correlation with clinical signs and symptoms. Diabetes Res Clin Pract 2007; 77 (1 suppl) S184-S189
• 177 Yan SF, Ramasamy R, Schmidt AM. Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat Clin Pract Endocrinol Metab 2008; 4: 285-293
• 178 Yilmaz D, Bayatli N, Un O et al. The effect of intracavernosal avanafil, a newer phosphodiesterase-5 inhibitor, on neonatal type 2 diabetic rats with erectile dysfunction. Urology 2014; 83: 508
• 179 Young MJ, Boulton AJM, McLeod AF et al. A multicentre study of the prevalence of diabetic peripheral neuropathy in the UK hospital clinic population. Diabetologia 1993; 36: 150-156
• 180 Zargaroff S, Sharma V, Berhanu D et al. National trends in the treatment of penile prosthesis infections by explantation alone vs. immediate salvage and reimplantation. J Sex Med 2014; 11: 1078-1085
• 181 Ziegler D. Treatment of diabetic polyneuropathy: Update 2006. Ann N Y Acad Sci 2006; 1084: 250-266