Erectile dysfunction

Abstract

Erectile dysfunction is a multidimensional but common male sexual dysfunction that involves an alteration in any of the components of the erectile response, including organic, relational and psychological. Roles for nonendocrine (neurogenic, vasculogenic and iatrogenic) and endocrine pathways have been proposed. Owing to its strong association with metabolic syndrome and cardiovascular disease, cardiac assessment may be warranted in men with symptoms of erectile dysfunction. Minimally invasive interventions to relieve the symptoms of erectile dysfunction include lifestyle modifications, oral drugs, injected vasodilator agents and vacuum erection devices. Surgical therapies are reserved for the subset of patients who have contraindications to these nonsurgical interventions, those who experience adverse effects from (or are refractory to) medical therapy and those who also have penile fibrosis or penile vascular insufficiency. Erectile dysfunction can have deleterious effects on a man's quality of life; most patients have symptoms of depression and anxiety related to sexual performance. These symptoms, in turn, affect his partner's sexual experience and the couple's quality of life. This Primer highlights numerous aspects of erectile dysfunction, summarizes new treatment targets and ongoing preclinical studies that evaluate new pharmacotherapies, and covers the topic of regenerative medicine, which represents the future of sexual medicine.

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Figure 1: Timeline of the understanding and treatment of erectile dysfunction.
Figure 2: Increasing prevalence of erectile dysfunction with age.
Figure 3: Penile smooth muscle contraction — the flaccid state.
Figure 4: Penile smooth muscle relaxation — the erect state.
Figure 5: Levels of androgen action in the control of sexual response.
Figure 6: Schematic representation of different types of hypogonadism.
Figure 7: Suggested diagnostic work-up for patients with erectile dysfunction.
Figure 8: Penile prostheses.
Figure 9: Potential future treatment options for erectile dysfunction.

References

  1. 1

    Virag, R., Zwang, G., Dermange, H. & Legman, M. Vasculogenic impotence: a review of 92 cases with 54 surgical operations. Vasc. Surg. 15, 9–17 (1981).

    Article  Google Scholar 

  2. 2

    Glina, S., Shindel, A., Eardley, I. & Ghanem, H. Cavernosal α-blockade: a new technique for investigating and treating erectile impotence by GS Brindley. J. Sex. Med. 5, 1791–1794 (2008).

    Article  PubMed  Google Scholar 

  3. 3

    Scott, F. B., Bradley, W. E. & Timm, G. W. Management of erectile impotence. Use of implantable inflatable prosthesis. Urology 2, 80–82 (1973).

    Article  CAS  PubMed  Google Scholar 

  4. 4

    Blumenthal, S. A. Earl Sutherland (1915–1974) [corrected] and the discovery of cyclic AMP. Perspect. Biol. Med. 55, 236–249 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. 5

    Ballard, S. A. et al. Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J. Urol. 159, 2164–2171 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. 6

    Gandaglia, G. et al. A systematic review of the association between erectile dysfunction and cardiovascular disease. Eur. Urol. 65, 968–978 (2014).

    Article  PubMed  Google Scholar 

  7. 7

    Feldman, H. A., Goldstein, I., Hatzichristou, D. G., Krane, R. J. & McKinlay, J. B. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J. Urol. 151, 54–61 (1994). This seminal manuscript defines the prevalence of erectile dysfunction.

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Corona, G. et al. Age-related changes in general and sexual health in middle-aged and older men: results from the European Male Ageing Study (EMAS). J. Sex. Med. 7, 1362–1380 (2010).

    Article  PubMed  Google Scholar 

  9. 9

    Rosen, R. et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur. Urol. 44, 637–649 (2003). This publication describes the relationship of LUTS and erectile dysfunction.

    Article  PubMed  Google Scholar 

  10. 10

    Nicolosi, A. et al. Sexual behavior and sexual dysfunctions after age 40: the global study of sexual attitudes and behaviors. Urology 64, 991–997 (2004).

    Article  PubMed  Google Scholar 

  11. 11

    Laumann, E. O. et al. Sexual problems among women and men aged 40–80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int. J. Impot. Res. 17, 39–57 (2005). An international study evaluating different aspect of sexual difficulties and some associated predictors.

    Article  CAS  PubMed  Google Scholar 

  12. 12

    Shabsigh, R., Perelman, M. A., Lockhart, D. C., Lue, T. F. & Broderick, G. A. Health issues of men: prevalence and correlates of erectile dysfunction. J. Urol. 174, 662–667 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Johannes, C. B. et al. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts Male Aging Study. J. Urol. 163, 460–463 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Moreira, E. D. et al. Incidence of erectile dysfunction in men 40 to 69 years old: results from a population-based cohort study in Brazil. Urology 61, 431–436 (2003).

    Article  PubMed  Google Scholar 

  15. 15

    Schouten, B. W. et al. Incidence rates of erectile dysfunction in the Dutch general population. Effects of definition, clinical relevance and duration of follow-up in the Krimpen study. Int. J. Impot. Res. 17, 58–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Seftel, A. D. et al. Coexisting lower urinary tract symptoms and erectile dysfunction: a systematic review of epidemiological data. Int. J. Clin. Pract. 67, 32–45 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Gacci, M. et al. Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur. Urol. 60, 809–825 (2011).

    Article  PubMed  Google Scholar 

  18. 18

    Corona, G., Rastrelli, G., Maseroli, E., Forti, G. & Maggi, M. Sexual function of the ageing male. Best Pract. Res. Clin. Endocrinol. Metab. 27, 581–601 (2013).

    Article  PubMed  Google Scholar 

  19. 19

    Jannini, E. A. et al. Health-related characteristics and unmet needs of men with erectile dysfunction: a survey in five European countries. J. Sex. Med. 11, 40–50 (2014).

    Article  PubMed  Google Scholar 

  20. 20

    Ludwig, W. & Phillips, M. Organic causes of erectile dysfunction in men under 40. Urol. Int. 92, 1–6 (2014).

    Article  PubMed  Google Scholar 

  21. 21

    Capogrosso, P. et al. One patient out of four with newly diagnosed erectile dysfunction is a young man — worrisome picture from the everyday clinical practice. J. Sex. Med. 10, 1833–1841 (2013).

    Article  PubMed  Google Scholar 

  22. 22

    Heruti, R., Shochat, T., Tekes-Manova, D., Ashkenazi, I. & Justo, D. Prevalence of erectile dysfunction among young adults: results of a large-scale survey. J. Sex. Med. 1, 284–291 (2004).

    Article  PubMed  Google Scholar 

  23. 23

    Sanders, S. A. et al. General erectile functioning among young, heterosexual men who do and do not report condom-associated erection problems (CAEP). J. Sex. Med. 12, 1897–1904 (2015).

    Article  PubMed  Google Scholar 

  24. 24

    Papagiannopoulos, D., Khare, N. & Nehra, A. Evaluation of young men with organic erectile dysfunction. Asian J. Androl. 17, 11–16 (2015).

    Article  PubMed  Google Scholar 

  25. 25

    Yao, F. et al. Erectile dysfunction may be the first clinical sign of insulin resistance and endothelial dysfunction in young men. Clin. Res. Cardiol. 102, 645–651 (2013).

    CAS  Google Scholar 

  26. 26

    Salonia, A. et al. Is erectile dysfunction a reliable proxy of general male health status? The case for the International Index of Erectile Function–Erectile Function domain. J. Sex. Med. 9, 2708–2715 (2012).

    Article  PubMed  Google Scholar 

  27. 27

    Andersson, K. E. & Wagner, G. Physiology of penile erection. Physiol. Rev. 75, 191–236 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Saenz de Tejada, I., Kim, N., Lagan, I., Krane, R. J. & Goldstein, I. Regulation of adrenergic activity in penile corpus cavernosum. J. Urol. 142, 1117–1121 (1989). A seminal paper on cell signalling in the corpora cavernosum.

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Lue, T. F. Erectile dysfunction. N. Engl. J. Med. 342, 1802–1813 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Lue, T. F. & Tanagho, E. A. Physiology of erection and pharmacological management of impotence. J. Urol. 137, 829–836 (1987).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    McCabe, M. P. & Althof, S. E. A systematic review of the psychosocial outcomes associated with erectile dysfunction: does the impact of erectile dysfunction extend beyond a man's inability to have sex? J. Sex. Med. 11, 347–363 (2014).

    Article  PubMed  Google Scholar 

  32. 32

    Brackett, N. L., Lynne, C. M., Ibrahim, E., Ohl, D. A. & Sonksen, J. Treatment of infertility in men with spinal cord injury. Nat. Rev. Urol. 7, 162–172 (2010).

    Article  PubMed  Google Scholar 

  33. 33

    Leungwattanakij, S. et al. Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum. J. Androl. 24, 239–245 (2003).

    Google Scholar 

  34. 34

    Ferrini, M. G. et al. Vardenafil prevents fibrosis and loss of corporal smooth muscle that occurs after bilateral cavernosal nerve resection in the rat. Urology 68, 429–435 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Ferrini, M. G., Kovanecz, I., Nolazco, G., Rajfer, J. & Gonzalez-Cadavid, N. F. Effects of long-term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie's disease. BJU Int. 97, 625–633 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. 36

    Ferrini, M. G. et al. 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. 6, 415–428 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Mulhall, J. P. et al. The functional and structural consequences of cavernous nerve injury are ameliorated by sildenafil citrate. J. Sex. Med. 5, 1126–1136 (2008). This manuscript describes the science behind the use of sildenafil to decrease erectile tissue damage after cavernous nerve injury.

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Kupelian, V., Araujo, A. B., Chiu, G. R., Rosen, R. C. & McKinlay, J. B. Relative contributions of modifiable risk factors to erectile dysfunction: results from the Boston Area Community Health (BACH) Survey. Prev. Med. 50, 19–25 (2010).

    Article  PubMed  Google Scholar 

  39. 39

    Bacon, C. G. et al. A prospective study of risk factors for erectile dysfunction. J. Urol. 176, 217–221 (2006).

    Article  PubMed  Google Scholar 

  40. 40

    Francis, M. E., Kusek, J. W., Nyberg, L. M. & Eggers, P. W. The contribution of common medical conditions and drug exposures to erectile dysfunction in adult males. J. Urol. 178, 591–596 (2007).

    Article  PubMed  Google Scholar 

  41. 41

    Wei, M. et al. Total cholesterol and high-density lipoprotein cholesterol as important predictors of erectile dysfunction. Am. J. Epidemiol. 140, 930–937 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. 42

    McVary, K. T., Carrier, S., Wessells, H. & Subcommittee on Smoking and Erectile Dysfunction Socioeconomic Committee, Sexual Medicine Society of North America. Smoking and erectile dysfunction: evidence based analysis. J. Urol. 166, 1624–1632 (2001). This publication examines the negative effects of smoking on erectile dysfunction.

    Article  CAS  PubMed  Google Scholar 

  43. 43

    Moreland, R. B. et al. PGE1 suppresses the induction of collagen synthesis by transforming growth factor-β 1 in human corpus cavernosum smooth muscle. J. Urol. 153, 826–834 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. 44

    Moreland, R. B. Is there a role of hypoxemia in penile fibrosis: a viewpoint presented to the Society for the Study of Impotence. Int. J. Impot. Res. 10, 113–120 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. 45

    Nehra, A. et al. Mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure. J. Urol. 156, 1320–1329 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Tal, R. et al. Persistent erectile dysfunction following radical prostatectomy: the association between nerve-sparing status and the prevalence and chronology of venous leak. J. Sex. Med. 6, 2813–2819 (2009).

    Article  PubMed  Google Scholar 

  47. 47

    Grimm, R. H. Jr et al. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS). Hypertension 29, 8–14 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Baskin, L. S. et al. The effect of testosterone on androgen receptors and human penile growth. J. Urol. 158, 1113–1118 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Boas, M. et al. Postnatal penile length and growth rate correlate to serum testosterone levels: a longitudinal study of 1962 normal boys. Eur. J. Endocrinol. 154, 125–129 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Filippi, S. et al. Testosterone partially ameliorates metabolic profile and erectile responsiveness to PDE5 inhibitors in an animal model of male metabolic syndrome. J. Sex. Med. 6, 3274–3288 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Vignozzi, L. et al. Testosterone regulates RhoA/Rho-kinase signaling in two distinct animal models of chemical diabetes. J. Sex. Med. 4, 620–630 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Hull, E. M. et al. Hormone–neurotransmitter interactions in the control of sexual behavior. Behav. Brain Res. 105, 105–116 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Isidori, A. M. et al. A critical analysis of the role of testosterone in erectile function: from pathophysiology to treatment — a systematic review. Eur. Urol. 65, 99–112 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Mills, T. M., Lewis, R. W. & Stopper, V. S. Androgenic maintenance of inflow and veno-occlusion during erection in the rat. Biol. Reprod. 59, 1413–1418 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Lugg, J., Ng, C., Rajfer, J. & Gonzalez-Cadavid, N. Cavernosal nerve stimulation in the rat reverses castration-induced decrease in penile NOS activity. Am. J. Physiol. 271, E354–E361 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. 56

    Giuliano, F., Rampin, O., Schirar, A., Jardin, A. & Rousseau, J. P. Autonomic control of penile erection: modulation by testosterone in the rat. J. Neuroendocrinol. 5, 677–683 (1993).

    Article  CAS  PubMed  Google Scholar 

  57. 57

    Traish, A. M. et al. Effects of castration and androgen replacement on erectile function in a rabbit model. Endocrinology 140, 1861–1868 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Reilly, C. M., Lewis, R. W., Stopper, V. S. & Mills, T. M. Androgenic maintenance of the rat erectile response via a non-nitric-oxide-dependent pathway. J. Androl. 18, 588–594 (1997).

    CAS  PubMed  Google Scholar 

  59. 59

    Sopko, N. A., Hannan, J. L. & Bivalacqua, T. J. Understanding and targeting the Rho kinase pathway in erectile dysfunction. Nat. Rev. Urol. 11, 622–628 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Liao, W., Huang, W., Guo, Y., Xin, M. & Fu, X. Testosterone promotes vascular endothelial cell migration via upregulation of ROCK-2/moesin cascade. Mol. Biol. Rep. 40, 6729–6735 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Zhang, X. H., Melman, A. & Disanto, M. E. Update on corpus cavernosum smooth muscle contractile pathways in erectile function: a role for testosterone? J. Sex. Med. 8, 1865–1879 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    di Villa, B. R. et al. Sphingosine 1-phosphate induces endothelial nitric-oxide synthase activation through phosphorylation in human corpus cavernosum. J. Pharmacol. Exp. Ther. 316, 703–708 (2006).

    Article  CAS  Google Scholar 

  63. 63

    Ohmori, T. et al. Sphingosine 1-phosphate induces contraction of coronary artery smooth muscle cells via S1P2. Cardiovasc. Res. 58, 170–177 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. 64

    Morelli, A. et al. Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Endocrinology 145, 2253–2263 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Zhang, X. H. et al. Testosterone regulates PDE5 expression and in vivo responsiveness to tadalafil in rat corpus cavernosum. Eur. Urol. 47, 409–416 (2005). This manuscript describes the animal model showing the effect of testosterone on cavernosal tissue.

    Article  CAS  PubMed  Google Scholar 

  66. 66

    Yang, R. et al. Lack of direct androgen regulation of PDE5 expression. Biochem. Biophys. Res. Commun. 380, 758–762 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Traish, A. M., Toselli, P., Jeong, S. J. & Kim, N. N. Adipocyte accumulation in penile corpus cavernosum of the orchiectomized rabbit: a potential mechanism for veno-occlusive dysfunction in androgen deficiency. J. Androl. 26, 242–248 (2005).

    Google Scholar 

  68. 68

    Andric, S. A., Janjic, M. M., Stojkov, N. J. & Kostic, T. S. Testosterone-induced modulation of nitric oxide–cGMP signaling pathway and androgenesis in the rat Leydig cells. Biol. Reprod. 83, 434–442 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Reilly, C. M., Stopper, V. S. & Mills, T. M. Androgens modulate the α-adrenergic responsiveness of vascular smooth muscle in the corpus cavernosum. J. Androl. 18, 26–31 (1997).

    CAS  Google Scholar 

  70. 70

    Bancroft, J. & Wu, F. C. Changes in erectile responsiveness during androgen replacement therapy. Arch. Sex. Behav. 12, 59–66 (1983).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Gray, P. B. et al. Dose-dependent effects of testosterone on sexual function, mood, and visuospatial cognition in older men. J. Clin. Endocrinol. Metab. 90, 3838–3846 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Buena, F. et al. Sexual function does not change when serum testosterone levels are pharmacologically varied within the normal male range. Fertil. Steril. 59, 1118–1123 (1993).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Kwan, M., Greenleaf, W. J., Mann, J., Crapo, L. & Davidson, J. M. The nature of androgen action on male sexuality: a combined laboratory-self-report study on hypogonadal men. J. Clin. Endocrinol. Metab. 57, 557–562 (1983).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Giannetta, E., Gianfrilli, D., Barbagallo, F., Isidori, A. M. & Lenzi, A. Subclinical male hypogonadism. Best Pract. Res. Clin. Endocrinol. Metab. 26, 539–550 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. 75

    Tajar, A. et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing study. J. Clin. Endocrinol. Metab. 95, 1810–1818 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Corona, G. et al. Testosterone supplementation and sexual function: a meta-analysis study. J. Sex. Med. 11, 1577–1592 (2014). Meta-analysis that examines the relationship between testosterone therapy and sexual function.

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Saad, F. et al. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur. J. Endocrinol. 165, 675–685 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Giltay, E. J. et al. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. J. Sex. Med. 7, 2572–2582 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Hackett, G. et al. Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters versus placebo in a population of men with type 2 diabetes. J. Sex. Med. 10, 1612–1627 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    Isidori, A. M. et al. Outcomes of androgen replacement therapy in adult male hypogonadism: recommendations from the Italian society of endocrinology. J. Endocrinol. Invest. 38, 103–112 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Basaria, S. et al. Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial. JAMA 314, 570–581 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Morgentaler, A. Testosterone, cardiovascular risk, and hormonophobia. J. Sex. Med. 11, 1362–1366 (2014).

    Article  PubMed  Google Scholar 

  83. 83

    Finkle, W. D. et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE 9, e85805 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Sharma, R. et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur. Heart J. 36, 2706–2715 (2015).

    Article  PubMed  Google Scholar 

  85. 85

    Sansone, A., Romanelli, F., Gianfrilli, D. & Lenzi, A. Endocrine evaluation of erectile dysfunction. Endocrine 46, 423–430 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Corona, G. et al. Psychobiological correlates of smoking in patients with erectile dysfunction. Int. J. Impot. Res. 17, 527–534 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. 87

    Cao, S., Gan, Y., Dong, X., Liu, J. & Lu, Z. Association of quantity and duration of smoking with erectile dysfunction: a dose–response meta-analysis. J. Sex. Med. 11, 2376–2384 (2004).

    Article  Google Scholar 

  88. 88

    Boddi, V. et al. Priapus is happier with Venus than with Bacchus. J. Sex. Med. 7, 2831–2841 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Wang, F., Dai, S., Wang, M. & Morrison, H. Erectile dysfunction and fruit/vegetable consumption among diabetic Canadian men. Urology 82, 1330–1335 (2013).

    Article  PubMed  Google Scholar 

  90. 90

    Cheng, J. Y., Ng, E. M., Ko, J. S. & Chen, R. Y. Physical activity and erectile dysfunction: meta-analysis of population-based studies. Int. J. Impot. Res. 19, 245–252 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Corona, G. et al. Erectile dysfunction and central obesity: an Italian perspective. Asian J. Androl. 16, 581–591 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  92. 92

    Vignozzi, L. et al. Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit. Mol. Cell. Endocrinol. 384, 143–154 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Corona, G. et al. The SUBITO-DE study: sexual dysfunction in newly diagnosed type 2 diabetes male patients. J. Endocrinol. Invest. 36, 864–868 (2013).

    CAS  PubMed  Google Scholar 

  94. 94

    Corona, G. et al. Sexual dysfunction at the onset of type 2 diabetes: the interplay of depression, hormonal and cardiovascular factors. J. Sex. Med. 11, 2065–2073 (2014).

    Article  PubMed  Google Scholar 

  95. 95

    Corona, G. et al. Hormonal association and sexual dysfunction in patients with impaired fasting glucose: a cross-sectional and longitudinal study. J. Sex. Med. 9, 1669–1680 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Guo, W. et al. Erectile dysfunction and risk of clinical cardiovascular events: a meta-analysis of seven cohort studies. J. Sex. Med. 7, 2805–2816 (2010).

    Article  PubMed  Google Scholar 

  97. 97

    Dong, J. Y., Zhang, Y. H. & Qin, L. Q. Erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies. J. Am. Coll. Cardiol. 58, 1378–1385 (2011).

    Article  PubMed  Google Scholar 

  98. 98

    Vlachopoulos, C. V., Terentes-Printzios, D. G., Ioakeimidis, N. K., Aznaouridis, K. A. & Stefanadis, C. I. Prediction of cardiovascular events and all-cause mortality with erectile dysfunction: a systematic review and meta-analysis of cohort studies. Circ. Cardiovasc. Qual. Outcomes 6, 99–109 (2013).

    Article  PubMed  Google Scholar 

  99. 99

    Yamada, T., Hara, K., Umematsu, H., Suzuki, R. & Kadowaki, T. Erectile dysfunction and cardiovascular events in diabetic men: a meta-analysis of observational studies. PLoS ONE 7, e4367 (2012).

    Google Scholar 

  100. 100

    Nehra, A. et al. The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin. Proc. 87, 766–778 (2012). This manuscript details how erectile dysfunction is an early symptom of cardiovascular disease.

    Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Jannini, E. A., McCabe, M. P., Salonia, A., Montorsi, F. & Sachs, B. D. Organic versus psychogenic? The Manichean diagnosis in sexual medicine. J. Sex. Med. 7, 1726–1733 (2010).

    Article  PubMed  Google Scholar 

  102. 102

    Corona, G. et al. Impairment of couple relationship in male patients with sexual dysfunction is associated with overt hypogonadism. J. Sex. Med. 6, 2591–2600 (2009).

    Article  PubMed  Google Scholar 

  103. 103

    Corona, G. et al. Male sexuality and cardiovascular risk. A cohort study in patients with erectile dysfunction. J. Sex. Med. 7, 1918–1927 (2010).

    Article  PubMed  Google Scholar 

  104. 104

    Althof, S. E., Rosen, R. C., Perelman, M. A. & Rubio-Aurioles, E. Standard operating procedures for taking a sexual history. J. Sex. Med. 10, 26–35 (2013).

    Article  PubMed  Google Scholar 

  105. 105

    Ghanem, H. M., Salonia, A. & Martin-Morales, A. SOP: physical examination and laboratory testing for men with erectile dysfunction. J. Sex. Med. 10, 108–110 (2013).

    Article  PubMed  Google Scholar 

  106. 106

    Buvat, J., Maggi, M., Guay, A. & Torres, L. O. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J. Sex. Med. 10, 245–284 (2013). A detailed review of testosterone deficiency, including current management modalities.

    Article  CAS  PubMed  Google Scholar 

  107. 107

    Rastrelli, G. et al. Flaccid penile acceleration as a marker of cardiovascular risk in men without classical risk factors. J. Sex. Med. 11, 173–186 (2014).

    Article  PubMed  Google Scholar 

  108. 108

    Corona, G. et al. Penile doppler ultrasound in patients with erectile dysfunction (ED): role of peak systolic velocity measured in the flaccid state in predicting arteriogenic ED and silent coronary artery disease. J. Sex. Med. 5, 2623–2634 (2008).

    Article  PubMed  Google Scholar 

  109. 109

    Sikka, S. C., Hellstrom, W. J., Brock, G. & Morales, A. M. Standardization of vascular assessment of erectile dysfunction: standard operating procedures for duplex ultrasound. J. Sex. Med. 10, 120–129 (2013).

    Article  PubMed  Google Scholar 

  110. 110

    Maiorino, M. I., Bellastella, G. & Esposito, K. Lifestyle modifications and erectile dysfunction: what can be expected? Asian J. Androl. 17, 5–10 (2015).

    Article  PubMed  Google Scholar 

  111. 111

    Esposito, K. et al. Dietary factors in erectile dysfunction. Int. J. Impot. Res. 18, 370–374 (2006).

    Article  CAS  PubMed  Google Scholar 

  112. 112

    Hannan, J. L., Heaton, J. P. W. & Adams, M. A. Recovery of erectile function in aging hypertensive and normotensive rats using exercise and caloric restriction. J. Sex. Med. 4, 886–897 (2007).

    Article  PubMed  Google Scholar 

  113. 113

    Kolotkin, R. L. et al. Improvements in sexual quality of life after moderate weight loss. Int. J. Impot. Res. 20, 487–492 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Belardinelli, R., Lacalaprice, F., Faccenda, E., Purcaro, A. & Perna, G. Effects of short-term moderate exercise training on sexual function in male patients with chronic stable heart failure. Int. J. Cardiol. 101, 83–90 (2005).

    Article  PubMed  Google Scholar 

  115. 115

    Kupelian, V., Link, C. L. & McKinlay, J. B. Association between smoking, passive smoking, and erectile dysfunction: results from the Boston Area Community Health (BACH) Survey. Eur. Urol. 52, 416–422 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Polsky, J. Y., Aronson, K. J., Heaton, J. P. & Adams, M. A. Smoking and other lifestyle factors in relation to erectile dysfunction. BJU Int. 96, 1355–1359 (2005).

    Article  PubMed  Google Scholar 

  117. 117

    Pourmand, G., Alidaee, M. R., Rasuli, S., Maleki, A. & Mehrsai, A. Do cigarette smokers with erectile dysfunction benefit from stopping?: a prospective study. BJU Int. 94, 1310–1313 (2004).

    Article  PubMed  Google Scholar 

  118. 118

    Chew, K. K. Alcohol consumption and male erectile dysfunction: an unfounded reputation for risk? J. Sex. Med. 6, 2340–2340 (2009).

    Article  PubMed  Google Scholar 

  119. 119

    Arackal, B. S. & Benegal, V. Prevalence of sexual dysfunction in male subjects with alcohol dependence. Indian J. Psychiatry 49, 109–112 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Aghighi, A., Grigoryan, V. H. & Delavar, A. Psychological determinants of erectile dysfunction among middle-aged men. Int. J. Impot. Res. 27, 63–68 (2014).

    Article  PubMed  Google Scholar 

  121. 121

    Schmidt, H. M., Munder, T., Gerger, H., Fruhauf, S. & Barth, J. Combination of psychological intervention and phosphodiesterase-5 inhibitors for erectile dysfunction: a narrative review and meta-analysis. J. Sex. Med. 11, 1376–1391 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Hatzimouratidis, K. et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur. Urol. 57, 804–814 (2010).

    Article  PubMed  Google Scholar 

  123. 123

    Goldstein, I. et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N. Engl. J. Med. 338, 1397–1404 (1998). This seminal paper was the first time that sildenafil was used as treatment for erectile dysfunction.

    Article  CAS  PubMed  Google Scholar 

  124. 124

    Yuan, J. et al. Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis. Eur. Urol. 63, 902–912 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. 125

    Corbin, J. D. Mechanisms of action of PDE5 inhibition in erectile dysfunction. Int. J. Impot. Res. 16, S4–S7 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. 126

    Nichols, D. J., Muirhead, G. J. & Harness, J. A. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br. J. Clin. Pharmacol. 53, S5–S12 (2002).

    Article  Google Scholar 

  127. 127

    Curran, M. & Keating, G. Tadalafil. Drugs 63, 2203–2212; discussion 2213–2214 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. 128

    Jung, J. et al. Tolerability and pharmacokinetics of avanafil, a phosphodiesterase type 5 inhibitor: a single- and multiple-dose, double-blind, randomized, placebo-controlled, dose-escalation study in healthy Korean male volunteers. Clin. Ther. 32, 1178–1187 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. 129

    Porst, H. et al. SOP conservative (medical and mechanical) treatment of erectile dysfunction. J. Sex. Med. 10, 130–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  130. 130

    Stuckey, B. G. et al. Sildenafil citrate for treatment of erectile dysfunction in men with type 1 diabetes: results of a randomized controlled trial. Diabetes Care 26, 279–284 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Boulton, A. J., Selam, J. L., Sweeney, M. & Ziegler, D. Sildenafil citrate for the treatment of erectile dysfunction in men with type II diabetes mellitus. Diabetologia 44, 1296–1301 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. 132

    Shabsigh, R. Testosterone therapy in erectile dysfunction and hypogonadism. J. Sex. Med. 2, 785–792 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. 133

    Padma-Nathan, H. et al. Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy. Int. J. Impot. Res. 20, 479–486 (2008).

    Article  CAS  PubMed  Google Scholar 

  134. 134

    Zelefsky, M. J. et al. Prophylactic sildenafil citrate improves select aspects of sexual function in men treated with radiotherapy for prostate cancer. J. Urol. 192, 868–874 (2014). This manuscript shows the benefit of sidenafil in decreasing the incidence of erectile dysfunction in patients undergoing radiotherapy for prostate cancer.

    Article  CAS  PubMed  Google Scholar 

  135. 135

    Corona, G., Razzoli, E., Forti, G. & Maggi, M. The use of phosphodiesterase 5 inhibitors with concomitant medications. J. Endocrinol. Invest. 31, 799–808 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. 136

    Giuliano, F., Jackson, G., Montorsi, F., Martin-Morales, A. & Raillard, P. Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database. Int. J. Clin. Pract. 64, 240–255 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Bosshardt, R. J., Farwerk, R., Sikora, R., Sohn, M. & Jakse, G. Objective measurement of the effectiveness, therapeutic success and dynamic mechanisms of the vacuum device. Br. J. Urol. 75, 786–791 (1995).

    Article  CAS  PubMed  Google Scholar 

  138. 138

    Price, D. E. et al. The management of impotence in diabetic men by vacuum tumescence therapy. Diabet. Med. 8, 964–967 (1991).

    Article  CAS  PubMed  Google Scholar 

  139. 139

    Levine, L. A. & Dimitriou, R. J. Vacuum constriction and external erection devices in erectile dysfunction. Urol. Clin. North Am. 28, 335–341 (2001).

    Article  CAS  PubMed  Google Scholar 

  140. 140

    Baltaci, S., Aydos, K., Kosar, A. & Anafarta, K. Treating erectile dysfunction with a vacuum tumescence device: a retrospective analysis of acceptance and satisfaction. Br. J. Urol. 76, 757–760 (1995).

    Article  CAS  PubMed  Google Scholar 

  141. 141

    Ganem, J. P., Lucey, D. T., Janosko, E. O. & Carson, C. C. Unusual complications of the vacuum erection device. Urology 51, 627–631 (1998).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    Raina, R. et al. Early use of vacuum constriction device following radical prostatectomy facilitates early sexual activity and potentially earlier return of erectile function. Int. J. Impot. Res. 18, 77–81 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Moreland, R. B., Kim, N., Nehra, A., Goldstein, I. & Traish, A. Functional prostaglandin E (EP) receptors in human penile corpus cavernosum. Int. J. Impot. Res. 15, 362–368 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. 144

    Padma-Nathan, H. et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study Group. N. Engl. J. Med. 336, 1–7 (1997).

    Article  CAS  PubMed  Google Scholar 

  145. 145

    Williams, G. et al. Efficacy and safety of transurethral alprostadil therapy in men with erectile dysfunction. MUSE Study Group. Br. J. Urol. 81, 889–894 (1998).

    Article  PubMed  Google Scholar 

  146. 146

    McCullough, A. R. et al. Recovery of erectile function after nerve sparing radical prostatectomy and penile rehabilitation with nightly intraurethralalprostadil versus sildenafil citrate. J. Urol. 183, 2451–2456 (2010).

    Article  CAS  PubMed  Google Scholar 

  147. 147

    Guay, A. T., Perez, J. B., Velasquez, E., Newton, R. A. & Jacobson, J. P. Clinical experience with intraurethralalprostadil (MUSE) in the treatment of men with erectile dysfunction. A retrospective study. Medicated urethral system for erection. Eur. Urol. 38, 671–676 (2000).

    Article  CAS  PubMed  Google Scholar 

  148. 148

    Costabile, R. A. et al. Efficacy and safety of transurethral alprostadil in patients with erectile dysfunction following radical prostatectomy. J. Urol. 160, 1325–1328 (1998).

    Article  CAS  PubMed  Google Scholar 

  149. 149

    Virag, R., Shoukry, K., Floresco, J., Nollet, F. & Greco, E. Intracavernous self-injection of vasoactive drugs in the treatment of impotence: 8-year experience with 615 cases. J. Urol. 145, 287–292; discussion 292–293 (1991).

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Nelson, C. J. et al. Injection anxiety and pain in men using intracavernosal injection therapy after radical pelvic surgery. J. Sex. Med. 10, 2559–2565 (2013).

    Article  PubMed  Google Scholar 

  151. 151

    Heaton, J. P. et al. Intracavernosal alprostadil is effective for the treatment of erectile dysfunction in diabetic men. Int. J. Impot. Res. 13, 317–321 (2001).

    Article  CAS  PubMed  Google Scholar 

  152. 152

    Althof, S. E. et al. Why do so many people drop out from auto-injection therapy for impotence? J. Sex. Marital Ther. 15, 121–129 (1989).

    Article  CAS  PubMed  Google Scholar 

  153. 153

    Weiss, J. N., Badlani, G. H., Ravalli, R. & Brettschneider, N. Reasons for high drop-out rate with self-injection therapy for impotence. Int. J. Impot. Res. 6, 171–174 (1994).

    CAS  PubMed  Google Scholar 

  154. 154

    Mulhall, J. P. et al. The causes of patient dropout from penile self-injection therapy for impotence. J. Urol. 162, 1291–1294 (1999).

    Article  CAS  PubMed  Google Scholar 

  155. 155

    Linet, O. I. & Ogrinc, F. G. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group. N. Engl. J. Med. 334, 873–877 (1996).

    Article  CAS  PubMed  Google Scholar 

  156. 156

    Tal, R., Teloken, P. & Mulhall, J. P. Erectile function rehabilitation after radical prostatectomy: practice patterns among AUA members. J. Sex. Med. 8, 2370–2376 (2011).

    Article  PubMed  Google Scholar 

  157. 157

    Trost, L. W., McCaslin, R., Linder, B. & Hellstrom, W. J. Long-term outcomes of penile prostheses for the treatment of erectile dysfunction. Expert Rev. Med. Devices 10, 353–366 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. 158

    Zermann, D. H., Kutzenberger, J., Sauerwein, D., Schubert, J. & Loeffler, U. Penile prosthetic surgery in neurologically impaired patients: long-term follow-up. J. Urol. 175, 1041–1044 (2006).

    Article  PubMed  Google Scholar 

  159. 159

    Levine, L. A., Estrada, C. R. & Morgentaler, A. Mechanical reliability and safety of, and patient satisfaction with the Ambicor inflatable penile prosthesis: results of a 2 center study. J. Urol. 166, 932–937 (2001).

    Article  CAS  PubMed  Google Scholar 

  160. 160

    Levine, L. A. & Lenting, E. A surgical algorithm for the treatment of Peyronie's disease. J. Urol. 158, 2149–2152 (1997).

    Article  CAS  PubMed  Google Scholar 

  161. 161

    Montorsi, F., Guazzoni, G., Bergamaschi, F. & Rigatti, P. Patient–partner satisfaction with semirigid penile prostheses for Peyronie's disease: a 5-year follow-up study. J. Urol. 150, 1819–1821 (1993).

    Article  CAS  PubMed  Google Scholar 

  162. 162

    Wilson, S. K. & Delk, J. R. 2nd. A new treatment for Peyronie's disease: modeling the penis over an inflatable penile prosthesis. J. Urol. 152, 1121–1123 (1994). This manuscript describes a technique used to correct Peyronie's disease and erectile dysfunction in the same procedure.

    Article  CAS  PubMed  Google Scholar 

  163. 163

    Martínez-Salamanca, J. I., Mueller, A., Moncada, I., Carballido, J. & Mulhall, J. P. Penile prosthesis surgery in patients with corporal fibrosis: a state of the art review. J. Sex. Med. 8, 1880–1889 (2011).

    Article  PubMed  Google Scholar 

  164. 164

    Dhar, N. B., Angermeir, K. W. & Montague, D. K. Long-term mechanical reliability of AMS 700CX/CXM inflatable penile prosthesis. J. Urol. 176, 2599–2601 (2006).

    Article  PubMed  Google Scholar 

  165. 165

    Hellstrom, W. J. et al. Implants, mechanical devices, and vascular surgery for erectile dysfunction. J. Sex. Med. 7, 501–523 (2010).

    Article  PubMed  Google Scholar 

  166. 166

    Trost, L. W., Baum, N. & Hellstrom, W. J. Managing the difficult penile prosthesis patient. J. Sex. Med. 10, 893–906 (2013).

    Article  PubMed  Google Scholar 

  167. 167

    Rajpurkar, A. & Dhabuwala, C. B. Comparison of satisfaction rates and erectile function in patients treated with sildenafil, intracavernous prostaglandin E1 and penile implant surgery for erectile dysfunction in urology practice. J. Urol. 170, 159–163 (2003).

    Article  CAS  PubMed  Google Scholar 

  168. 168

    Vardi, Y. et al. Evaluation of penile revascularization for erectile dysfunction: a 10-year follow-up. Int. J. Impot. Res. 16, 181–186 (2004).

    Article  CAS  PubMed  Google Scholar 

  169. 169

    Wespes, E., Wildschutz, T., Roumeguere, T. & Schulman, C. C. The place of surgery for vascular impotence in the third millennium. J. Urol. 170, 1284–1286 (2003).

    Article  PubMed  Google Scholar 

  170. 170

    Manning, M. et al. Long-term follow up and selection criteria for penile revascularization in erectile failure. J. Urol. 160, 1680–1684 (1998).

    Article  CAS  PubMed  Google Scholar 

  171. 171

    Sohn, M. & Martin-Morales, A. Surgical Treatment of Erectile Dysfunction (Porst JB, 2006).

    Google Scholar 

  172. 172

    Montague, D. K. et al. Chapter 1: the management of erectile dysfunction: an AUA update. J. Urol. 174, 230–239 (2005).

    Article  PubMed  Google Scholar 

  173. 173

    Araujo, A. B., Durante, R., Feldman, H. A., Goldstein, I. & McKinlay, J. B. The relationship between depressive symptoms and male erectile dysfunction: cross-sectional results from the Massachusetts Male Aging Study. Psychosom. Med. 60, 458–465 (1998). This is an important study, as it helps to define the relationship between erectile dysfunction and depression. The MMAS provides population-based data that demonstrate sound evidence for this relationship.

    Article  CAS  PubMed  Google Scholar 

  174. 174

    Nelson, C. J., Mulhall, J. P. & Roth, A. J. The association between erectile dysfunction and depressive symptoms in men treated for prostate cancer. J. Sex. Med. 8, 560–566 (2011).

    Article  PubMed  Google Scholar 

  175. 175

    Shabsigh, R. et al. Increased incidence of depressive symptoms in men with erectile dysfunction. Urology 52, 848–852 (1998).

    Article  CAS  PubMed  Google Scholar 

  176. 176

    Shiri, R. et al. Bidirectional relationship between depression and erectile dysfunction. J. Urol. 177, 669–673 (2007).

    Article  PubMed  Google Scholar 

  177. 177

    Mallis, D. et al. Psychiatric morbidity is frequently undetected in patients with erectile dysfunction. J. Urol. 174, 1913–1916 (2005).

    Article  PubMed  Google Scholar 

  178. 178

    Hedon, F. Anxiety and erectile dysfunction: a global approach to ED enhances results and quality of life. Int. J. Impot. Res. 15, S16–S19 (2003).

    Article  PubMed  Google Scholar 

  179. 179

    Hale, V. E. & Strassberg, D. S. The role of anxiety on sexual arousal. Arch. Sex. Behav. 19, 569–581 (1990).

    Article  CAS  PubMed  Google Scholar 

  180. 180

    Beck, J. G. & Barlow, D. H. The effects of anxiety and attentional focus on sexual responding — II: cognitive and affective patterns in erectile dysfunction. Behav. Res. Ther. 24, 19–26 (1986).

    Article  CAS  PubMed  Google Scholar 

  181. 181

    de Boer, B. J., Bots, M. L., Nijeholt, A. A., Moors, J. P. & Verheij, T. J. The prevalence of bother, acceptance, and need for help in men with erectile dysfunction. J. Sex. Med. 2, 445–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. 182

    Nelson, C. J. et al. Men's experience with penile rehabilitation following radical prostatectomy: a qualitative study with the goal of informing a therapeutic intervention. Psychooncology 24, 1646–1654 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  183. 183

    Schover, L. R. et al. Defining sexual outcomes after treatment for localized prostate carcinoma. Cancer 95, 1773–1785 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  184. 184

    Sundaram, C. P. et al. Long-term follow-up of patients receiving injection therapy for erectile dysfunction. Urology 49, 932–935 (1997).

    Article  CAS  PubMed  Google Scholar 

  185. 185

    Huang, S. A. & Lie, J. D. Phosphodiesterase-5 (PDE5) inhibitors in the management of erectile dysfunction. P T 38, 407–419 (2013).

    PubMed  PubMed Central  Google Scholar 

  186. 186

    Jiann, B. P., Yu, C. C. & Tsai, J. Y. Compliance of sildenafil treatment for erectile dysfunction and factors affecting it. Int. J. Impot. Res. 18, 146–149 (2006).

    Article  CAS  PubMed  Google Scholar 

  187. 187

    Klotz, T., Mathers, M., Klotz, R. & Sommer, F. Why do patients with erectile dysfunction abandon effective therapy with sildenafil (Viagra)? Int. J. Impot. Res. 17, 2–4 (2005).

    Article  CAS  PubMed  Google Scholar 

  188. 188

    Lindau, S., Laumann, E., Levinson, W. & Waite, L. Synthesis of scientific disciplines in pursuit of health: the Interactive Biopsychosocial Model. Perspect. Biol. Med. 46, S74–S86 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  189. 189

    Goldfarb, S., Baron, S. & Lindau, S. in Women and Health (eds Goldman, M. B., Troisi, R. & Rexrode, K. M. ) 347–357 (Academic Press, 2013).

    Google Scholar 

  190. 190

    Lindau, S., Sandbo, S., Goldfarb, S. & Dickler, M. in Cancer and Sexual Health (eds Mulhall, J. P., Goldstein, I., Incrocci, L & Rosen, R. ) 415–455 (Springer, 2011).

    Google Scholar 

  191. 191

    Fisher, W., Rosen, R., Eardley, I., Sand, M. & Goldstein, I. Sexual experience of female partners of men with erectile dysfunction: the female experience of men's attitudes to life events and sexuality (FEMALES) study. J. Sex. Med. 2, 675–684 (2005). An important study that furthers our understanding of how erectile dysfunction can affect a couple's relationship and helps to define possible strategies that a couple could use to cope with the emotional strain caused by erectile dysfunction.

  192. 192

    Jiann, B. P., Su, C. C. & Tsai, J. Y. Is female sexual function related to the male partners' erectile function? J. Sex. Med. 10, 420–429 (2013).

    Article  PubMed  Google Scholar 

  193. 193

    Fisher, W. A. et al. Improving the sexual quality of life of couples affected by erectile dysfunction: a double-blind, randomized, placebo-controlled trial of vardenafil. J. Sex. Med. 2, 699–708 (2005).

    Article  CAS  PubMed  Google Scholar 

  194. 194

    Goldstein, I. et al. Women's sexual function improves when partners are administered vardenafil for erectile dysfunction: a prospective, randomized, double-blind, placebo-controlled trial. J. Sex. Med. 2, 819–832 (2005). This manuscript describes the benefits to their female partner when erectile dysfunction is treated in their partner.

    Article  CAS  PubMed  Google Scholar 

  195. 195

    Tran, S. N. et al. Prospective evaluation of early postoperative male and female sexual function after radical prostatectomy with erectile nerves preservation. Int. J. Impot. Res. 27, 69–74 (2015).

    Article  PubMed  Google Scholar 

  196. 196

    Albersen, M., Shindel, A. W., Mwamukonda, K. B. & Lue, T. F. The future is today: emerging drugs for the treatment of erectile dysfunction. Expert Opin. Emerg. Drugs 15, 467–480 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Hakim, L., Van der Aa, F., Bivalacqua, T. J., Hedlund, P. & Albersen, M. Emerging tools for erectile dysfunction: a role for regenerative medicine. Nat. Rev. Urol. 9, 520–536 (2012).

    Article  CAS  PubMed  Google Scholar 

  198. 198

    Hatzimouratidis, K. & Hatzichristou, D. Phosphodiesterase type 5 inhibitors: the day after. Eur. Urol. 51, 75–88; discussion 89 (2007).

    Article  CAS  PubMed  Google Scholar 

  199. 199

    Burnett, A. L. et al. Future sexual medicine physiological treatment targets. J. Sex. Med. 7, 3269–3304 (2010). A good review summarizing future prospects being researched in the treatment of erectile dysfunction.

    Article  CAS  PubMed  Google Scholar 

  200. 200

    Chitaley, K. et al. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat. Med. 7, 119–122 (2001).

    Article  CAS  PubMed  Google Scholar 

  201. 201

    Gratzke, C. et al. Activated RhoA/Rho kinase impairs erectile function after cavernous nerve injury in rats. J. Urol. 184, 2197–2204 (2010).

    Article  CAS  PubMed  Google Scholar 

  202. 202

    Bivalacqua, T. J. et al. RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. Proc. Natl Acad. Sci. USA 101, 9121–9126 (2004).

    Article  CAS  PubMed  Google Scholar 

  203. 203

    Jin, L. et al. Elevated RhoA/Rho-kinase activity in the aged rat penis: mechanism for age-associated erectile dysfunction. FASEB J. 20, 536–538 (2006).

    Article  CAS  PubMed  Google Scholar 

  204. 204

    Albersen, M. et al. Increased Rho-kinase 2 and an increase of synthetic smooth muscle-specific marker expression is observed in the corpus cavernosum of patients with severe erectile dysfunction. J. Urol. 191, e526 (2014).

    Article  Google Scholar 

  205. 205

    Oudot, A. et al. Combination of BAY 60-4552 and vardenafil exerts proerectile facilitator effects in rats with cavernous nerve injury: a proof of concept study for the treatment of phosphodiesterase type 5 inhibitor failure. Eur. Urol. 60, 1020–1026 (2011).

    Article  CAS  PubMed  Google Scholar 

  206. 206

    Albersen, M., Linsen, L., Tinel, H., Sandner, P. & Van Renterghem, K. Synergistic effects of BAY 60-4552 and vardenafil on relaxation of corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure. J. Sex. Med. 10, 1268–1277 (2013).

    Article  CAS  PubMed  Google Scholar 

  207. 207

    US National Library of Science. Multiple dose escalation study (14 days) to investigate safety, tolerability, PK and PD of vardenafil and BAY60-4552. ClinicalTrials.gov [online],https://clinicaltrials.gov/ct2/show/NCT01110590(2010).

  208. 208

    US National Library of Science. Clinical proof-of-concept study for the combination BAY60-4552 / vardenafil for the treatment of erectile dysfunction not sufficiently responsive to standard therapy with PDE5 inhibitors. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01168817?term=NCT01168817&rank=1 (2010).

  209. 209

    Melman, A., Bar-Chama, N., McCullough, A., Davies, K. & Christ, G. The first human trial for gene transfer therapy for the treatment of erectile dysfunction: preliminary results. Eur. Urol. 48, 314–318 (2005). This manuscript describes the first human trial of gene transfer therapy for erectile dysfunction treatment.

    Article  CAS  PubMed  Google Scholar 

  210. 210

    Albersen, M., Weyne, E. & Bivalacqua, T. J. Stem cell therapy for erectile dysfunction: progress and future directions. Sex. Med. Rev. 1, 50–64 (2013). This manuscript discusses the current status and future outlook of stem cell therapy for erectile dysfunction treatment.

    Article  PubMed  Google Scholar 

  211. 211

    Lin, G. et al. Potential of adipose-derived stem cells for treatment of erectile dysfunction. J. Sex. Med. 6 (Suppl. 3), 320–327 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  212. 212

    Bahk, J. Y., Jung, J. H., Han, H., Min, S. K. & Lee, Y. S. Treatment of diabetic impotence with umbilical cord blood stem cell intracavernosal transplant: preliminary report of 7 cases. Exp Clin. Transplant. 8, 150–160 (2010).

    PubMed  Google Scholar 

  213. 213

    Yiou, R. et al. Safety of intracavernous bone marrow-mononuclear cells for postradical prostatectomy erectile dysfunction: an open dose-escalation pilot study. Eur Urol. http://dx.doi.org/10.1016/j.eururo.2015.09.026 (2015).

  214. 214

    US National Library of Science. Evaluate the use of liposuction and cell separation devices for autologous fat (adipose) derived cells to treat the symptoms of erectile dysfunction. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01601353 (2015).

  215. 215

    US National Library of Science. Allogeneic human bone marrow derived mesenchymal stem cells in localized prostate cancer (MSC). ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01983709 (2015).

  216. 216

    US National Library of Science. Autologous adipose-derived stromal cells delivered into the corpus cavernous in patients with erectile dysfunction. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02087397 (2014).

  217. 217

    US National Library of Science. Can fat derived stem cells (SVF) be used in the treatment of erectile dysfunction after prostatectomy. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02240823 (2015).

  218. 218

    US National Library of Science. Safety of autologous bone marrow derived mesenchymal stem cells in erectile dysfunction. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02344849 (2015).

  219. 219

    US National Library of Science. Evaluate the safety and feasibility of injecting PMD-MSC into the penis to treat the symptoms of mild to moderate ED (PMD-MSC-ED-01). ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02398370 (2015).

  220. 220

    US National Library of Science. Safety and clinical outcomes study: SVF deployment for orthopedic, neurologic, urologic, and cardio-pulmonary conditions. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01953523 (2015).

  221. 221

    Michal, V. Vascular surgery in the treatment of imporence; its present possibilities and prospects. Czech Med. 3, 213–217 (1980).

    CAS  PubMed  Google Scholar 

  222. 222

    Brindley, G. S. Cavernosal α-blockade: a new technique for investigating and treating erectile impotence. Br. J. Psychiaty 143, 332–337 (1983).

    Article  CAS  Google Scholar 

  223. 223

    Campeau, L. Grading of angina pectoria. Circulation 54, 522–523 (1976).

    Article  CAS  PubMed  Google Scholar 

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Authors

Contributions

Introduction (R.T.); Epidemiology (A.S.); Mechanisms/pathophysiology (L.J., J.M., A.M.I.); Diagnosis, screening and prevention (G.C., M.M.); Management (L.J., J.M., F.A.Y., W.J.G.H.); Quality of life (C.N., S.G., S.P.); Outlook (M.A.); overview of Primer (L.J., J.M., F.A.Y., W.J.G.H.).

Corresponding authors

Correspondence to John P. Mulhall or Wayne J. G. Hellstrom.

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Competing interests

M.A. has received grants from Ferring, Bayer, ESSM and ISSM, and served as an advisor for Sandoz, Sobi and Sanofi. G.C. has received consultancy fees from Bayer, Besins, Otsuka, Eli-Lilly and Menarini. A.M.I. has served as an advisor for Otsuka, Shire, Besins, Novartis and Menarini. M.M. has served as an advisor and/or received speaker's fees from Bayer, Ely Lilly, Menarini, Prostrakan and Intercept. C.J.N. has served as an unpaid advisor for American Medical Systems. S.P. has served as an advisor for Pfizer, Sprout Pharmaceuticals, Emotional Brain and Strategic Science Technologies, and received speaker's fees from Pfizer. R.T. has served as an advisor for Lilly and Orient Europharma, and received speaker's fees from Lilly. J.P.M. has received grants from CIACT, NIH and SMSNA, and served as an advisor for Lilly, Pfizer and AMS. W.J.G.H. has served as an advisor for Abbvie, American Medical Systems, Coloplast and Pfizer. The other authors declare no competing interests.

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Yafi, F., Jenkins, L., Albersen, M. et al. Erectile dysfunction. Nat Rev Dis Primers 2, 16003 (2016). https://doi.org/10.1038/nrdp.2016.3

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