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Les inhibiteurs de la phosphodiestérase de type 5 : une révolution dans le traitement des symptômes du bas appareil urinaire?

Phosphodiesterase type 5 inhibitors: a revolution in the treatment of lower urinary tract symptoms?

Basic and Clinical Andrology volume 22, pages 80–91 (2012)Cite this article

Résumé

Contexte

L’incidence des symptômes du bas appareil urinaire (SBAU) liés à une hypertrophie bénigne de prostate (HBP) augmente avec l’âge puisqu’ils touchent 50 % des patients âgés de plus de 50 ans et 90 % de ceux âgés de plus de 80 ans. La prévalence et la sévérité de la dysfonction érectile (DE) augmentent également avec l’âge. Sa prévalence est évaluée à 31,6 % dans une population générale d’adultes âgés de plus de 40 ans. Les SBAU comme la DE altèrent de façon significative la qualité de vie (QdV) des patients et de leur partenaire. Plusieurs études ont montré que les SBAU constituent un facteur de risque de DE indépendant de l’âge et des autres comorbidités. La sévérité des SBAU est corrélée à celle de la DE. Les hypothèses physiopathologiques pour expliquer le lien entre SBAU et DE sont : une augmentation du tonus sympathique, une altération du système NO/cGMP, une altération du système rho-kinase et une athéromatose pelvienne.

Objectif

Évaluer les résultats et comprendre le mécanisme d’action de l’administration d’un inhibiteur de la phosphodiestérase de type 5 (IPDE 5) sur les SBAU liés à une HBP.

Matériels et méthodes

Une revue de la littérature a été réalisée à partir des articles originaux et des articles de synthèse déjà disponibles, sélectionnés par le moteur de recherche Pubmed de la National Library of Medecine. Les mots clés utilisés pour cette recherche ont été : benign prostatic hyperplasia; cyclic nucleotide phosphodiesterase type 5; LUTS; erectile dysfunction.

Résultats

Cette revue de la littérature montre que l’administration d’un inhibiteur de la phosphodiestérase de type 5 améliore les SBAU de manière significative dans 12 essais cliniques randomisés, avec un bénéfice également sur la DE et l’absence d’effets secondaires indésirables graves rapportés.

Conclusion

Le traitement des SBAU par les IPDEs 5 semble très prometteur, même s’il ne dispose pas d’une AMM dans cette indication en France. Récemment, le tadalafil à la posologie de 5 mg a été approuvé aux États-Unis par la FDA dans les troubles mictionnels liés à l’HBP, avec ou sans DE.

Abstract

Context

The incidence of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH) increases with age, affecting 50% of patients aged over 50 years and 90% of those aged over 80 years. The prevalence and severity of erectile dysfunction (ED) also increase with age. Its prevalence is estimated to be 31.6% in men over 40 years. LUTS as well as ED significantly affect the quality of life of patients and their partners. Several studies have shown that LUTS represent an independent risk factor for ED. The severity of LUTS is correlated with that of ED. The pathophysiological hypothesis linking LUTS to ED are an increase in sympathetic tone, alteration of NO/cGMP system, alteration of rho kinase system, and pelvic atherosclerosis.

Goal

Some treatments of LUTS have adverse effects on the erectile function. The phosphodiesterase type 5 inhibitors (IPDE 5) revolutionized the treatment of ED.

Material and methods

Several recent clinical studies evaluated the effect of daily treatment by IPDE 5 on LUTS secondary to BPH among patients with or without ED.

Results

This review shows that IPDE 5 administration improves LUTS significantly in 12 randomized clinical trials, as well as in both storage and voiding parts of the international prostate symptom score (IPSS) and in quality of life questionnaire. No adverse events were observed, and ED, which has a high prevalence among this population, was also improved.

Conclusion

The treatment of LUTS by IPDE 5 looks very promising, even though they are not yet approved for this indication in France.

Abbreviations

AMM:

autorisation de mise sur le marché

CGI-I:

clinical global impression of improvement

DE:

dysfonction érectile

GC:

guanylate-cyclase

GMPc:

guanosine monophosphate phosphate cyclic

GTP:

guanosine triphosphate

HAV:

hyperactivité vésicale

HBP:

hyperplasie bénigne de prostate

IIEF-EF:

international index of erectile function-erectile function domain

IPDE 5:

inhibiteur de la phosphodiestérase de type 5

IPSS:

international prostate symptom score

IPSS-Qol:

international prostate symptom score quality of life

NO:

monoxyde d’azote

NOS:

monoxyde d’azote synthase

QdV:

qualité de vie

RPM:

résidu postmictionnel

SBAU:

symptômes du bas appareil urinaire

TSS-BPH:

treatment satisfaction scale, benign prostatic hyperplasia

Références

  1. Garraway WM, Collins GN, Lee RJ (1991) High prevalence of benign prostatic hypertrophy in the community. Lancet 338:469–471

    PubMed  CAS  Article  Google Scholar 

  2. Rosen R, Altwein J, Boyle P, et al (2003) Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol 44:637–649

    PubMed  Article  Google Scholar 

  3. Giuliano F, Chevret-Masson M, Tsatsaris A, et al (2002) Prevalence of erectile dysfunction in France: results of an epidemiological survey of a representative sample of 1004 men. Eur Urol 42:382–389

    PubMed  Article  Google Scholar 

  4. McVary KT (2005) Erectile dysfunction and lower urinary tract symptoms secondary to BPH. Eur Urol 47:838–845

    PubMed  Article  Google Scholar 

  5. Braun MH, Sommer F, Haupt G, et al (2003) Lower urinary tract symptoms and erectile dysfunction: co-morbidity or typical “Aging Male” symptoms? Results of the “Cologne Male Survey”

  6. Ponholzer A, Temml C, Obermayr R, Madersbacher S (2004) Association between lower urinary tract symptoms and erectile dysfunction. Urology 64:772–776

    PubMed  Article  Google Scholar 

  7. Shiri R, Häkkinen J, Koskimäki J, et al (2005) Association between the bothersomeness of lower urinary tract symptoms and the prevalence of erectile dysfunction. J Sex Med 2:438–444

    PubMed  Article  Google Scholar 

  8. Elhilali M, Emberton M, Matzkin H, et al (2006) Long-term efficacy and safety of alfuzosin 10 mg once daily: a 2-year experience in real-life practice. BJU Int 97:513–519

    PubMed  CAS  Article  Google Scholar 

  9. Köhler TS, McVary KT (2009) The relationship between erectile dysfunction and lower urinary tract symptoms and the role of phosphodiesterase type 5 inhibitors. Eur Urol 55:38–48

    PubMed  Article  Google Scholar 

  10. Abrams P, Cardozo L, Fall M, et al (2002) The standardisation of terminology of lower urinary tract function. Report from the standardisation subcommittee of the ICS. Neurourol Urodyn 21:167–178

    PubMed  Article  Google Scholar 

  11. Haab F, Amarenco G, Coloby P, et al (2004) Terminologie des troubles fonctionnels du bas appareil urinaire: adaptation française de la terminologie de l’International Continence Society. Prog Urol 14:1103–1111

    PubMed  Google Scholar 

  12. Desgranchamps F, De La Taille A, Azzouzi AR, et al (2006) Management of non complicated BPH: proposition for a renewed decision tree. World J Urol 24:367–370

    Article  Google Scholar 

  13. Irani J, Brown CT, Van Der Meulen J, Emberton MA (2003) Review of guidelines on benign prostatic hyperplasia and lower urinary tract symptoms: are all guidelines the same? BJU Int 92:937–942

    PubMed  CAS  Article  Google Scholar 

  14. Vela-Navarrete R, Gonzalez-Enguita C, Garcia-Cordoso JV, et al (2005) The impact of medical therapy on surgery for benign prostatic hyperplasia: a study comparing changes in decade. BJU Int 7:1045–1048

    Article  Google Scholar 

  15. Beckman TJ, Mynderse LA (2005) Evaluation and medical management of benign prostatic hyperplasia. Mayo Clin Poc 10:1356–1362

    Article  Google Scholar 

  16. Murray E, Davis H, Tai SS, et al (2001) Randomised controlled trial of an interactive multimedia decision aid on benign prostatic hyperplasia in primary care. BMJ 323:1–6

    Article  Google Scholar 

  17. Abrams P, Kaplan S, De Koning, et al (2006) Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol 175:999–1004

    PubMed  CAS  Article  Google Scholar 

  18. McConnell JD, Roehrborn CG, Bautista OM, et al (2003) The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 349:2387–2398

    PubMed  CAS  Article  Google Scholar 

  19. Kirby RS, Roehrborn CG, Boyle P, et al (2003) Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology 61:1119–1126

    Article  Google Scholar 

  20. Nichol MB, Knight TK, Wu J, et al (2009) Evaluation use patterns of and adherence to medications for benign prostatic hyperplasia. J Urol 5:2214–2221

    Article  Google Scholar 

  21. Stene E (1994) Three years safety and efficacy data on the use of finasteride in the treatment of benign prostatic hyperplasia. Urology 43:284–294

    Article  Google Scholar 

  22. Van Kerrebroeck P, Jardin A, Laval KU, Van Cangh P (2000) Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily vs 2,5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI study group. Eur Urol 3:306–313

    Article  Google Scholar 

  23. Lepor H (1998) Long term of tamsulosine in benign prostatic hyperplasia: placebo-controlled, double-bind extension of phase III trial. Urology 6:901–906

    Article  Google Scholar 

  24. Phillips B. Levels of evidence and grades of recommandation. Oxford centre for evidence-based medicine.http://www.cebm.net/levels_of_evidence.asp

  25. Roehrborn CG, McVary KT, Elion-Mboussa A, Vikturp L (2008) Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol 180:1228–1234

    PubMed  CAS  Article  Google Scholar 

  26. McVary K, Monnig W, Camps Jr, et al (2007) Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double-blind trial. J Urol 177:1071–1077

    PubMed  CAS  Article  Google Scholar 

  27. Stief C, Porst H, Neuser D, et al (2008) A randomised, placebo controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol 53:1236–1244

    PubMed  CAS  Article  Google Scholar 

  28. Dmochowski R, Roehrborn C, Klise S, et al (2010) Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: a randomized, placebo controlled 12-week clinical trial. Urology 183:1092–1097

    CAS  Article  Google Scholar 

  29. Tamimi N, Mincik I, Haughie S, et al (2010) A placebocontrolled study investigating the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of men with lower urinary tract symptoms associated with clinical benign prostatic hyperplasia. BJU Int 106:674–680

    PubMed  CAS  Article  Google Scholar 

  30. Giuliano FA, Lamb J, Crossland A, et al (2010) A placebo-controlled exploratory study investigating the efficacy and safety of the phosphodiesteras type 5 inhibitor UK-369,003 for the treatment of men with storage lower urinary tract symptoms associated with a clinical diagnosis of overactive bladder. BJU Int 106:666–673

    PubMed  CAS  Article  Google Scholar 

  31. Roherborn CG, Kaminetsky JC, Auerbach SM, et al (2010) Changes in peak urinary flow an voiding efficiency in men with signs and symptoms of benign prostatic hyperplasia during once daily tadalafil treatment. BJU Int 105:502–507

    Article  Google Scholar 

  32. Ergedie RB, Auerbach S, Roehrborn CG, et al (2012) Tadalafil 2,5 mg or 5 mg administred once daily for 12 weeks in men both erectile dysfunction and signs and symptoms of nenign prostatic hyperplasia: results of a randomized, placebo-controlled, doubleblind study. J Sex Med 9:271–281

    Article  Google Scholar 

  33. Porst H, Kim ED, Casabé AR, et al (2011) Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol 60:1105–1113

    PubMed  CAS  Article  Google Scholar 

  34. Oelke M, Giuliano F, Mirone V, et al (2012) Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomized, parallel, placebo-controlled clinical trial. Eur Urol 61:917–925

    PubMed  CAS  Article  Google Scholar 

  35. Broderick GA, Brock GB, Roehrborn CG, et al (2010) Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology 75:1452–1458

    PubMed  Article  Google Scholar 

  36. McVary KT, Roehrborn CG, Kaminetsky JC, et al (2007) Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol 177:1401–1407

    PubMed  CAS  Article  Google Scholar 

  37. Bechara A, Romano S, Casabé A, et al (2008) Comparative efficacy assessment of tamsulosine vs tamsulosine plus tadlafil in the treatment of LUTS/BPH. Pilot study. J Sex Med 5:2170–2178

    PubMed  CAS  Article  Google Scholar 

  38. Kaplan SA, Gonzales RR, Te AE (2007) Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol 51:1717–1723

    PubMed  CAS  Article  Google Scholar 

  39. Mulhall JP, Guhring P, Parker M, Hopps C (2006) Assessment of the impact of sildenafil citrate on lower urinary tract symptoms in men with erectile dysfunction. J Sex Med 3:662–667

    PubMed  CAS  Article  Google Scholar 

  40. Sairam K, Kulinskaya E, McNicholas TA, et al (2002) Sildenafil influences lower urinary tract symptoms. BJU Int 90:836–839

    PubMed  CAS  Article  Google Scholar 

  41. Nieminen T, Tammela LJ, Koobi T, Kahonen M (2006) The effects of tamsulosine and sildenafil in separate and combined regimens on detailed hemodynamics in patients with benign prostatic enlargement. J Urol 176:2551–2556

    PubMed  CAS  Article  Google Scholar 

  42. van Leeuwen JH, Castro R, Busse M, Bemelmans BL (2006) The placebo effect in the pharmacologic treatment of patients with lower urinary tract symptoms. Eur Urol 50:440–453

    PubMed  Article  Google Scholar 

  43. Ückert S, Kuthe A, Jonas U, Stief CG (2001) Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. J Urol 166:2484–2490

    PubMed  Article  Google Scholar 

  44. Waldkirch E, Ückert S, Langnäse K (2007) Immunohistochemical distribution of cyclic GMP-dependent protein kinase-1 in human prostate tissue. Eur Urol 52:495–502

    PubMed  CAS  Article  Google Scholar 

  45. Ückert S, Oelke M, Stief CG, et al (2006) Immunohistochemical distribution of cAMP and cGMP-phosphodiesterase (PDE) isoenzymes in the human prostate. Eur Urol 49:740–745

    PubMed  Article  Google Scholar 

  46. Takeda M, Tang R, Shapiro E, et al (1995) Effects of nitric oxide on human and canine prostates. Urology 45:440–446

    PubMed  CAS  Article  Google Scholar 

  47. Guh JH, Chueh SC, Hwang TL, et al (1998) Cell proliferation in human prostatic smooth muscle cells involves the modulation of protein kinase C isozymes. Eur J Pharmacol 359:281–284

    PubMed  CAS  Article  Google Scholar 

  48. Cook AL, Haynes JM (2004) Protein kinase G II mediated proliferative effects in human cultured prostatic stromal cells. Cell Signal 16:253–261

    PubMed  CAS  Article  Google Scholar 

  49. Bloch W, Klotz T, Loch C, et al (1997) Distribution of nitric oxide synthase implies a regulation of circulation, smooth muscle tone, and secretory function in the human prostate by nitric oxide. Prostate 33:1–8

    PubMed  CAS  Article  Google Scholar 

  50. Kramer G, Mitteregger D, Marberger M (2007) Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur Urol 51:1202–1216

    PubMed  CAS  Article  Google Scholar 

  51. Werkstrom V, Svensson A, Andersson KE, Hedlund P (2006) Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects. BJU Int 98:414–423

    PubMed  Article  Google Scholar 

  52. Bittencourt JA, Tano T, Gajar SA, et al (2009) Relaxant effects of sildenafil on the human isolated bladder neck. Urology 73:427–430

    PubMed  Article  Google Scholar 

  53. Filippi S, Morelli A, Sandner P, et al (2007) Characterization and functional role androgen-dependent PDE5 activity in the bladder. Endocrinology 148:1019–1029

    PubMed  CAS  Article  Google Scholar 

  54. Fathian-Sabet B, Bloch W, Klotz T, et al (2001) Localization of constitutive nitric oxide synthase isoforms and the nitric oxide target enzyme soluble guanylyl cyclase in the human bladder. J Urol 5:1724–1729

    Article  Google Scholar 

  55. Truss MC, Uckert S, Stief CG, et al (1996) Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle. I. Identification and characterization. Urol Res 24:123–128

    PubMed  CAS  Google Scholar 

  56. Birder LA, Apodaca G, De Groat WC, Kanai AJ (1998) Adrenergic and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder. Am J Physiol 12:226–229

    Google Scholar 

  57. Oger S, Behr-Roussel D, Gorny D, et al (2008) Signaling pathways involved in sildenafil-induced relaxation of human detrusor. 102th meeting American Urological Association. Orlando, USA

  58. Persson K, Igawa Y, Mattinsson A, Andersson KE (1992) Effects of inhibition of the L-arginine/ nitric oxide pathway in the rat lower urinary tract in vivo and in vitro. Br J Pharmacol 107:178–184

    PubMed  CAS  PubMed Central  Article  Google Scholar 

  59. Moon A (2002) Influence of nitric oxide signalling pathways on pre-contracted human detrusor smooth muscle in vitro. BJU Int 89:942–949

    PubMed  CAS  Article  Google Scholar 

  60. Yanai Y, Hashitani H, Sasaki S, et al (2008) Role of nitric oxide/ cyclic GMP pathway in regulating spontaneous excitations in detrusor smooth muscle of the guinea-pig bladder. Neurourol Urodyn 27:446–453

    PubMed  CAS  Article  Google Scholar 

  61. Morelli A, Filippi S, Fibbi B, et al (2009) Vardenafil modulates bladder contractility through cGMP-mediated inhibition of RhoA/Rho-kinase signaling pathway in spontaneously hypertensive rats. J Sex Med 6:1594–1608

    PubMed  CAS  Article  Google Scholar 

  62. Werkstrom V, Hedlund P, Lee T, Andersson KE (2009) Vardenafil-induced relaxation and cyclic nucleotide levels in normal and obstructed rat urinary bladder. BJU Int 104:1740–1745

    PubMed  Article  Google Scholar 

  63. Matsumoto S, Hanai T, Uemura H (2010) Chronic treatment with a PDE5 inhibitor increases contractile force of normal bladder in rats. Int Urol Nephrol 42:53–56

    PubMed  CAS  Article  Google Scholar 

  64. Smet PJ, Jonavicius J, Marshall VR, de Vente J (1996) Distribution of nitric oxide synthase-immunoreactive nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cGMP immunohistochemistry. Neuroscience 71:337–348

    PubMed  CAS  Article  Google Scholar 

  65. Ozawa H, Chancellor MB, Jung SY, et al (1996) Effect of intravesical nitric oxide therapy on cyclophosphamide-induced cystitis. J Urol 6:2211–2216

    Google Scholar 

  66. Tinel H, Stelte-Ludwig B, Hutter J, Sandner P (2006) Pre-clinical evidence for the use of phosphodiesterase-5 inhibitors for treating benign prostatic hyperplasia and lower urinary tract symptoms. BJU Int 98:1259–1263

    PubMed  CAS  Article  Google Scholar 

  67. Behr-Roussel D, Oger S, Caisey S, et al (2011). Vardenafil decreases bladder afferent nerve activity in unanesthetized, decerebrate, spinal cord-injured rats. Eur Urol 59:272–279

    PubMed  CAS  Article  Google Scholar 

  68. Caremel R, Oger-Roussel S, Behr-Roussel D, et al (2010) Nitirc oxyde/cyclic guanosine monophosphate signalling mediates an inhibitory action on sensory pathways of the micturation reflex in the rat. Eur Urol 58:616–625

    PubMed  CAS  Article  Google Scholar 

  69. Berger AP, Deibl M, Leonhartsberger N, et al (2005) Vascular damage as a risk factor for benign prostatic hyperplasia and érectile dysfonction. BJU Int 96:1073–1088

    PubMed  Article  Google Scholar 

  70. Pinggera A, Schuster F, Frauscher G, Bartsch H (2004) Sildenafil citrate causes a three fold increase in periurethral prostatic blood flow. J Urol 171:A1348

    Article  Google Scholar 

  71. Morelli A, Filippi S, Comeglio P, et al (2010) Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats. J Sex Med 7:107–120

    PubMed  CAS  Article  Google Scholar 

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  1. Hôpital Charles-Nicolle, 1, rue de Germont, pavillon Derocque, F-76000, Rouen, France

    R. Caremel, E. Laccarier & L. Sibert

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Caremel, R., Laccarier, E. & Sibert, L. Les inhibiteurs de la phosphodiestérase de type 5 : une révolution dans le traitement des symptômes du bas appareil urinaire?. Basic Clin. Androl. 22, 80–91 (2012). https://doi.org/10.1007/s12610-012-0172-5

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Mots clés

  • Symptômes du bas appareil urinaire
  • Dysfonction érectile
  • Épidémiologie
  • Hypertrophie bénigne de prostate
  • Inhibiteur de phosphodiestérase de type 5

Keywords

  • Phosphodiesterase type 5 inhibitors
  • Lower urinary tract symptoms
  • Erectile dysfunction
  • Epidemiology
  • Benign prostatic hyperplasia

Basic and Clinical Andrology

ISSN: 2051-4190