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Erectile Dysfunction: New Paradigms in Treatment

1. Discuss diagnosis of erectile dysfunction
2. Treatments of ED using Viagra, Cialis, Trimix (intracavernosal injections)
3. Evaluate penile prosthesis and implant as ED surgical therapy options

  • Inicia sesión para ver los comentarios

Erectile Dysfunction: New Paradigms in Treatment

  1. 1. Erectile Dysfunction: New Paradigms in Treatment Ranjith Ramasamy, MD Director, Male Reproductive Urology University of Miami
  2. 2. Epidemiologic Survey: Prevalence of ED* No erectile dysfunction (48%) Erectile dysfunction (52%) Men aged 40 to 70 years (N=1290) Minimal (17%) Complete (10%) Moderate (25%) *Massachusetts Male Aging Study. Adapted from Feldman HA, et al. J Urol. 1994;151:54-61.
  3. 3. • Erections are a complex event, requiring – Intact arterial and venous system – Normal innervation – Normal hormonal factors – Functioning erectile tissue (the penis) Physiology of Normal Erections Abnormalities in any or all of these will lead to ED.
  4. 4. ON Breakdown by PDE5cGMP Vascular smooth muscle relaxation Inflow to corpus cavernosum Sexual stimulation NANC Mechanism of Erections: Chemical Pathway cGMP=cyclic guanosine monophosphates. NO=nitric oxide. PDE5=phosphodiesterase type 5.
  5. 5. Erect PenisFlaccid Penis Mechanism of Erections: Cross Section Cavernosal artery Tunica albuginea UrethraCorpus spongiosum Dorsal nerve Dorsal vein Dorsal artery Corpora cavernosa National Erectile Dysfunction Foundation. Understanding Erectile Dysfunction. 1998.
  6. 6. Pathophysiologic Mechanism of ED: The Common Link Dzau VJ, et al. Am J Cardiol. 1997;80:33I-39I. NIH Consensus Development Panel on Impotence. JAMA. 1993;270:83-90. Oxidative stress Endothelial cell injury Diabetes ED Thrombosis Atherosclerosis Tobacco Dyslipidemia Precursors Outcomes Hypertension Vasoconstriction
  7. 7. The Link Between ED and Other Conditions May Be Endothelial Dysfunction 0 0.01 0.02 0.03 0.04 0.05 0 10 20 30 40 50 60 70 80 ED Control Kaiser DR. J Am Coll Cardiol. 2004;43:179-184. Flow-mediatedvasodilation(%) Time (s) Brachial Artery Flow-Mediated Vasodilation P=0.014
  8. 8. ED May Be Clinically Evident Prior to CAD Symptoms Among 300 patients with CAD and angina • Prevalence of ED among patients was 49% • Mean time between onset of ED symptoms and onset of CAD is 38.8 months (range 1-168) • All patients with type 1 diabetes had ED prior to CAD 0 10 20 30 40 50 60 All ED Severe ED ED symptoms prior to CAD CAD=coronary artery disease Montorsi F. Eur Urol. 2003;44:360-364. Percent
  9. 9. Relationship of ED to Silent MI in Type 2 Diabetes • 133 men with type 2 diabetes and documented asymptomatic CAD were compared with 127 men with type 2 diabetes and negative cardiac evaluation • ED was highly correlated with the presence of asymptomatic silent MI and CAD • Men with type 2 diabetes who present with ED and no cardiac history need cardiac evaluation Gazzaruso C, et al. Circulation. 2004;110:22-26.
  10. 10. ED as Prognostic Indicator in Young Men Inman et al. A population-based, longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc. 2009; 84: 108–113 -1400 community- dwelling men - Incidence densities of CAD were calculated after adjustment for age and potential confounders - ED in younger men is associated with a marked increase in the risk of future cardiac events
  11. 11. It doesn’t take much for a man with testosterone to become aroused
  12. 12. The Interpersonal Dilemma
  13. 13. • Reluctance to discuss ED because of embarrassment, shame, or ignorance about normal sexual functioning • Cultural beliefs about discussing sexuality • Discomfort • Fear of offending patient or causing discomfort • Lack of confidence in diagnosing and treating ED • Interpersonal differences with patient (cultural, religious, ethnic) • Concern with appearing “overly interested” in patient’s sex life PhysicianPatient Barriers to Identifying Erectile Dysfunction (ED) Humphery S, Nazareth I. Fam Pract. 2001;18:516-518.
  14. 14. ED Treatment-Seeking Behavior in Urology Offices No ED 56% ED 44% 0 10 20 30 40 50 60 70 80 Embarrassed ED part of aging Unaware urologists treat ED ED not important Prevalence of previously unreported ED among 500 men (aged ≥50) visiting for non-ED complaint Reasons for Failure to Discuss ED With Urologist Baldwin K, et al. Int J Impot Res. 2003;15:87-89. Percentage
  15. 15. Diagnosing ED • Basic evaluation of sexual dysfunction – Sexual, medical, and psychosocial history • Focused physical examination • Recommended diagnostic tests including – Glucose, lipids, serum chemistries, testosterone, prostate-specific antigen (PSA), and complete blood count Empiric trials of therapy are discouraged without this basic evaluation. The Process of Care Consensus Panel. Int J Impot Res. 1999;11:59-70. Meuleman E, et al. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Plymbridge Distributors; 2000:115-138.
  16. 16. Classification of ED: Psychogenic or Organic? Psychogenic Organic Sudden onset Gradual onset Complete immediate loss Incremental progression AM erections present Lack of AM erections Varies with partner and circumstance Lack of erections under most sexually stimulating circumstances Ralph D, et al. BMJ. 2000;321:499-503. With permission from the BMJ Publishing Group.
  17. 17. Erectile Dysfunction: Management
  18. 18. Interventions • Lifestyle/drug therapy modification • Psychosocial counseling and education • Androgen replacement therapy • Oral therapy Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, UK: Health Publication, Ltd; 2000:711-726.
  19. 19. First-Line Intervention: Drug Therapy Modifications • Modify drug regimens associated with ED1 – Antihypertensives/diuretics2 – Selective serotonin reuptake inhibitors3 – Hormonal agents (eg, antiandrogens)4,5 – Histamine-2-receptor antagonists6 1. Lue TF. N Engl J Med. 2000;342:1802-1813. 2. Grimm RH Jr, et al. Hypertension. 1997;29:8-14. 3. Rosen RC, et al. J Clin Psychopharmacol. 1999;19:67-85. 4. Jackson G, et al. Int J Clin Pract. 1999;53:445-451. 5. Ralph D, et al. BMJ. 2000;321:499-503. 6. Lundberg PO, Biriell C. Int J Impot Res. 1993;5:237-239.
  20. 20. Evaluating for hypogonadism: ED and Testosterone • The chemical mechanism for normal erections seems to be testosterone dependent • Men with low testosterone have a diminished response to PDE5i • Improvement of other health problems, including low testosterone, → improved response rates with PDE5i 2*2*
  21. 21. Diagnostic Testosterone Testing: Initial Tests • Serum Total Testosterone (free plus protein-bound) Morning sample recommended in young men Reasonable screening tool • Serum Free Testosterone (nonprotein-bound) Better in older/obese men • Serum Bioavailable T (free plus albumin-bound) Measures albumin-bound and free testosterone Best test, most expensive . Tenover J.L..Tenover J.L.. Endocrinol Metab Clin North Am.Endocrinol Metab Clin North Am. 1998;27:969-987.1998;27:969-987. Braunstein G.D.. In:Braunstein G.D.. In: Basic & Clinical EndocrinologyBasic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:403.. 5th ed. Stamford, Conn: Appleton & Lange; 1997:403.
  22. 22. DM: Hypogonadism and ED • Both ED and Hypogonadism (low T) are increased in the diabetic patient • There does not appear to be a common pathophysiology – ED peripheral neuropathy, small vessel→ angiopathy and endothelial dysfunction – HypoT obesity, metabolic syndrome or→ dysfunctional adipocytes • Each abnormal state needs to be diagnosed and treated as with any other patient
  23. 23. • Men with DM are 2X as likely to have low T levels than they are to have normal T levels • DM independently predicts low levels of testosterone • Patients with DM had even greater declines in Testosterone than those with Metabolic Syndrome (MetS) Corona G, et al,Corona G, et al, J Sex MedJ Sex Med, 272-283, 2011., 272-283, 2011. DM: Hypogonadism and ED
  24. 24. Hypogonadism and ED: Intervention • Intervention with TRT in hypogonadal men has shown improvement in: – Individual body weight – Waist circumference – Lipid profiles – MetS complete reversal→ 1 • Randomized, double blind trial intramuscular TU for 12 months improved MetS parameters, waist circumference and fat mass2 1.1. Haider A, et al,Haider A, et al, German Soc EndocrGerman Soc Endocr, 118:167-171, 2010., 118:167-171, 2010. .. AversaAversa A, et al,A, et al, J Endocr InvestJ Endocr Invest, 33:776-783, 2010., 33:776-783, 2010.
  25. 25. Guidelines on Testosterone and ED • AUA Recs: Testosterone therapy is not indicated for the treatment of erectile dysfunction in the patient with a normal serum testosterone level. • EUA Recs: Laboratory testing must be tailored to the patient’s complaints and risk factors. Hormonal tests include a morning sample of total testosterone.
  26. 26. Testosterone level and ED Zitzmann M, et alith serum testosterone in older men. J Clin Endocrinol Metab. 2006 Nov;91(11):4335-43. Epub 2006 Aug 22. -In erectile dysfunction hard to tease out contribution of metabolic risk factors, smoking, etc - concentrations below 8 nmol/liter (230ng/dl) consistently contributed to ED
  27. 27. Androgen Replacement Oral TabletsOral Tablets IntramuscularIntramuscular InjectionsInjections Pellet ImplantsPellet Implants TransdermalTransdermal GelsGels TransdermalTransdermal PatchesPatches
  28. 28. TRT Formulation-Specific Adverse Effects Oral tablets – Effects on liver and cholesterol (methyltestosterone) Intramuscular injections of testosterone enanthate or cypionate – Fluctuation in mood or libido – Pain at injection site – Excessive erythrocytosis (especially in older patients) Transdermal patches – Skin reactions at application site Transdermal gel – Potential risk for testosterone transference to partner Pellet implants – Infection, expulsion of pellet Bhasin S, et al.Bhasin S, et al. J Clin Endocrinol MetabJ Clin Endocrinol Metab, 91:1995-2010, 2006., 91:1995-2010, 2006. 5*5*
  29. 29. First-Line Therapy: Oral Agents • US Food and Drug Administration (FDA)- approved phosphodiesterase type 5 (PDE5) inhibitors – Sildenafil citrate –1998 – Vardenafil –2003 – Tadalafil –2003 – Avanafil-2012 • Investigational oral agents – Yohimbine and L-arginine Goldstein I. Int J Impot Res. 2000;12(suppl 1):S75-S80. Greiner KA, Weigel JW. Am Fam Physician. 1996;54:1675-1682. Klotz T, et al. Urol Int. 1999;63:220-223. Lue TF. N Engl J Med. 2000;342: 1802-1813. Padma-Nathan H, Giuliano F. Urol Clin North Am. 2001;28:321-334.
  30. 30. PDE5 Inhibitors: Onset and Duration of Activity PDE5 inhibitor Onset (min) Duration (h) Sildenafil1,2 30-60* 4* Tadalafil3-5 120 36‡ Vardenafil6-8 25* 4 Avanafil 7 35-45 5 1. Viagra® (sildenafil) prescribing information, September 2002. 2. Boolell M, et al. Int J Impot Res. 1996;8:47-52. 3. Padma-Nathan H. J Urol. 2001;165(suppl):224. Abstract 923. 4. Porst H. J Urol. 2002;167(suppl):176. Abstract 709. 5. Brock GB, et al. J Urol. 2002;168:1332-1336. 6. Vivanza (vardenafil) EU prescribing information, March 2003. 7. Klotz T, et al. World J Urol. 2001;19:32-39. 8. Stark S, et al. Eur Urol. 2001;40:181-188. 7. Kedia G et al Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. Ther Adv Urol. 2013 Feb;5(1):35-41
  31. 31. When to refer a patient to a Urologist? • PDE5i treatment failure • Daily Cialis 5mg + Viagra 100mg PRN
  32. 32. Your Patient Has Failed Phosphodiesterase Type 5 (PDE5) Inhibitor Therapy . . . What Now? • Reeducate and rechallenge with same agent • Switch to another PDE5 inhibitor • Try different therapeutic approach – Vacuum erection devices – Prostaglandin E1(PGE1) injections – Implants
  33. 33. Evaluation of Penile Blood Flow • Duplex Ultrasonography – Penile blood flow study (CIS & blood flow measurement by US) is most reliable & least invasive evidence based assessment of ED • Red = towards probe • Blue = away from probe – Can visualize dorsal & cavernous arteries in real time
  34. 34. 2nd line - Ultrasound • Technique – Measure flow velocities 5-10 min after injection – Rate erectile quality – Look at both cavernous arteries
  35. 35. 2nd line - Ultrasound • Peak Systolic Velocity (PSV) – PSV < 25 correlates with abnormal pudendal arteriography – Severe unilateral arterial insufficiency >10 cm/s asymmetry – Severe vascular ED, diameter increase is <75%, diameter rarely exceeds 0.7 mm
  36. 36. 2nd line - Ultrasound • Veno-occlusive Dysfuntion – Need to trap blood & limit venous outflow – Venogenic impotence • High systolic flow (>25 cm/s) • Persistent end-diastolic flow (EDV) (>5 cm/s) – Resistive Index (RI) • RI = PSV – EDV/PSV – Measure 20 min after injection & stimulation • RI > 0.9 normal • RI < 0.75 venous leakage
  37. 37. Recommendations on US • Intracavernosal injection with color duplex Doppler ultrasound – Most informative diagnostic test – Least invasive for vascular ED, high vs. low flow priapism, Peyronie’s plaque – Useful measurements • PSV, cavernous artery diameter, EDV, RI • PSV <25 = severe cavernous artery insufficiency • PSV >35 = normal inflow • Negative relationship between age & PSV
  38. 38. Vacuum Erection Devices
  39. 39. Second-Line Therapy: Vacuum Erection Devices (VEDs) • Lack of interest in drug therapy • Specific contraindications to drug therapy • Patient preference Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:357-404.
  40. 40. VED: Basic Principles • Externally applied device mechanically effects penile blood engorgement • Cylinder/pump placed over penis creates closed chamber; pump creates vacuum, drawing blood into corpora cavernosa • Constrictive elastic ring then placed at base of penis to restrict flow of suctioned blood Levine LA, Dimitriou RJ. Urol Clin North Am. 2001;28:335-341. Montague DK, et al, for the AUA Clinical Guidelines Panel on Erectile Dysfunction. J Urol. 1996;156:2007-2011.
  41. 41. Medicated Urethral System for Erection (MUSE)
  42. 42. Second-Line Therapy: Transurethral System • Lack of response to oral therapy1 • Contraindications to specific oral drugs1 • Adverse reactions/intolerance to oral drugs1 • Rapid, predictable erection • Failed penile prostheses2 • Failed intracavernosal therapy3 • Patient preference 1. Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:711- 726. 2. Benevides MD, Carson CC. J Urol. 2000;163:785-787. 3. Engel JD, McVary KT. Urology. 1998;51:687-692.
  43. 43. Transurethral Alprostadil (MUSE) Smooth muscle–relaxing urethra suppository mimics physiology of erection (PGE1)
  44. 44. Transurethral Medications • Method of application: 2-mm pellet into urethra • Mechanism of action: urethral absorption and distribution into cavernosal tissue → smooth muscle relaxation • Study results – 66% of 1511 patients had erections in office – Of these, 65% had successful intercourse at home vs 18.6% with placebo – Treatment efficacy was similar regardless of age or cause of ED (vascular, diabetes, surgery, or trauma) • Overall success reported was 30% to 60% Alprostadil: MUSE Padma-Nathan H, et al. N Engl J Med. 1997;336:1-7.
  45. 45. Intracavernosal Injection
  46. 46. Smooth muscle–relaxing medication injected directly into the penis (papaverine, phentolamine, PGE1) Penile Injection Therapy
  47. 47. Second-Line Therapy: Intracavernosal Injection • Lack of response to oral therapy1,2 • Contraindications to specific oral drugs1 • Adverse reactions/intolerance to oral drugs1 • More reliable, instant, predictable erection • Patient preference 1. Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:711-726. 2. Shabsigh R, et al. Urology. 2000;55:477-480.
  48. 48. Penile Injection Therapy: Advantages • Highly effective • Mimics natural physiology of erection • No effect on sensation, ejaculation, fertility • Higher level of discretion, thus spontaneity
  49. 49. Penile Injection Therapy: Disadvantages • Poor long-term tolerability (dropout rate >60%) • Bruising, prolonged erection, cavernosal fibrosis, pain at injection site, penile deformity (rare) • Cumbersome, especially for patients with poor manual dexterity/vision or severe obesity • Requires training, follow-up, and dosing adjustments • May be risky with heart disease, previous strokes, or liver or blood disorders • May not be covered by insurance
  50. 50. Low Intensity Shockwave Therapy • Not incorporated into AUA guidelines yet • Shockwaves at 1/10th the dose of traditional ESWL for stones Vardi Y, et al.. Can low-intensity extracorporeal shockwave therapy improve erectile function? European Urology. 2010;58: 243-48
  51. 51. Low Intensity Shockwave Therapy • Meta-analysis: combined improvement in IIEF-EF score isMeta-analysis: combined improvement in IIEF-EF score is 4.284.28 • Greater than theGreater than the minimal clinically important difference (MCID) of 4 IIEF points as described by Rosen et al. • Zero adverse effects
  52. 52. Should We Doing Implants Earlier? Clavijo RI, et al Time course and predictors of use of erectile dysfunction treatment in a Veterans Affairs medical center. Int J Impot Res. 2016 May 19.
  53. 53. Penile Prosthesis Implantation
  54. 54. Types of Prostheses • Malleable/semirigid (AMS, Mentor) • Mechanical rod (Duraphase) • Inflatable – 2-piece (Ambicor) – 3-piece – AMS (CX, CXM) – Coloplast ( Titan )
  55. 55.
  56. 56. Penile Implant Indications • Oral drug (PDE5 inhibitor) failure – Radical prostatectomy – Diabetes mellitus • Scarred penis – Priapism – Previous implant – Trauma • Peyronie’s disease • Severe venous leak
  57. 57. Issues Regarding Informed Consent • Size of penis—stretched penile length • Possible need for revision surgery – Infection – Malfunction – Tissue damage • Sensation • Ejaculation • Discuss alternative treatments, eg, vacuum constriction device (VCD), Medicated Urethral System for Erections (MUSE), etc • Variety of prostheses • Reduced erectile function if device removed
  58. 58. Reliability—Device Survival Montague Ultrex 78% 5 years Levine Ambicor 93% 3-5 years Choi CXM 90% 5 years Carson CX 86% 5 years Montorsi AMS700 96% 5 years Wilson Mentor Alpha-1 93% 5 years Govier AMS 91% 3 years Dhabuwala Mentor 96% 5 years AMS 84% 5 years
  59. 59. Penile Implant -Satisfaction • In contemporaryIn contemporary series,series, satisfaction issatisfaction is >80%>80% Bernal, R et al. Adv in Uro. 2012
  60. 60. Reasons for Dissatisfaction With Penile Implant • Loss of penile length • Reduced sexual spontaneity • Unrealistic expectations • Malfunction • Infection- 1-4%
  61. 61. Implant Surgical Technique • Infrapubic approach – Familiar surgical approach for urologists – Easy placement of reservoir – Potential injury to dorsal penile nerve • Penoscrotal approach – Easy dissection and corporal dilation – Penile nerves not in surgical field – Blind placement of reservoir sometimes difficult
  62. 62. Post-Op Care: • Foley catheter for 24 hours • Bed rest from 48 hours • Cylinder straight, up and deflated • Warm baths bid starting on post-op day #3 • Prosthesis cycling at 6 to 8 weeks
  63. 63. Keys to Successful IPP Surgery: • Dedicated set of instruments • Penile pack • Full inventory of devices • Strategy to decrease skin bacteria flora • Strategy to prevent contact with the skin during the procedure
  64. 64. Conclusions • ED can be identified and managed in the primary care setting—detection is key! • Effective treatments are available • Treatment efficacy can be optimized by establishing its proper usage and pursuing risk-factor modification and vascular disease treatment
  65. 65. Thank @ranjithramamd