Christopher C.K. Ho. Consultant Urologist Oriental Melaka Medical Centre Adjunct Professor, Taylor s University

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1 Christopher C.K. Ho MD, MS, MRCSEd, MBU, MFSTEd, AM, FICS, FECSM, FRCSEd, FRCS(Urol)(Glasg), FACS Consultant Urologist Oriental Melaka Medical Centre Adjunct Professor, Taylor s University

2 Inability to maintain an erection firm enough to have sexual intercourse

3 3 Anatomy of the penis: cross section Adapted from Hsieh C-H, Liu S-P, Hsu G-L, et al. Advances in understanding of mammalian penile evolution, human penile anatomy and human erection physiology: clinical implications for physicians and surgeons. Med Sci Monit. 2012;18(7):RA118-RA125; Wagner G, de Tejada IS. Update on male erectile dysfunction. BMJ. 1998;316(7132):678-82; Andersson K-E, Wagner G. Physiology of penile erection. Physiol Rev. 1995;75:

4 4 Normal erection physiology Adapted from: Wagner G, de Tejada IS. Update on male erectile dysfunction. BMJ. 1998;316(7132): Krane RJ, Goldstein I, de Tejada IS. Impotence. N Engl J Med. 1998;321(24):

5 How does PDE 5 inhibitor work? 1. Inhibit release of NO 2. Inhibit conversion of ATP 3. Inhibit breakdown of cgmp to 5-GMP 4. Inhibit conversion of camp to 5-AMP

6 How does PDE 5 inhibitor work? 1. Inhibit release of NO 2. Inhibit conversion of ATP 3. Inhibit breakdown of cgmp to 5-GMP 4. Inhibit conversion of camp to 5-AMP

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8 8 Category of erectile dysfunction Common disorders Pathophysiology Psychogenic Performance anxiety, relationship problems, psychological stress, depression Loss of libido, overinhibition, or impaired nitric oxide release Neurogenic Hormonal Vasculogenic (arterial or cavernosal) Drug induced Caused by other systemic diseases and aging Stroke or Alzheimer s disease, spinal cord injury, radical pelvic surgery, diabetic neuropathy, pelvic injury Hypogonadism, hyperprolactinemia Atherosclerosis, hypertension, diabetes mellitus, trauma, Peyronie s disease Antihypertensive and antidepressant drugs, antiandrogens, alcohol abuse, cigarette smoking Old age, diabetes mellitus, chronic renal failure, coronary heart disease Failure to initiate nerve impulse or interrupted neural transmission Loss of libido and inadequate nitric oxide release Inadequate arterial flow or impaired veno-occlusion Central suppression, decreased libido, alcoholic neuropathy, vascular insufficiency Usually multifactorial, resulting in neural and vascular dysfunction Adapted from Lue TF. Erectile dysfunction. N Engl J Med. 2000;342:

9 Which antihypertensive has the least effect on erectile function? 1. B blocker 2. Diuretics 3. Alpha blocker 4. ACE inhibitor 5. ARB

10 Which antihypertensive has the least effect on erectile function? 1. B blocker 2. Diuretics 3. Alpha blocker 4. ACE inhibitor 5. ARB

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12 Lifestyle modification Stop smoking Lose weight Control diabetes and hypertension Exercise Psychological counselling

13 13 First-line treatment: PDE5i is a class of vasodilators that work on the nitric oxide-cgmp mechanism to help restore natural erectile function in the presence of sexual stimulation Sildenafil citrate was the first licensed oral medication for ED, receiving marketing authorization in 1998 Vardenafil and tadalafil received marketing authorization in 2003 Wespes E, Amar E, Hatzichristou D, et al. EAU Guidelines on erectile dysfunction: an update. Eur Urol. 2006;49: ; Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract. 2006;60: ; Mulhall J, Althof SE, Brock GB, et al. Erectile dysfunction: monitoring response to treatment in clinical practice recommendations of an international study panel. J Sex Med. 2007;4: ; Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol. 2003;92(suppl):9M-18M; Wespes E, Amar E, Eardley I, et al. Erectile dysfunction and premature ejaculation. Guidelines on Male Sexual Dysfunction

14 14 Pharmacokinetic parameters of the selective PDE5 inhibitors Parameter Tadalafil (fasted) 20 mg Sildenafil (fasted) 100 mg Vardenafil (fasted) 20 mg C max, ng/ml T max*, h 2 (0.5-6) 1* (0.5-2) 1* (0.5-2) t 1/2, h Protein binding, % 94% 96% 95% Bioavailability, % Not Applicable (N/A) 41% 15% * Dependent on food intake (ie slower absorption of the drug and an increase in T max by approximately 1h after a fatty meal) Wespes E, Amar E, Eardley I, et al. Erectile dysfunction and premature ejaculation. Guidelines on Male Sexual Dysfunction. 2012; CIALIS [package insert]. Indianapolis, IN: Eli Lilly and Company; 2011; LEVITRA [package insert]. West Haven, CT: Bayer HealthCare Pharmaceuticals; 2011; VIAGRA [package insert]. New York, NY: Pfizer Inc; 2011.

15 Udenafil (Zydena) Fast acting (within 1 hour) Longer duration ( 12 hours) Avanafil Fast acting ( 15 mins) Duration 6 hours Oral dispersible tablets (ODT) Sublingual No need water

16 A small needle is used to inject medication directly into the penis. The medication allows blood to flow into the penis creating an erection. Some Advantages Effective erection On-set of erection within 5 to 20 minutes

17 17 Intracavernosal injection therapy For those patients who don t respond to oral drugs This involves injecting agents that relax smooth muscle into one of the two corpora cavernosa Penile erection will occur whether or not sexual stimulation is present after 5-15 minutes The only drug currently licensed for use in intracavernosal injection therapy is prostaglandin E1 (alprostadil) Efficacy rates are about 70% Drop-out rates of 41-68% have been described The most-common complications are penile pain, prolonged erections, priapism, and fibrosis Dorsal veins Dorsal artery and nerve 9 0 o Corpora caverno sa Uret hra Corpus spongiosum Albersen M, Mwamukonda KB, Shindel AW, et al. Evaluation and treatment of erectile dysfunction. Med Clin N Am. 2011;95: ; Hatzimouratidis K, Amar E, Eardley I, et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol. 2010;57: ; Wespes E, Amar E, Hatzichristou D, et al. EAU Guidelines on erectile dysfunction: an update. Eur Urol. 2006;49: Costable RA, Mammen T, Hwang Kathleen. An overivew and expert opinion on the use of alprostadil in the treatment of sexual dysfunction. Expert Opin. Pharmacother. 2008;9(8):

18 Intracavernosal prostaglandin injection is contraindicated in 1. Diabetic patient 2. Patient with IHD 3. Patient on nitrates 4. Patient on anticoagulant 5. Patient who failed PDE5 inhibitor

19 Intracavernosal prostaglandin injection is contraindicated in 1. Diabetic patient 2. Patient with IHD 3. Patient on nitrates 4. Patient on anticoagulant 5. Patient who failed PDE5 inhibitor

20 Some Disadvantages Risk of erection lasting 4 hours or more (priapism) Fear of sticking needle in penis Possible bleeding at injection site Requires training Possible pain at injection site Cavernosal fibrosis Poor long-term tolerability

21 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

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23 Some Advantages Non-invasive Drug free Cost effective Some Disadvantages Cumbersome Unnatural erection Erection is not warm to the touch Bruising/burst blood vessels Penile pain/discomfort Numbness Delayed ejaculation

24 An Option For men who have tried other option without success 40 year history High patient and partner satisfaction

25 One-Piece Non-Inflatable Two-Piece Inflatable Three-Piece Inflatable

26 Some Advantages Totally concealed in body Device is inflated to provide rigidity and deflated for concealment Erection longevity is controllable When deflated, the cylinders are soft and flaccid Expands in girth (all AMS 700 cylinders) and length (AMS 700 LGX and Ultrex cylinders)

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29 Men treated with PRN ED treatments report missing spontaneity more than any other aspect of ED and more than untreated men with ED * Spontaneity 16% 48% Closeness with partner * Sex 7% 8% 17% 20% ED patient treated with on demand therapy (Sildenafi Inability to have erections 8% 17% Confidence * 12% 10% 5% 16% Intimacy Man with ED never treated * 3% *p<0.05 Knowing I could satisfy my partner 16% Frequency of sex 3% 11% 0% 10% 20% 30% 40% 50% 60% Living With ED. Harris Interactive, Eli Lilly & Company Limited data on file, UKCLS01128a April 2012

30 Predicted Pharmacokinetic Modeling 5mg OD vs. Frequent 20-mg On-Demand Dosing Predicted weekly plasma tadalafil concentrations during 5-mg once daily dosing at steady state or 20-mg on-demand patterns representing twice- or thrice-weekly administration 1 "Adapted from Wrishko et al. J. Sex. Med 2009" UKCLS01128a April 2012

31 Mean Per-Patient % Successful Intercourse at Baseline and Endpoint 100 Significantly Improved Erectile Function 1,2 SEP 3: Did your erection last long enough to have successful intercourse? % 73%* 82%** 47% 44% 52% 27% 56%* 61%** 12% 13% 14% 27%* 33%* n=34 n=32 n=32 n=23 n=22 n=26 n=35 n=38 n=38 Mild Moderate Severe The efficacy of CIALIS for once daily use was maintained throughout a 6-month, double-blind, placebo-controlled trial 1 Select Important Safety Information CIALIS is contraindicated in patients using any form of organic nitrate, either regularly and/or intermittently, as the combination could cause a sudden, unsafe drop in blood pressure. 9% 4% 1% 2% Placebo 1 CIALIS 2.5 mg 1 CIALIS 5 mg 1 Baseline SEP 3 value 2 *P.05. **P SEP=Sexual Encounter Profile. 1. Rajfer J, et al. Int J Impot Res. 2007;19(1): Data on file, Lilly Research Laboratories: CIA A.

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33 Key Eligibility Criteria and Patient Stratification Inclusion criteria: Sexually active men 18 years of age with a 3-month history of ED Taking the maximum dose of sildenafil citrate (100 mg), vardenafil (20 mg), or tadalafil (20 mg) PRN for 1 month prior to study entry IIEF-EF domain score 17 and <26 at Visit 1 Kim ED, et al. J Sex Med Epub. Doi: /jsm For Training Purposes

34 Percentage of Men with IIEF-EF Domain Score 26 at Endpoint (mean %) Percentage of Men With Normal Erectile Function at Endpoint *p<.001 vs. placebo Fisher s exact test * 39.6 * 0 Placebo (N=199) Tadalafil 2.5 to 5 mg (N=194) Tadalafil 5 mg (N=197) Approximately 40% of men in each tadalafil arm were able to achieve normal erectile function Kim ED, et al. J Sex Med Epub. Doi: /jsm For Training Purposes

35 LVIP Tadalafil once daily: Significantly improved erectile function in men with mild-to-moderate impairments in erectile function following incomplete response to PRN PDE5 inhibitor treatment Approximately 40% of the men were able achieve normal erectile function Well tolerated May be a viable option to help restore normal erectile function for men with ED who had incomplete response to PRN Kim ED, et al. J Sex Med Epub. Doi: /jsm For Training Purposes

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37 Study Design 1058 men randomized: US, Canada, Australia, Germany, Italy, Greece, France, Spain, Sweden, Mexico Screening Washout Period Placebo Run-in Period Treatment Period Criteria: Age 45 years, BPH-LUTS >6 months, IPSS 13, Q max 4-15 ml/s Measures: Primary: Total IPSS Secondary: BII, IPSS subscores, IPSS QoL, LUTS GAQ, IIEF-EF, Q max Safety: TEAEs, SAEs, PSA, PVR No Study Drug Placebo QD, N = 211 Tadalafil 2.5 mg QD, N = 208 Placebo QD Tadalafil 5 mg QD, N = 212 Tadalafil 10 mg QD, N = 216 Tadalafil 20 mg QD, N = 209 Baseline & Randomization Week Visit Roehrborn et al. J Urol 2008;180(4):

38 Mean Change in IPSS IPSS Change from Baseline to Endpoint Treatment Baseline 12-week LS Mean Change (ANCOVA, LOCF) 0-1 ANCOVA, MMRM Placebo Tadalafil 2.5 mg * 5 mg * 10 mg * 20 mg * *p< * * * Placebo Tadalafil 2.5 mg * Tadalafil 5 mg Tadalafil 10 mg Tadalafil 20 mg * * * * * * * * -7 Baseline Week 4 Week 8 Week 12 Roehrborn et al. J Urol 2008;180(4):

39 Tadalafil Placebo (N = 210) 2.5 mg (N = 208) 5 mg (N = 212) 10 mg (N = 216) 20 mg (N = 208) IPSS subscores Storage * -1.96* -2.07* Voiding * -2.94* -3.13* -3.12* IPSS QoL * -0.92* -0.88* LUTS GAQ * 73.0* 74.2* IIEF-EF * 6.97* 7.98* 8.34* Q max (ml/s) Roehrborn et al. J Urol 2008;180(4):

40 Treatment of erectile dysfunction Frequent sexual activity Patient and/or partner desires greater spontaneity Lower urinary tract symptoms secondary to BPH Partial responders to conventional PDE 5 inhibitors For Training Purposes

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46 The first meta-analysis of Li-ESWT on men with ED was published by Clavijo et al. 7 randomized controlled trials, with a total of 602 patients with vasculogenic ED. Results demonstrated a statistically significant improvement in the International Index of Erectile Function (IIEF-EF) scores in men who had undergone Li-ESWT as opposed to men who had undergone sham therapy. Clavijo RI, Kohn TP, Kohn JR, Ramasamy R. Effects of low-intensity extracorporeal shockwave therapy on erectile dysfunction: A systematic review and metaanalysis. J Sex Med 2017;14:27-35

47 Low intensity shock wave treatment is effective in the short term but treatment efficacy was maintained after 2 years in only half of the patients. In patients with milder forms of erectile dysfunction the beneficial effect is more likely to be preserved. Kitrey ND, et al. Low Intensity Shock Wave Treatment for Erectile Dysfunction-How Long Does the Effect Last? J Urol Jul;200(1):

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49 Topiglan (1% alprostadil, an ingredient commonly used in penile injections and suppositories), was effective in approximately 40% of the men tested However, the manufacturer has found that the gel loses potency in storage Goldstein, I; Payton, T.R.; Schechter, P.J. A double-blind, placebo-controlled, efficacy and safety study of topical gel formulation of 1% alprostadil (Topiglan) for the in-office treatment of erectile dysfunction. Urology. Feb (2):301-5

50 MED2005 containing 0.2 percent glyceryl trinitrate, or nitroglycerin Works by releasing nitric oxide gas when rubbed in to widen tiny blood vessels and increase flow to the penis. University College London Hospitals and other centres did trials on more than 220 men with ED. 44 per cent managed erections within five minutes and it took less than 10 for 70 per cent. One in four men experienced a clinically significant improvement during the trial. Work 12 times faster than viagra - a drug used to cure ED. Ralph DJ, Eardley I, Taubel J, et al. Efficacy and Safety of MED2005, a Topical Glyceryl Trinitrate Formulation, in the Treatment of Erectile Dysfunction: A Randomized Crossover Study. J Sex Med 2018;15:

51 Clinical studies are still in early phases (demonstrating the safety of the treatment, before larger trials evaluate its effectiveness). An early safety study showed significant improvement for several patients Melman, Arnold; et al. hmaxi-k Gene Transfer in Males with Erectile Dysfunction: Results of the First Human Trial. Human Gene Therapy. Dec Vol. 17, No. 12.

52 Stem cell treatments have been tested extensively in rats, and more recently in small human trials. The results have been promising. In a study involving men who had been through prostate removal, more than half recovered erectile function sufficient for penetrative sex. Other early-stage studies have also shown positive results Lin, Ching-Shwun et al. Stem Cell Therapy for Erectile Dysfunction: A Critical Review. Stem Cells and Development. Feb ; 21(3): Haahr, Martha Kirstine; Jensen, Charlotte Harken; Toyserkani, Navid Mohamadpour; et al. Safety and Potential Effect of a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: An Open-Label Phase I Clinical Trial. EBioMedicine. Mar :

53 There have been hundreds of clinical studies for PRP injections; most show little if any effect. The therapy is now being extensively promoted as a treatment for ED. There are even claims that PRP injections can increase penis size. Neither claim is supported by clinical studies so far. Wu, Chien Chihet al. The Neuroprotective Effect of Platelet rich Plasma on Erectile Function in Bilateral Cavernous Nerve Injury Rat Model. The Journal of Sexual Medicine. Nov Volume 9, Issue 11, Pages

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55 Herbal medications where studies on ED have been done were P. ginseng, B. superba, Epimedium herbs (icariin), T. terrestris, S. longipedunculata, P. guineense, L. meyenii (Maca), and yohimbine. Out of these, only P. ginseng, B. superba, L. meyenii (Maca), and yohimbine have published studies done on humans. Tongkat Ali not proven CCK Ho, HM Tan. Rise of Herbal and Traditional Medicine in Erectile Dysfunction Management. Curr Urol Rep (2011) 12:

56 A meta-analysis of seven placebo-controlled trials deemed yohimbine superior to placebo for the treatment of ED with rare adverse events. Ernst E, Pittler MH. Yohimbine for erectile dysfunction: a systematic review and meta-analysis of randomized clinical trials. J Urol 1998;159:433-6

57 Meta-analysis of seven randomized controlled trials (RCTs) using P. ginseng on humans and found that six of the RCTs reported the therapeutic efficacy (improvement of erectile function) of P. ginseng compared with placebo Zhang H, Zhou Q, Li X, et al.: Ginsenoside Re increases human sperm motility by induction of nitric oxide synthase. Arch Pharm Res. 2006;29(2):145 51

58 A prospective, randomized, double blind study of 30 men showed that Tribulus terrestris was not more effective than placebo on improving IIEF scores or serum total testosterone Santos CA, Jr, Reis LO, Destro-Saade R, et al. Tribulus terrestris versus placebo in the treatment of erectile dysfunction: A prospective, randomized, double blind study. Actas Urol Esp 2014;38:244-8

59 While some studies have showed up to a third of patients reported improvement in penile erection and sexual activity, systematic review showed insufficient data to conclude that acupuncture is an effective intervention for treating ED Cui X, Zhou J, Qin Z, et al. Acupuncture for Erectile Dysfunction: A Systematic Review. Biomed Res Int 2016;2016: Lee MS, Chin BC, Ernst E. Acupuncture for treating erectile dysfunction: a systematic review. BJU Int 2009;104:366-70

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61 ED can be treated Lifestyle modification First line treatment is PDE 5 inhibitor Proper advice on pharmacokinetics Other treatment options Intracavernosal prostaglandin injection Vacuum pump Penile prosthesis

62 Low dose tadalafil is an option for PRN partial responders Treatment of erectile dysfunction Frequent sexual activity Patient and/or partner desires greater spontaneity Combined BPH/LUTS and ED EDSWT Proven effective but lasts probably only 2 years

63 Promising developments Topical nitroglycerin Stem cells Gene therapy Herbal/Complementary No robust studies Ginseng, Yohimbine, Tribulus terrestris may have a role

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