clinical Erectile dysfunction

Ian A R Smith When tablets don’t work Nicholas McLeod Prem Rashid

with cardiovascular disease including Background lack of exercise, obesity, smoking, Erectile dysfunction (ED) is a common clinical problem managed in the general practice hypercholesterolaemia and the metabolic setting. While the majority of men will find phosphodiesterase-5 (PDE-5) inhibitors syndrome.6,7 This is an important consideration effective, there is a subgroup of men who require second and third line therapies. as ED may be an early marker of subclinical Objective metabolic and vascular disease.8 Many This article provides an overview of ED and its management with particular focus on the medications can potentiate ED including group of patients in whom oral agents fail. commonly used antihypertensives such as Discussion calcium channel blockers, angiotensin II Erectile dysfunction is a multifactorial condition that affects approximately 40% of receptor antagonists, angiotensin converting Australian men. The incidence of ED is age related however, it shares common risk factors enzyme receptor antagonists, beta blockers with cardiovascular disease and metabolic disorders. The management of ED should and thiazides. begin with an assessment of cardiovascular risk factors, advice on lifestyle modification, the physical symptoms of ED are often and a trial of PDE-5 inhibitors. Second line therapies include intracavernosal injections associated with depression, a loss of self and vacuum erection devices, while third line therapy entails penile implants. Factors confidence, loss of intimacy in a relationship, that influence treatment success include partner inclusion, good patient selection, as and a reduced quality of life.9 Although public well as ongoing support and education. awareness of ED has improved in the past Keywords: erectile dysfunction; men’s health decade, less than half the men with the disorder seek treatment.10 A delay often occurs between the onset of symptoms and attendance in the primary care setting, with a mean time of 1.0–3.5 years.10 The goals of ED treatment are to Erectile dysfunction (ED) is the persistent restore quality of life and allow the patient and inability to attain and maintain an his partner to enjoy a satisfying sex life. erection sufficient to permit satisfactory sexual performance.1 The overall Assessment prevalence of ED in Australia is estimated Consultations around the issue of erectile at 40%.2,3 The risk of developing ED is age dysfunction should be conducted in a relaxed, related, occurring in approximately 26% of reassuring, and nonjudgmental manner. The first men aged 50–59 years, and approximately step is to take a full medical, sexual, surgical 40% of men aged 60–69 years.2,4 With and psychosocial history (Table 2). A focused the advent of phosphodiesterase-5 physical examination includes: PDE-5 inhibitors, the management of ED • a genital examination occurs predominantly in the primary care • assessment of secondary sexual setting. Risk factors for ED are shown in characteristics Table 1. Guidelines for assessment and • a digital rectal examination to assess the management of ED are available from prostate gland. Andrology Australia5 (see Resources). A cardiovascular risk assessment should be performed before commencing a patient on a Erectile dysfunction is primarily an organic PDE-5 inhibitor and advising the resumption of condition, sharing common risk factors sexual activity.11,12 Kostis et al, have developed

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Table 1. Risk factors associated with Management Table 3. Stepwise approach to erectile dysfunction6,7 The management of ED should follow a stepwise management of erectile dysfunction approach as outlined in Table 3. Importantly, First line • Hypertension partners play a key role in supporting the • Lifestyle modifications (eg. quitting • Cardiovascular disease patient, allaying anxiety and achieving treatment smoking, exercise, weight loss) • Diabetes mellitus compliance; a couples based approach should be • Management of cardiovascular risk • Smoking encouraged. factors • Alcohol First line: PDE-5 inhibitors • Trial of PDE-5 inhibitors (at least • Prostate surgery four attempts with two different • Pelvic trauma There are currently three PDE-5 inhibitors on PDE-5 inhibitors) in the absence of • Pelvic radiotherapy the market: sildenafil (Viagra™), vardenafil contraindications • Medications (Levitra™) and tadalafil (Cialis™), which is Second line • Depression available as a daily dose. Features of these • Self intracavernosal injections • Penile abnormalities (eg. Peyronie medications are described in Table 4. The • Vacuum erection devices disease) efficacy of this class of medication is well • Hormonal therapies (eg. testosterone • Obesity established for the general population, as well replacement) • Sleep apnoea as in men following radical prostatectomy and • Combination therapy • Hyperlipidaemia radiotherapy for prostate cancer and those with Third line • Spinal cord trauma diabetes mellitus, spinal cord injury, multiple • Penile prostheses • Medical conditions such as multiple sclerosis, and depression.11,17,18 PDE-5s are sclerosis contraindicated following a recent myocardial successful intercourse increases with each infarction, concurrent nitrate therapy, and high treatment attempt, therefore patients should be a cardiovascular risk stratification algorithm, risk cardiovascular disease. encouraged to persevere with a trial of at least to evaluate the degree of cardiovascular risk the success rate of PDE-5 inhibitors is two PDE-5 inhibitors for up to four attempts of associated with sexual activity.13 Men who have dependent upon the aetiology of the ED and each, and at the maximum dosage.19 Information intermediate or high risk cardiovascular disease can range from approximately 43–89%.19 A regarding the need for sexual stimulation and the should obtain a cardiologist opinion before poorer response to PDE-5 inhibitors is seen onset and duration of action of PDE-5 inhibitors commencement. in the context of adverse factors such as can also increase success rates. it is important to establish the severity of ED. following prostate surgery (43%), diabetes Second line: vacuum devices, A validated questionnaire such as the Sexual with neuropathy (50%) and peripheral vascular 19 intercavernosal injections and Health Inventory for Men can accurately detect disease (63%). A better response is seen in an testosterone therapy and quantify ED.14,15 This brief questionnaire can otherwise healthy male whose ED is secondary be completed by the patient in the waiting room to depression (89%), neurological disease (85%) Following a complete trial with PDE-5 before the consultation or between the initial and smoking (80%).19 inhibitors, second line therapies can be used in consultation and follow up (see Resources). other factors contributing to the failure combination with PDE-5 inhibitors to improve Given that ED and lower urinary tract symptoms of PDE-5s include incorrect usage, worsening response, or as a single therapy when PDE-5s commonly coexist, it is advisable to screen corporal endothelial dysfunction, poor tolerance are contraindicated. The advantages and patients for voiding symptoms using a screening to side effects, and hypoandrogenism.19 For initial disadvantages of vacuum erection devices tool such as the International Prostate Symptom nonresponders, education alone can improve (VEDs) and intercavernosal injections are shown Score Sheet7,16 (see Resources). the response by 40–55%.19 The probability of in Table 5.

Vacuum erection devices Table 2. History taking in patients with erectile dysfunction Vacuum erection devices provide a safe, cost Sexual Medical Urological effective, and noninvasive alternative for men Nature of problem Medical history History of lower urinary tract who have failed oral pharmacotherapy. Negative Mode of onset Psychological history symptoms pressure is applied to the penis, producing Degree of disability Surgical history Penile complaints (eg. pain, passive engorgement of the corpora cavernosa, Precipitating factors Medications curvature) resulting in an erection that can be maintained Recreational drug use by an elastic band at the base of the penis for 30 Alcohol use minutes (Figure 1). Successful vaginal penetration Smoking history is as high as 90%, however device satisfaction

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Table 4. PDE-5 inhibitors Drug Onset of action Half life Adverse effects Sildenafil Tmax* 30–120 2–5 hours • Headache minutes • Flushing Median 60 minutes • Dyspepsia Vardenafil Tmax 30–120 minutes 4.5 hours • Headache Median 60 minutes • Flushing • Dyspepsia Tadalafil Tmax 30–120 minutes 15.5 hours • Headache Median 120 minutes • Flushing Figure 1. Second line treatment: vacuum • Dyspepsia erection device * Tmax = median time to peak plasma concentration of drug

Table 5. Advantages and disadvantages of VEDs and intracavernosal injections Therapy Advantage Disadvantage Contraindications Vacuum • Effective in all • Bruising • Bleeding disorders erection aetiological groups • Interference of • Anticoagulation devices • Do not require ejaculation due to therapy erectile reserve constriction ring • Noninvasive • Loss of acute • Low complication angle of erection rates • Pain • No restriction on • ‘Nonphysiological’ frequency of use erection • Requires the use of bulky Figure 2. Second line treatment: self equipment intracavernosal injection Intracavernosal • Suitable for all • Risk of priapism • Conditions that injections causes of ED • Fibrosis of tunica predispose to trials comparing PGE1 to placebo demonstrated albuginea priapism a 63.6% success rate of alprostadil, with a • Painful erections • Sickle cell anaemia relatively low incidence of priapism (0.35–4.0%) • Tolerance • Leukaemia and tunica albuginea fibrosis (1–23%).21,23 • Urethral bleeding Combination therapy • Hypotension • Low compliance Combination intracavernosal injections such as rates Trimix (phentolamine, papaverine, and PGE1) and Quadmix (phentolamine, papaverine, ranges from 26–94%, and long term use reduces injection technique, and dosing, before beginning prostaglandin E1 and atropine) can be initiated satisfaction to 50–64% after 2 years.11,20 Proper home injections (Figure 2). Discontinuation rates after an unsuccessful trial of alprostadil. Although instruction and manual dexterity are crucial to the with intracavernosal therapy range from 40.7– data is limited, the reported rate of full erection success of, and compliance with, VEDs. Quality 68.0%.11 A return of spontaneous erections has is more than 90%.22,24 There is, however, a higher devices with an instructional DVD and technical been reported in men undergoing intracavernosal incidence of priapism with combination therapy, support can be obtained from medical aid sources. injections.22 and these need to be prepared by a compound Alprostadil (Caverject Impulse®) is a chemist and generally warrant urologist referral Self intracavernosal injections vasoactive mediator that acts primarily on for monitoring. Injectable agents effective in treating ED where cavernosal smooth muscle receptors.20 Erection Testosterone therapy PDE-5 inhibitors have failed include papaverine, usually occurs within 5–20 minutes of injection phentolamine and alprostadil (PGE1).20,21 Men and can last up to 2–3 hours after ejaculation.20 Testosterone supplementation can be considered must receive education on the risk of priapism, A meta-analysis of four randomised controlled for all men who have signs and symptoms of

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‘Penile rehabilitation’ is indicated guide: www.andrologyaustralia.org postoperatively and is usually • The Sexual Health Inventory for Men (SHIM): initiated by the urologist. This often www.rohbaltimore.com/SHIM.pdf includes injectables or PDE-5s • The International Prostate Symptom Score from several weeks postoperation. Sheet (IPSS): www.gp-training.net/protocol/ If erections are failing despite docs/ipss.doc. rehabilitation, the clinician should ensure that a complete trial of Authors Ian A R Smith MBBS, BMedSc, is a urology reg- first and second line therapies istrar, Liverpool Hospital, Sydney, and Associate has occurred. A man motivated to Conjoint Lecturer, Faculty of Medicine, University resume sexual activity who fails of Western Sydney and University of New South these therapies will most likely Wales. [email protected] benefit from a penile implant. This Nicholas McLeod BSc, BMed(Hons), is a urology decision needs careful consideration, registrar, Department of Urology, Port Macquarie ideally with partner involvement. Base Hospital, New South Wales A urologist with an interest in Prem Rashid MBBS, FRACGP, FRACS(Urol), PhD, is urological surgeon, Port Macquarie Base Hospital, Figure 3. Third line treatment: three piece inflatable prosthetic surgery should be penile prosthesis and Conjoint Associate Professor, Rural Clinical consulted. School, University of New South Wales, Port Macquarie, New South Wales. low testosterone confirmed by two low morning Summary of important points serum testosterone levels. This will include • Erectile dysfunction is a significant clinical Conflict of interest: Prem Rashid has been a visitor the subgroup of men suffering from late onset problem largely undertreated in the to the American Medical Systems (AMS) USA hypoandrogenism.25 The management of these community; the issue should be explored in manufacturing facility undertaking a cadaveric patients is complex and should be comanaged any man who is over 40 years of age or has dissection clinic and observing operative with an endocrinologist and/or urologist. cardiovascular disease. procedures by high volume implant urologists • Erectile dysfunction may be an early marker of affiliated with AMS during that time. He also has Third line: penile prosthesis subclinical metabolic and vascular disease. acted as a consultant for Coloplast, AstraZeneca, A penile prosthesis is indicated when there is a • The physical symptoms of ED are often Hospira & Abbott Pharmaceuticals. No commercial lack of efficacy, or dissatisfaction with first and associated with depression, a loss of self organisation initiated or contributed to the writing second line treatments. Currently, three classes of confidence, loss of intimacy in a relationship, of this article apart from granting permission to penile implants are available: semirigid malleable and a reduced quality of life. use diagrams of their respective devices. rod devices and two piece, and three piece • The severity of ED should be evaluated with a References inflatable hydraulic implants. self assessment questionnaire. 1. nih Consensus Conference. Impotence. NIH the three piece inflatable devices, composed • Partner inclusion will improve success of Consensus Development Panel on Impotence. of paired cylinders, a scrotal pump, and a reservoir treatment and increase treatment compliance. JAMA 1993;270:83–90. 2. mcKinlay JB. The worldwide prevalence and epi- are considered the gold standard of inflatable • Treatment of ED should follow a stepwise demiology of erectile dysfunction. Int J Impot Res implants (Figure 3). Satisfaction with this device approach, including ongoing education and 2000;12(Suppl 4):S6–11. is approximately 90% and device durability at 10 support. 3. chew KK, Stuckey B, Bremner A, et al. Male erec- 26,27 tile dysfunction: its prevalence in Western Australia years is 75%. Complications include corporal/ • PDE-5s are first line treatment. They are and associated sociodemographic factors. J Sex urethral erosion (1–11%), infection (0.68–1.06%) contraindicated in the context of recent Med 2008;5:60–9. and mechanical failure (0.8–10.3%).26 In a man myocardial infarction, concurrent nitrate 4. Bacon CG, Mittleman MA, Kawachi I, et al. Sexual function in men older than 50 years of age: results comfortable with having an implant, they are well therapy, and high risk cardiovascular disease. from the health professionals follow-up study. Ann tolerated. • Second line treatments for ED can be offered Intern Med 2003;139:161–8. in conjunction with PDE-5 inhibitors to 5. Andrology Australia. Erectile dysfunction: diagnosis and management. GP summary guide 9, July 2007. Erectile dysfunction following increase success rates. Available at www.andrologyaustralia.org. radical prostatectomy • Penile implants are well tolerated and have 6. Rosenberg MT. Diagnosis and management of erectile dysfunction in the primary care setting. Int The pathophysiology of ED following radical high success rates in well selected patients. J Clin Pract 2007;61:1198–208. prostatectomy is multifactorial and is related to Resources 7. mcVary KT. Clinical practice. Erectile dysfunction. N cavernous nerve injury and fibrosis of cavernosal Engl J Med 2007;357:2472–81. 8. shabsigh R, Arver S, Channer KS, et al. The triad of smooth muscle due to poor oxygenation and • Andrology Australia. Erectile dysfunction: erectile dysfunction, hypogonadism and the meta- venous leak.28 diagnosis and management. GP summary bolic syndrome. Int J Clin Pract 2008;62:791–8.

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