Erectile dysfunction (ED) is defined as the inability

Erectile dysfunction Erectile dysfunction (ED), and those suffering with it, have remained behind the screen for decades. Public awareness and knowledge, however, are increasing and it is no longer considered the social taboo of earlier years. Greater understanding of the pathophysiological aetiology of ED has resulted in a surge of research activities investigating its aetiology, associations and management, hence the need for regular up-to-date reviews. Dr S Pisipati, Specialist Registrar in Urology, South West Deanery Dr T Ladds, Specialist Urology Nurse, Manchester Royal Infirmary Manchester, UK Mr Ian Pearce, Consultant Urological Surgeon, Manchester Royal Infirmary, Manchester, UK email ian.pearce@cmmc.nhs.uk Erectile dysfunction (ED) is defined as the inability to obtain and/or maintain an erection sufficient for sexual intercourse to the mutual satisfaction of both partners. The Massachusetts Male Aging Study (MMAS) revealed the prevalence of ED to be over 50% in non-institutionalised 40 70 year olds with the incidence and severity of erectile dysfunction increasing with each subsequent decade (Figure 1). 1 Aetiology Cohort studies have reproduced the findings of the MMAS with the conclusion that increasing age is the single most influential independent risk factor for both the onset and severity of ED. 2,3 Originally considered to be purely psychogenic in origin, ED is now almost always believed to be multifactorial with a degree of organic aetiology. Some of the most common pathophysiological causes are listed in Box 1. 4,5 Assessment It is highly recommended that the initial consultation should be with both the patient and his partner, but clearly this decision must rest with the patient. A focused sexual history should be elicited taking care to document the presence of any known risk factors as above. In addition, the nature of the ED should be sought including any issues the patient may have with respect to libido, tumescence, ejaculation, orgasm and detumescence. Several formal symptom scores that aim to quantify the extent of ED, have been developed and validated with the International Index of Erectile Function (IIEF-5) being the most commonly used. 6,7,8 This focuses on five domains, each with a numerical score of one to five, thus allowing a maximum score of 25. ED can then be classified according to the IIEF-5 score (Box 2). A focused physical examination must be performed with particular emphasis on the genitourinary, endocrine, vascular and neurological systems. 9 All lower limb peripheral pulses should be palpated and any cardiac murmurs or arrhythmias identified. The external genitalia should be examined with a view to excluding congenital or acquired abnormalities. Peyronie s plaques, preputial abnormalities, microphallus and carcinomas, all occasionally present with ED. The presence of small testis, reduced or absent secondary sexual characteristics may suggest hypogonadism requiring further investigations as below. It is now well recognised that both psychological and physiological aetiologies play a significant role in the majority of patients with ED and the initial history from the patient is fundamental to differentiating those patients with primarily physiological ED from those with primarily psychogenic ED (Box 3). Investigations The choice of investigations depends on the individual circumstances of the patients. The British Society of Sexual Medicine guidelines for ED suggest that all patients should have fasting plasma glucose and serum lipids. 10 Hypogonadism is a treatable cause of ED that may also make men less responsive, or even non-responsive to phosphodiesterase type 5 (PDE5) inhibitors, 11,12 therefore, all men with ED should have serum testosterone measured. 10 Serum free testosterone is a more reliable measure and this can be calculated from total testosterone, sex hormone GM2 Midlife and Beyond 2009 June 15

Men s health 5 0 Box 1: Aetiological factors for ED 4 0 3 0 2 0 1 0 0 N o E D M in im a l E D M o d e r a te E D Figure 1: Prevalence of ED in MMAS C o m p l e te E D Hypertension Diabetes Cigarette smoking Hyperlipidaemia Major pelvic surgery Pelvic radiotherapy Peyronie s Penile fracture Spinal cord disorders Drugs antihypertensives, antidepressants etc. Psychosocial 5 binding globulin (SHBG) and albumin levels. Serum LH, FSH and prolactin are recommended if serum testosterone levels are borderline or low. Most patients do not need further investigations unless specifically indicated. Further specialised investigations need to be tailored to the individual based on the severity of the problem, to investigate the underlying pathology with a view to potential surgical intervention. Indications for specialised investigations include: 4,10 Young patients who have always had difficulty in obtaining and/or sustaining erection Primary erectile disorder (not caused by organic disease, or psychogenic disorder) Patients with a history of trauma Where an abnormality of the testis or penis is found on examination Patients unresponsive to medical therapies, that may desire surgical intervention for ED Patients with complex psychiatric or psychosexual disorders Patients with complex endocrine disorders Specific tests may be indicated at the request of the patient or his partner Medico-legal reasons (eg. implantation of penile prosthesis, cases of sexual abuse). Nocturnal penile tumescence and rigidity (NPTR) assessment, though not routinely advocated, may be used to assess nocturnal erections in order to determine the presence of a functional erectile mechanism. 13 Intracavernosal injection of prostaglandin E1 can also be performed to determine response to such treatment and to assess penile deformities such as that witnessed in Peyronie s disease. A positive erection test is defined as a rigid erectile response that appears within 10 minutes of the intracavernous injection, (stimulation required), and lasts for at least 30 minutes. Vascular integrity can be assessed using colour Doppler ultrasound. Cavernosography is used to assess the venous occlusive mechanism when a primary venous leakage is suspected in young men with lifelong ED or those with post pelvic trauma ED. ED and cardiovascular status Coronary heart disease (CHD) is associated with the same risk factors as ED 2 and may be regarded as a manifestation of a more generalised arteriopathy that is likely to affect the arterial inflow to the corpora cavernosum of the penis. ED in men with CHD is probably related to this generalised arteriopathy that contributes to both conditions. Guidance on the assessment and management of ED in the cardiovascular patient was updated in 2002 and contains the following key message: 14 Sexual activity is no more stressful to the heart than a number of other common daily activities such as lifting and carrying objects (9 20 kg), walking one mile in 20 minutes on the level, gardening, playing golf etc. Subsequent guidance on the diagnosis and management of ED published by an expert panel of the committee of British Society of Sexual Medicine makes the following key points on the association between ED and CHD. 15 All men with unexplained ED should have a thorough evaluation and any risk factors for CHD that are 16 June 2009 Midlife and Beyond GM2

Men s health Box 2: Severity of ED Severity of ED IIEF 5 Score No ED 22 25 Mild ED 17 21 Mild to Moderate ED 12 16 Moderate ED 8 11 Severe ED 5 7 identified should be addressed. A man with ED and no cardiac symptoms is a cardiac patient until proven otherwise 14 The pro-active management of ED in the cardiovascular patient provides an ideal and effective opportunity to address other cardiovascular risk factors and improve treatment outcomes Men with previously diagnosed CHD should be asked about ED as part of their routine surveillance and management; ED treatments should be offered to all who desire them Patients at low cardiac risk 10 should be managed in primary care Patients at intermediate cardiac risk 10 should be reevaluated, in primary or secondary care as appropriate, and assigned to either the low- or high-risk group Patients that remain in the group defined as high cardiac risk 10 should not be offered treatment for ED in primary care. Such treatment may not be absolutely contraindicated but their assessment and management should be supervised by a specialist team, which will probably include a cardiologist There is no evidence that currently licensed treatments for ED add to the overall cardiovascular risk in patients with or without previously-diagnosed cardiovascular disease. Management The primary goal of management of ED is to enable sexual intercourse to the satisfaction of both partners. In order to effectively manage patients with ED, patients must be fully informed of all treatment options available and have a reasonable expectation of the level of success offered by Box 3: Differentiation between psychogenic and organic ED Psychogenic ED each potential therapy. Effective management requires an assessment of the severity of the issue and accurate identification of possible risk factors. Advice can then be given regarding reduction or even, elimination of these risks, bearing in mind, however, that medication should not be altered without the appropriate dialogue with the relevant prescribing physician. Patients should be given advice regarding smoking, alcohol ingestion and diet where appropriate and may benefit from further referral to other healthcare professionals eg, dieticians, psychosexual counsellors, endocrinologists or self help groups. Providing both the partners with educational material will also be of great benefit. Oral pharmacotherapy Organic ED Sudden onset Gradual onset Situational Constant Variable with different Occurs under all circumstances circumstances Can achieve fully rigid Affects non-coital non-coital erection erections Nocturnal/early morning Nocturnal/early morning erections present erections absent/weak Phosphodiesterase type 5 (PDE5) inhibitors are the mainstay of oral pharmacotherapy for ED. Nitric oxide released by the parasympathetic nerve endings and by the vascular endothelium in the corpus cavernosum stimulates guanylate cyclase in the smooth muscle to produce cyclic GMP (cgmp) that then acts as a second messenger to produce smooth muscle relaxation and thus increased arterial inflow leading to tumescence. PDE5 enzyme hydrolyses cgmp, thus terminating its effect, and inhibition of PDE5 will potentiate the pro-erectile effects of cgmp (Figure 2). 16 Three PDE5 inhibitors have been approved by the 18 June 2009 Midlife and Beyond GM2

Figure 2: Mechanism of action of PDE5 inhibitors European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) (Table 4). Treatment of men with ED of mixed aetiology results in 70 75% of men achieving an erection of sufficient rigidity to allow satisfactory penetrative intercourse. Lower efficacy rates of 50 60% and 30 40% are seen in men with diabetes and radical pelvic surgery respectively. Side effects with all these drugs include headache (11 15%), facial flushing (3 14%), dyspepsia (4 8%) and nasal congestion (2 6%). Sildenafil, at higher doses, can inhibit PDE6 in the retina, resulting in occasional transient visual changes. Contraindications to PDE5 inhibitors include: Ischaemic heart disease Patients on nitrates / GTN spray Hypotension Recent stroke Unstable angina Myocardial infarction. Patients should be exposed to a minimum of eight treatment attempts prior to increasing the dose of any of these medications, and before being labelled as nonresponders, they should have tried at least two medications. They should also be informed to take only one tablet per day, and initially no more than three per week with adequate sexual stimulation. The initial recommended dose to be commenced for the different PDE5 inhibitors is shown in box 4. The initial dose is, however, further reduced in patients >65 years and in those with hepatic or renal impairment. Dietary fat decreases the rate of absorption of sildenafil and vardenafil, thus delaying the onset of their action. No interaction with alcohol up to concentrations of 0 5 0 6 mg/kg, has been observed with any of the three drugs. Currently, research is ongoing to determine the efficacy of daily PDE5 inhibitors in traditional non-responders with early studies showing promising results. Vacuum erection devices Vacuum devices provide passive engorgement of the corpora cavernosa in conjunction with a constriction ring placed at the base of the penis to retain blood within the corpora. They are highly effective in inducing erections (hinged at the level of the constriction ring) satisfactory Box 4: Pharmacokinetics of PDE5 inhibitors Parameter Sildenafil (Viagra) Tadalafil (Cialis) Vardenafil (Levitra) Onset of action 30 60 mins 30 mins 30 mins T max. 1 hour 2 hours 2 hours T1/2 2 6 3 7 hours 17 5 hours 3 9 hours Duration of action 12 hours 36 hours 6 8 hours Doses available 25, 50, 100 mg 10, 20 mg 5, 10, 20 mg Recommended starting dose 50 mg 10 mg 10 mg GM2 Midlife and Beyond 2009 June 19

Men s health for intercourse, regardless of the aetiology 17,18 and satisfaction rates range between 35% 19 and 84%. 20 Vacuum therapy is appropriate for patients refractory to medical therapy or where medical therapy is contraindicated. Manual and electric devices are currently available. In addition to a standard pump and cylinder, the manual model has a pump lever whilst the electric model has a pump power button and vacuum release button. Tension rings of different sizes help to maintain an erection. Vacuum therapy is proven to be successful in 90% of cases. 20,21 Vacuum therapy can be used in three ways; to create an erection on demand; to augment a natural partial erection; to improve natural erections and recondition the penile tissues by improving blood supply and tissue elasticity. The tension ring should not be left for over 30 minutes. Vacuum devices are contraindicated for patients with sickle cell disease, multiple myeloma, Hodgkin s lymphoma or blood dyscrasias that carry a risk of clotting or priapism. Intracavernosal injection therapy Patients not responding to oral therapy may be offered intracavernous injections with high success rates. Intracavernous prostaglandin injection therapy is the most effective form of pharmacotherapy for ED and has been used for more than 20 years. 22 Alprostadil (Caverject TM, Viridal TM ) was the first and until recently the only licensed drug approved for intracavernous ED treatment. 23 It can be used in doses from 5 40 micrograms. Erections occur within 5 15 minutes after penile injection and last 30 40 minutes, although the duration is dose-dependent. Patients (or partners in patients with limited manual dexterity) are taught to selfadminister the injection avoiding the ventrally sited urethra and the dorsal neurovascular bundle. Sexual stimulation following the injection is required for tumescence. Efficacy rates are approximately 70 80% in the general ED population. 24 The reproducibility and satisfaction rate is high, however, long-term compliance can be low with as many as 50% of patients withdrawing from therapy in the first 2 3 months. 22 Adverse effects include postinjection penile pain, 22 priapism (1%), 25 22, 26 fibrosis (2%) and mild hypotension when used in higher doses. Patients are advised regarding adequate hydration and to perform mild to moderate exercise in cases of prolonged erections. Patients should be advised to attend the emergency department should the erection persist over four hours and an information leaflet to this effect should be given to all patients and recorded in the notes. Penile prosthesis A penile prosthesis is at the far end of the spectrum of management options for ED. It is offered to patients who have failed to respond to or are unable to continue with other less invasive therapies. They are particularly suitable for patients with severe ED in conjunction with Peyronie s disease or following prolonged priapism. Malleable and inflatable penile prosthesis are currently available in the market. Inflatable prosthesis, the most preferred variety has three main components corporal cylinders, a pump that resides in the scrotum and a reservoir that is placed within the perivesical space postero-superior to the external inguinal ring. Satisfaction rates are approximately 89% with a 5- year- mechanical survival of 93% and a revision rate of 7% per year. 27,28 Patients should be warned regarding the possible complications of a penile prosthesis including infection (10%), erosion, mechanical failure and penile pain. In addition, patients should be aware that an erection with a prosthesis offers rigidity only, without the usual increase in girth and length one would expect of a normal erection. Conclusion ED is an extremely common condition with increasing age being the strongest independent risk factor. As social taboos are eliminated and awareness increases, so too does the number of patients presenting with ED. A thorough assessment is required in order to delineate possible correctable aetiological factors and specialist investigations may be employed in certain circumstances. PDE5 inhibitors have revolutionised the management of ED since their introduction in the mid 1990s and response rates in the region of 70% are common place. More invasive treatment modalities including intracavernosal prostaglandin injections, vacuum devices and penile prosthesis are reserved for those either failing oral pharmacotherapy, or in whom pharmacotherapy is contraindicated or not tolerated. We have no conflict of interest 20 June 2009 Midlife and Beyond GM2

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