Erectile Dysfunction Arthur L. Burnett*,† From the Johns Hopkins University, Baltimore, Maryland

Purpose: An overview of the latest concepts advanced with regard to the epidemiology, pathophysiology, and management of male ED is provided. Materials and Methods: Published literature and current paradigms promoted by consensus bodies in the field with regard to the management of ED were reviewed. Results: ED is a neurovascular phenomenon modulated by hormonal, local biochemical, and biomechanical/structural factors of the penis. Once viewed primarily as a psychological issue, ED is now understood to represent predominantly organic etiologies. It has a significant association with cardiovascular disease and could serve as a harbinger of subsequent cardiovascular events. Goal directed assessment and management implies a focus on patient (and partner) preferences regarding various treatment options. These options range from oral pharmacological agents to surgery and may be pursued according to a stepwise management approach. Psychosocial interventions also may serve as useful therapeutic adjuncts. Conclusions: ED is a highly manageable disorder in most patients. The patient and his partner have integral roles in the decision making process, since preferences regarding the importance of sexual activity, and the risks and benefits of treatment will vary greatly among individuals. Key Words: penis, impotence, penile erection, phosphodiesterase V

sights suggest that ED may be viewed as a vascular disease and plausibly represents an early manifestation or indicator of covert CV disease existing beyond the genital organ. An additional element that contributes to the significance of the problem is that ED is frequently an issue of the couple. Both the patient and his partner may be affected by the problem and should be involved in management decisions.3

D is increasingly recognized as a public health problem with both psychosocial correlates and associations with clinical comorbidities. The understanding and management of ED has evolved greatly, as evidenced by the increased recognition of its organic etiologies. This condition greatly affects patient quality of life, self-esteem, and ability to maintain intimate relationships. The phases of the male sexual response cycle include libido, which is related to fantasies, thoughts, and feelings about sexual activity; arousal, which specifically addresses the ability to achieve erection; and the ejaculatory phase or orgasm. This 3-phase model evolved from the work of Masters and Johnson, and later Kaplan. The focus of this discussion is the area of ED management, understanding that the greatest degree of scientific and clinical progress in the area of male sexual dysfunction has occurred in this area. Originally known by the imprecise and pejorative term impotence, ED is now defined as the consistent inability to attain or maintain penile erections of sufficient quality to allow satisfactory sexual intercourse.1,2 ED was previously believed to be largely psychogenic in origin. While there are strong psychosocial correlates, there is increasing recognition of its relationship to clinical comorbidities that indicate an organic basis in the majority of presentations. It is also considered to be a significant public health problem, given its relationship to diabetes, vascular diseases, dyslipidemia, hypertension, and cigarette smoking, of which all are prevalent conditions in the United States population. New in-

E

EPIDEMIOLOGY Two key population based studies, done early in the epidemiological investigation of ED, can be credited with advancing the understanding of the prevalence of the disorder. The National Health and Social Life Survey, which defined various types of sexual dysfunction in men and women, documented an ED incidence of 18% in men 50 to 59 years old.4 The initial report of the longitudinal Massachusetts Male Aging Study showed an incidence of erectile dysfunction in 52% of men 40 to 70 years old with 10% of the study population experiencing severe ED.5 As more epidemiological data accrue, information is emerging regarding the extent and impact of risk factors and comorbidities associated with ED. In addition to CV disease, pelvic trauma, neurological disease/injury, and aging have all been associated with the disorder. ORs have recently been established for conditions such as diabetes, hypertension, and various cardiac and vascular diseases; diabetes alone quadruples the risk (see table).6,7 Recent studies have supported the association between lower urinary tract symptoms, bladder outlet obstruction, and BPH with ED, although the exact pathophysiological relationship between prostate disease and ED remains unclear.6 In addition to the increased risk related to chronic disease, ED may be associated with medication use in up to

* Correspondence: 600 North Wolfe St., Marburg 407, Baltimore, Maryland 21287 (telephone: 410-614-3986; FAX: 410-614-3695; email: [email protected]). † Financial interest and/or other relationship with Pfizer, Guilford Pharmaceuticals, Bayer/GlaxoSmithKline and Lilly/ICOS.

0022-5347/06/1753-0025/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION

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Vol. 175, S25-S31, March 2006 Printed in U.S.A. DOI:10.1016/S0022-5347(05)00309-5

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ERECTILE DYSFUNCTION Major ED risk factors6,7 Chronic Disease

Age Adjusted OR

Diabetes Prostate disease Peripheral vascular disease Cardiac problems Hyperlipidemia Hypertension

4.1 2.9 2.6 1.8 1.7 1.6

25% of all cases. Certain antihypertensive agents, particularly diuretics and ␤-blockers, are highly associated with ED.8 However, it is interesting that angiotensin-converting enzyme inhibitors and ␣-adrenergic antagonists (␣-blockers) do not appear to increase the ED risk.8,9 It is possible that the underlying vascular pathology, arteriosclerosis, actually may be the critical pathogenic element for the manifestation of ED, primarily affecting blood flow and circulation in the penile vascular bed. Conceivably, any sort of antihypertensive agent that decreases systemic pressure and, therefore, attenuates the pressure gradient in the pelvic area would exacerbate the vascular physiology and be detrimental to erectile function. Clearly, this area is in need of greater study. Other medications associated with ED include hormonal agents (eg antiandrogens),10 –12 protease inhibitors,13 cytotoxic agents,14 H2 antagonists,11,12 and selective serotonin reuptake inhibitors.10 –12,15 Selective serotonin reuptake inhibitors are known to be effective for treating depression, which in itself is associated with a higher incidence of ED. Shabsigh et al evaluated 120 patients whose chief complaint was either ED or voiding dysfunction associated with BPH, screening them for depressive symptoms with a questionnaire derived from the Primary Care Evaluation of Mental Disorders and the Beck Depression Inventory.16 Depressive symptoms were documented in 54% of the men with ED only (mean age 54.5 years), in 56% with ED plus BPH (mean age 55.8 years), and in 21% with BPH only (mean age 61.2 years). It is not certain whether ED precedes depression or vice versa, but the authors stated that ED is clearly a multifactorial condition that warrants a multidisciplinary approach to management. In addition to depression, several other emotional conditions have been determined to be risk factors for ED, including stress, general unhappiness, dissatisfaction with partner, greater than 20% decrease in income, pessimistic attitude, marital change, and employment change.4,17 A number of modifiable life-style factors contribute to ED. Sedentary life-style, obesity, heavy drinking, recreational drug use, and smoking all increase the risk of ED.11,18 –20 This is an area of increasing interest, because it suggests several ways that patients can decrease their own symptoms.

not yet fully understood. The Appendix lists various causes of ED that are frequently identified to imply psychogenic or organic etiologies. Psychogenic and organic categories of ED for practical purposes differ in presentation, severity, and association with certain environmental variables.12 Psychogenic ED generally is characterized by sudden onset with complete and immediate loss of sexual function, although this may vary with the partner and circumstance. The patient, with some exceptions, tends to display erections upon awakening. Organic ED typically is more gradual in onset with incremental progression of dysfunction, except ED caused by immediate traumatic events. Erections are not routinely observed with organic ED, even in the most stimulatory sexual encounters. Making the distinction may be helpful in directing ED management for the patient. If the assigned etiology is organic, the patient would primarily address comorbid conditions contributing to the problem. Counseling would be recommended as a major part of the treatment regimen for the patient having psychogenic ED. PATHOPHYSIOLOGY It is widely recognized that erections are fundamentally neurovascular phenomena combining neurotransmission and vascular biological responses. Additionally, hormonal stimuli, local biochemical interactions, and biomechanical mechanisms influence this neurovascular control. While basic science investigations exploring the physiology and pathophysiology of the penis have advanced the field, recognition of clinical disease states associated with ED also has provided significant insight into its pathophysiology. In terms of the vascular relationship, clinicians increasingly view ED as an endothelial dysfunction, implying a vascular disturbance involving the endothelium, and certain risk factors that lead to oxidative stress actually may have a role in the underlying pathogenesis for many disease states associated with ED. Pathophysiology is revealed by conditions that affect the hemodynamics of the erectile response, which normally involves increased blood flow entry into the penis and restricted venous outflow. Accordingly, classic vascular impairments (separate from diabetes mellitus) represent as many as 40% of all ED presentations (fig. 1). Atherosclerosis, which occurs with diabetes and other vascular diseases, is a pathological risk factor.1,10,20,21–23 Vascular disease that impairs cavernous smooth muscle relaxation and veno-occlusive function in the penis also should be recognized to

CLASSIFICATION As noted, the conceptual psychogenic and organic etiologies combine in representing the spectrum of ED, although the division recently has become less distinct. A contention is that the psychogenic assignment does not necessarily mean that the origin is solely emotionally or psychologically based; there may be an organic basis related to neuronal circuitry and other biological regulatory factors gone awry that are

FIG. 1. Percent distribution of organic causes of ED. Adapted from Goldstein.51

ERECTILE DYSFUNCTION include CV conditions and even neuropathic changes of the penis resulting from radical pelvic surgery.10 Penile deformities, such as Peyronie’s disease, congenital penile curvature, and fibrosis resulting from such conditions as priapism or penile trauma, all adversely affect penile hemodynamics.1,10,20,24 Direct trauma to the genital area including the perineum either as a single or repeated event, such as that caused by excessive bicycle riding, which exerts compressive effects on the pudendal vasculature, is also an offender.25 Considered to be primary organic causes of ED in 5% of cases, neurogenic illnesses and injuries (excluding iatrogenic pelvic treatments) include pelvic or spinal cord injury, multiple sclerosis or other demyelinating conditions, neuropathies, pudendal nerve injury, stroke, Alzheimer’s disease, and Parkinson’s disease.1,10,14,26 –28 Endocrine factors have a role in approximately 3% of organic ED cases. Hypogonadism, hypothyroidism, hyperthyroidism, pituitary tumor, and hyperprolactinemia all may lead to ED.10,29 –31 While ED previously was viewed to be predominantly a hormonal problem, current concepts indicate that only a minority of cases involve an endocrine cause primarily.

PRINCIPLES OF MANAGEMENT Goal directed assessment is an important element in initiating management of ED. The patient and partner should be involved in clinical decisions, recognizing that patient preferences and expectations regarding management options can vary greatly. Partner interviews have been shown to impact diagnosis and treatment in 58% of cases.25,32 An interview with the partner of the patient is a critical component of the evaluation process. Early detection and screening are feasible actions in many patients considered to be at high risk for ED. For example, patients who have a sedentary life-style or are heavy cigarette users may be identified as individuals at risk for ED. Patients treated for hypertension or diabetes are at risk and could be in need of ED management. While many diagnostic tools in use for ED management were designed for clinical trial use, they still may offer screening devices, if not a means to facilitate dialogue, for patients at high risk. The Sexual Health Inventory for Men, for instance, can be used for this purpose, as well as to monitor treatment responses in individual patients.33 Figure 2 shows an algorithm for the diagnosis and treatment of ED. Initial assessment begins with gaining an understanding of the presenting condition by taking a thorough sexual (differentiating ED from premature ejaculation, libidinal disorders, etc), medical (including medications), surgical, and social history. Physical examination is important to evaluate all aspects of patient health, particularly the neurological and vascular systems. The genitalia of the patient should be examined for any unusual characteristics, such as deformity, scarring, or angulation of the penis. Blood studies may be ordered to confirm or rule out underlying disease. This may include fasting blood glucose, lipid profile, urinalysis, and complete blood count. An endocrine assessment, such as morning time total testosterone measurement, may be done when hypogonadism is suspected. Other endocrine tests such as thyroid-stimulating hormone measurement may be performed depending on clinical sus-

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FIG. 2. Algorithm for ED assessment and treatment. Exam, examination. Labs, laboratory studies. Adapted from Lue52 and Jardin53 et al.

picion of thyroid disease. Thus, laboratory tests generally should be tailored to the individual clinical presentation. Depending on the complexity of the case, a referral to a urologist or ED specialist for additional tests may be appropriate. The specialist may recommend combined penile injection of vasodilators and sexual stimulation, duplex ultrasonography, cavernosonography, pelvic/penile arteriography, nocturnal penile tumescence testing, and/or neurological tests. A patient who presents with atypical ED parameters (eg an adolescent or young adult with primary ED) is a reasonable candidate for referral. Some patients may request referral for additional assurance that his case has received an appropriate and comprehensive evaluation. This may enable the patient to make treatment decisions with a greater degree of confidence and comfort. Referral and additional testing are appropriate if it is believed the patient will require invasive and/or complex therapy. Cases having legal ramifications also may be subject to extensive diagnostic testing. Sexual activity carries an increased risk of CV events. The incidence of nonfatal MI is approximately 2.5 times higher in men with no history of MI; it is approximately 2.9 times higher in men with a history of MI. Although the incidence is only 20/1,000,000 individuals, the evaluation process should include assessment of CV risk, particularly in men with prior MI. Patients classified as having high risk would be those with unstable or refractory angina, a recent history of MI, certain arrhythmias, or uncontrolled hypertension. For these patients, sexual activity should be deferred until the cardiac condition is stabilized,34 at which point the patient may be considered for medical management of ED. TREATMENT PRACTICES Goal directed assessment was mentioned; goal directed treatment is also appropriate. It is imperative to consider what the patient (and partner) actually wants or expects to accomplish through treatment. Patients vary in their level of acceptance of their sexual disorders, and some may not wish

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ERECTILE DYSFUNCTION

to attempt more invasive therapies. At the same time, a more significant, invasive intervention may be best pursued depending on the extent of the problem that may require a more definitive intervention, such as penile prosthesis surgery, and the patient may feel strongly about proceeding in this fashion. In general, however, the least invasive therapies may be offered first. A number of noninvasive options currently are available as first line therapy. First line therapy. Management of ED may be initiated most commonly by a combination of pharmacological therapy and counseling, along with modification of life-style habits. Patients should be counseled to modify any detrimental behaviors that may be present (eg cigarette smoking, excessive alcohol use, recreational drug use, lack of exercise, and uncontrolled diabetes) to improve their sexual ability or prevent ED from progressing. If a patient is on medications associated with ED, the medication regimen may need to be adjusted. Psychosexual counseling is often appropriate, even when the etiology is largely organic, since psychosocial overlays coexist in many patients. Interventions regarding anxiety management, cognition, and/or behavioral interventions may be beneficial. Androgen replacement therapy is a first line option when hormonal factors are involved in ED and arguably it is worth implementing even when other confounding etiologies are present. It is recognized that androgen therapy offers other potential benefits than sexual function, including benefits for decreased muscle mass, lethargy, depression, and osteoporosis, of which all are related to decreased androgen levels. Of note, risk associations such as prostate disease risk should be discussed, and a risk-to-benefit evaluation should be considered before implementing therapy. PDE-5 inhibitors, a relatively new class of vasoactive drugs, represent the centerpiece of ED treatment. The PDE-5 enzyme is predominantly expressed in the smooth muscle of the corpus cavernosum.35,36 It hydrolyzes cyclic guanosine monophosphate, which is the intracellular mediator of the nitric oxide signaling pathway. Nitric oxide causes relaxation of the smooth muscle, enabling the vasodilation that is necessary for erection to occur. Because of its role in the vasodilation process, PDE-5 offers a selective target for implementation of oral therapy. PDE-5 inhibitors prevent the breakdown of cyclic guanosine monophosphate, thereby, permitting the biological cascade of events that is required for normal erectile function.37 Currently, there are 3 PDE-5 agents commercially available for the treatment of ED in the United States: sildenafil, tadalafil, and vardenafil. Their biochemical potency and selectivity are relatively similar. Slight differences exist with regard to maximal serum concentration, time to maximal concentration, bioavailability, clearance, and protein binding. Perhaps the most salient difference among them is the longer half-life of elimination documented for tadalafil (17.5 hours, compared with 3 to 5 hours for sildenafil and 4 to 5 hours for vardenafil).38 – 40 Differences in molecular structure of tadalafil may account for this distinction. Common to all drugs is the need for sexual stimulation to bring about nitric oxide release, upon which the therapy acts pharmacologically. In comparing efficacy of the PDE-5 inhibitors, it is important to note that published studies for each agent reveal a comparative evaluation with placebo and not to each other.

FIG. 3. PDE-5 inhibitor efficacy in successful intercourse. Adapted from Padma-Nathan,54 Brock55 and Porst56 et al.

Trial parameters and patient characteristics may vary somewhat among studies. The most relevant end point from the patient perspective is success in completing sexual intercourse. This outcome was similar across studies of the PDE-5 inhibitors, ranging from 61% to 71% for the recommended starting dose for each inhibitor (fig. 3). Dose titration may be performed for all 3 agents to maximize the patient response to therapy. Success with the PDE-5 inhibitors is optimized through patient-partner involvement in treatment decisions, as well as modification of existing risk factors that affect the patient ability to achieve an erection.41,42 In patients with comorbidities, if the condition is well controlled, success rates for PDE-5 inhibitors are enhanced: 85% for treated hypogonadism (vs 75% for untreated hypogonadism), and 62% for controlled diabetes (vs 44% for uncontrolled diabetes).42 This trend tends to hold true for numerous other comorbidities. The PDE-5 inhibitors can cause AEs related to vasodilation and vasorelaxation in other parts of the body that express PDE-5. Headache, flushing, and dyspepsia have been reported to varying degrees for all 3 agents.38 – 40 Patients on sildenafil also have reported nasal congestion, visual disturbances, and diarrhea; patients on tadalafil also have reported nasal congestion, back pain, and myalgia; and patients on vardenafil also have reported rhinitis, sinusitis, and flu-like symptoms. Discontinuation rates due to AEs are similar, ranging from 2.1% to 2.5%.43,44 All 3 PDE-5 inhibitors have been shown to potentiate the hypotensive effects of organic nitrates and, therefore, they are contraindicated in patients using nitrate therapy.38 – 40 Cardiac safety has been discussed in relation to the PDE-5 inhibitors and has been a subject of great interest. There were early concerns related to whether the therapy would exacerbate risks of MI or other CV events in patients on these medications. Long-term studies, however, have shown no increase in MI or death rates; although the PDE-5 inhibitors are contraindicated in patients in whom sexual activity is inadvisable due to underlying CV disease, unless appropriate CV intervention has been performed.38 – 40 Another concern relates to the possibility of tachyphylaxis, the rapidly decreasing response to a drug therapy following its repeated use. One study showed evidence of poor long-term efficacy,45 but the patient population followed for 2 years was small (82), such that the study was not

ERECTILE DYSFUNCTION definitive. The likelihood of progression of ED in some patients offers a plausible explanation for some decreased response with time. Other studies have demonstrated sustained efficacy during 1 to 3 years,46 – 48 suggesting that tachyphylaxis is unlikely. Caution should be exercised in patients on ␣-blockers. The Food and Drug Administration recently revised its position allowing ␣-blocker use with all currently approved PDE-5 inhibitors with precautionary warnings. Nonarteritic anterior ischemic optic neuropathy has also become a concern, but it should be made clear that the risk of this condition is associated with a high risk population, such as individuals with long-term diabetes and hypertension, and the incidence risk while using PDE-5 inhibitors in this population may be no greater than their known incidence for this complication in the absence of PDE-5 inhibitors.38 – 40 Second line therapy. When oral therapy and other first line treatments do not achieve satisfactory outcomes, localized treatments are available. These range from intrapenile pharmacological injections to vacuum constriction devices. Alprostadil (prostaglandin E1) is the most commonly prescribed injectable agent for localized treatment of ED. Alprostadil may be administered by intracavernous injection or transurethral insertion. Its exact mechanism is unknown, but it is believed to induce relaxation of corporeal smooth muscle through interaction with certain receptors that stimulate cyclic adenosine monophosphate. This treatment has been used for many years, sometimes in combination with phentolamine and papaverine. Intracavernous injections of alprostadil have demonstrated efficacy in greater than 70% of patients studied.10 It carries a relatively low risk of priapism, although 17% to 34% of patients in some studies reported painful erections. The transurethral delivery of alprostadil involves a small pellet that is inserted into the urethra, where it is absorbed through the urethral lining into erectile tissue. This treatment has been shown to be effective in 43% of men with ED, although efficacy was inconsistent.10,49 Penile pain was a commonly reported AE (32%). Both forms of alprostadil delivery require patient counseling regarding self-administration and dose titration. This therapy is not recommended in patients at risk for priapism. Alprostadil is also available as a topical cream. Two small studies documented efficacy in achieving erection ranging from 39% to 75%, although successful intercourse was not one of the outcomes measured.50 Penile erythema and/or skin discomfort was a commonly reported AE. A nonpharmacological therapy that has been in use for many years is the vacuum constriction device. It is designed to mechanically draw blood into the penis, at which point a constriction band is applied to hold the blood in the penis, so that intercourse can be achieved. The vacuum constriction device is considered highly effective and it is less expensive in the long term than most other treatments. There is a learning curve with this technology, and AEs can include bruising, unnatural erection, petechiae, numbness, and trapped ejaculation.10 There are no systemic side effects, however, and essentially no contraindications. Surgery. When oral and injectable therapies fail to produce satisfactory results, implantation of a penile prosthesis is highly effective and demonstrates the highest level of satis-

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faction among treatments for ED according to patient surveys. It is recognized that the penile prosthesis does not allow a natural erectile response.10 Current devices show excellent operability with low risk of malfunction, infection or need for revision. Revascularization is primarily recommended in young men with congenital or traumatic ED.10 It is a curative measure, but very expensive. Poor results have been documented in older men with generalized disease. CONCLUSIONS Treatment for ED has evolved greatly in the last few decades, most notably in the development of effective pharmacological therapies. The PDE-5 inhibitors figure prominently in ED treatment, because of their convenience, effectiveness, and high tolerability; however, they may not be appropriate or successful in all patients. Alternative therapies are available and may be pursued to achieve success in treating the majority of patients. It is important to recognize that patient and partner involvement is key to the implementation of successful therapy. APPENDIX Causes/categories of ED10,17,20,32 Psychogenic

Organic

Depression Performance anxiety Relationship problems Psychological problems Psychological distress

Vascular factors Neurogenic factors Hormonal factors Medications Penile injury/disease

Abbreviations and Acronyms AE BPH CV ED MI PDE-5

⫽ ⫽ ⫽ ⫽ ⫽ ⫽

adverse event benign prostatic hyperplasia cardiovascular erectile dysfunction myocardial infarction phosphodiesterase type 5

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