Key points

Introduction

In the expanding field of men’s health, much recent attention has been directed toward sexual health, an integral part of overall male wellness. Erectile dysfunction (ED) or impotence is a multifactorial disorder that continues to be an evolving public health concern. With the introduction of readily accessible, effective, and generally safe oral medications, men are now turning to primary care physicians and midlevel providers to manage conditions of sexual dysfunction and are often offered therapy with inadequate or no evaluation. Typically, the failure or poor efficacy of first-line treatments often leads to urology referral. Other reasons for specialty referral may be trauma, uncertainty of diagnoses, or simply the wish of patients or providers to better understand the cause of the ED. This article focuses on the office-based work-up, diagnosis, and management of 2 important and variable conditions in male sexual dysfunction, ED and Peyronie’s disease (PD).

Background

ED is the consistent or recurrent inability to attain or maintain penile erection adequate for sexual intercourse. ED is a common male disability associated with aging that significantly impacts quality of life and interpersonal well-being. A 3-month minimum duration is generally accepted for establishment of the diagnosis, although in certain cases of trauma or surgically induced ED, a 3-month minimum may not be necessary. Although objective testing or partner reports help support a diagnosis of ED, these cannot replace patients’ self-reports in classifying the dysfunction or establishing the diagnosis.

Early landmark studies, such as the Massachusetts Male Aging Study (MMAS) and the National Health and Social Life Survey, used single-item scales, which assessed erection difficulties over several months or in the past year. In the MMAS, a community-based survey of men between 40 and 70 years of age, 52% of all respondents reported some degree of ED: 17% mild, 25% moderate, and 10% complete. The MMAS showed that the incidence increased with patient age, with an incidence of 12.4 for men aged 40 to 49 years, 29.8 for men aged 50 to 59 years, and 46.4 for men aged 60 to 69 years. Other studies from the 1990s estimated that half of men older than 40 years had ED. The degree of bother associated with ED has been shown to be inversely related to aging. Men older than 70 years typically report a lesser degree of bother as compared with their younger counterparts. Distress and treatment seeking related to ED is found to be higher in younger and middle-aged men. Recent investigation of the causes and risk factors for ED has revealed an association between ED, benign prostatic hyperplasia, and lower urinary tract symptoms.

The prevalence and incidence of ED are highly correlated with the presence of specific risk factors and comorbidities, suggesting that ED may be an early marker for cardiovascular and other disease states. In fact, the symptoms of ED can predate the clinical diagnosis of associated vascular disease by up to 3 years. Cardiovascular comorbidities (such as hypertension and hypercholesterolemia), diabetes mellitus, and metabolic syndrome have been associated with ED in multiple cross-sectional and longitudinal studies. Recent studies in hypogonadal men with testosterone deficiency syndrome (TDS) have demonstrated the positive benefits of normalizing testosterone in men with sexual problems. The development of new treatment options has provided men with TDS with improved and effective methods for hormone replacement, including topical gels and time-released pellets. In addition, the introduction of oral phosphodiesterase-5 (PDE-5) inhibitors resulted in patients presenting to their physicians in increasing numbers for evaluation and treatment earlier. It is estimated that 25 to 30 million men worldwide are taking PDE-5 inhibitors and that an additional 50 million or more are potential candidates for treatment.

Introduction

In the expanding field of men’s health, much recent attention has been directed toward sexual health, an integral part of overall male wellness. Erectile dysfunction (ED) or impotence is a multifactorial disorder that continues to be an evolving public health concern. With the introduction of readily accessible, effective, and generally safe oral medications, men are now turning to primary care physicians and midlevel providers to manage conditions of sexual dysfunction and are often offered therapy with inadequate or no evaluation. Typically, the failure or poor efficacy of first-line treatments often leads to urology referral. Other reasons for specialty referral may be trauma, uncertainty of diagnoses, or simply the wish of patients or providers to better understand the cause of the ED. This article focuses on the office-based work-up, diagnosis, and management of 2 important and variable conditions in male sexual dysfunction, ED and Peyronie’s disease (PD).

Background

ED is the consistent or recurrent inability to attain or maintain penile erection adequate for sexual intercourse. ED is a common male disability associated with aging that significantly impacts quality of life and interpersonal well-being. A 3-month minimum duration is generally accepted for establishment of the diagnosis, although in certain cases of trauma or surgically induced ED, a 3-month minimum may not be necessary. Although objective testing or partner reports help support a diagnosis of ED, these cannot replace patients’ self-reports in classifying the dysfunction or establishing the diagnosis.

Early landmark studies, such as the Massachusetts Male Aging Study (MMAS) and the National Health and Social Life Survey, used single-item scales, which assessed erection difficulties over several months or in the past year. In the MMAS, a community-based survey of men between 40 and 70 years of age, 52% of all respondents reported some degree of ED: 17% mild, 25% moderate, and 10% complete. The MMAS showed that the incidence increased with patient age, with an incidence of 12.4 for men aged 40 to 49 years, 29.8 for men aged 50 to 59 years, and 46.4 for men aged 60 to 69 years. Other studies from the 1990s estimated that half of men older than 40 years had ED. The degree of bother associated with ED has been shown to be inversely related to aging. Men older than 70 years typically report a lesser degree of bother as compared with their younger counterparts. Distress and treatment seeking related to ED is found to be higher in younger and middle-aged men. Recent investigation of the causes and risk factors for ED has revealed an association between ED, benign prostatic hyperplasia, and lower urinary tract symptoms.

The prevalence and incidence of ED are highly correlated with the presence of specific risk factors and comorbidities, suggesting that ED may be an early marker for cardiovascular and other disease states. In fact, the symptoms of ED can predate the clinical diagnosis of associated vascular disease by up to 3 years. Cardiovascular comorbidities (such as hypertension and hypercholesterolemia), diabetes mellitus, and metabolic syndrome have been associated with ED in multiple cross-sectional and longitudinal studies. Recent studies in hypogonadal men with testosterone deficiency syndrome (TDS) have demonstrated the positive benefits of normalizing testosterone in men with sexual problems. The development of new treatment options has provided men with TDS with improved and effective methods for hormone replacement, including topical gels and time-released pellets. In addition, the introduction of oral phosphodiesterase-5 (PDE-5) inhibitors resulted in patients presenting to their physicians in increasing numbers for evaluation and treatment earlier. It is estimated that 25 to 30 million men worldwide are taking PDE-5 inhibitors and that an additional 50 million or more are potential candidates for treatment.

Identification of risk factors/comorbidities

The Second International Consultation on Sexual Dysfunction identified specific risk factors for ED. The factors have been well studied and include cigarette smoking; diabetes mellitus; hormonal disorders; cardiovascular disease; hypertension; chronic renal failure; lower urinary tract symptoms; poor overall health; chronic neurologic diseases; spinal cord injury; surgery and radiotherapy for prostate cancer; psychiatric conditions, including anxiety disorders and depression; medications; and recreational drugs. Recognition of screening for these important risk factors is vital in the proper clinical evaluation of ED. The International Society of Sexual Medicine (ISSM) categorizes ED into 3 main groups: (1) psychogenic; (2) organic; and (3) mixed (organic and psychogenic), the most common type. The first goal of the in-office evaluation is the identification of risk factors and classification of patients with ED into one of these 3 groups.

Psychogenic ED

Identifying the proper psychogenic component to ED helps in guiding the treatment plan. According to the ISSM’s classification, psychogenic ED may be generalized or situational. Generalized psychogenic ED usually relates to a primary lack of sexual arousability, aging-related decline in arousability, personality characteristics, or a chronic disorder of sexual intimacy. It is usually not associated with a particular sexual partner, situation, or performance concern. The situational type of psychogenic ED is associated with a specific partner, performance concerns, or adjustment-related issues. Partner-related issues may include lack of arousability in a specific relationship, sexual object preference, and partner conflict or threat. Performance-related issues can be associated with situational performance anxiety or with other sexual dysfunctions, such as premature ejaculation or disorders of orgasm. Adjustment-related issues include major life stress, such as significant illness and death of a partner. Concomitant depressive and anxiety disorders have been associated with ED. The treatment of these disorders often reduces the severity and may treat the ED, although it is important to recognize the potential sexual side effects of the various antidepressant agents. In certain patients, psychological counseling and behavioral therapy may be helpful in addition to medical treatments for ED.

Organic ED

If the clinical evaluation suggests an organic cause, the ISSM’s classification system identifies the following major subgroups: neurogenic, hormonal, arterial, cavernosal (venogenic), and drug induced. In addition, various disease states are identified as potential causes of ED through unclear mechanisms.

Lifestyle factors, including smoking, obesity, and lack of exercise, have been shown to be significant predictors of organic ED. In a randomized, prospective, controlled trial, intensive lifestyle modification improved erectile function and associated cardiovascular and inflammatory markers.

Neurologic

There are many neurologic conditions that can affect ED. In theory, any neurologic condition involving autonomic innervation of the corpora cavernosa may impact the ability to produce a normal erection. Polyneuropathy, which commonly involves autonomic dysfunction, has been shown to be a source of ED. A study by Vardi and colleagues reported a 38% coincidence of polyneuropathy and ED in patients with diabetes and a 10% coincidence of the two in patients without diabetes. Male sexual dysfunction is also seen in other neurologic conditions, such as Parkinson disease, dementia, multiple sclerosis, and other neurodegenerative diseases. In these disorders, the cause of ED is thought to result from a complex relationship of altered erectile nerve function, generalized sensorimotor impairment, cognitive decline, illness-related stress, and decreased interpersonal interaction. Epilepsy has also been linked to neurologic ED as well as reduced sexual interest/libido and desire. Multiple sclerosis has been found to have an incidence of ED in the range of 40% to 80%. In these cases, ED typically presents 5 to 10 years after the onset of progressive neurologic symptoms. Stroke, one of the most common neurologic conditions worldwide, is associated with ED in 50% to 65% of patients. Patients who have had a stroke also report a loss of sexual interest and desire and ejaculatory dysfunction. Patients with various spinal cord injuries may have significant problems with ED and other related sexual dysfunction. These problems tend to be most bothersome in regard to future quality of life.

Endocrine

Erections, sexual behavior, desire, and interest can be affected by abnormalities of endocrine function. Gonadal function in men may deteriorate in a progressive way as part of the normal aging process. A low testosterone level is the most widely recognized and investigated hormonal alteration associated with the aging process, and hypogonadotropic hypogonadism may be an associated finding in ED. There is increasing evidence that androgens are fundamental, not just for sexual behavior and desire but also for various physiologic and signaling pathways regulating erection as well as for preserving bone density and muscle mass. Although hypogonadism is the most common endocrine cause of ED, thyroid disease, other pituitary disorders, adrenal disease, and hyperprolactinemia may all be associated with ED. The production of several hormones, including dehydroepiandrosterone, thyroxine, melatonin, prolactin, and growth hormone, is also affected by age and may have implications in erectile function. In significantly hypogonadal men, androgen-replacement therapy has been shown to improve nocturnal penile tumescence testing as well as erotic stimulus-evoked erections. The exact role of androgens in normal and abnormal erectile function remains an area of investigation.

Vascular

Vascular disease is the most common cause of organic ED. Vasculogenic ED accounts for approximately 60% to 80% of all cases and can be classified into 3 subtypes: arterial, venoocclusive, or mixed vascular insufficiency. ED shares a common pathophysiology with other vascular disease states, such as heart disease, stroke, and peripheral vascular disease. The accepted pathophysiologic mechanism is thought to be a reduction of inflow into the cavernosal arteries and venoocclusive dysfunction secondary to atherosclerotic occlusive disease. The concept of ED as a marker of other underlying vascular disease is, in part, based on the finding that penile vascular disease shares a causal pathway with other vascular disease states, such as cerebrovascular disease, myocardial infarction, coronary artery disease, hypertension, hyperlipidemia, and peripheral vascular disease. In studies, the quality of penile inflow has been related directly to common vascular comorbidities, including age, diabetes mellitus, hypertension, atherosclerotic vascular diseases, hyperlipidemia, and cigarette smoking. Another study, surveying men during hospitalization for myocardial infarction, showed 64% reported some degree of ED. There have also been reports showing an 18% prevalence of ED in men before experiencing a myocardial infarction, compared with 45% after the event.

Other conditions are commonly revealed during the clinical evaluation of patients with ED, including cigarette smoking, diabetes mellitus, chronic renal failure, and history of prostate cancer. Cigarette smoking deleteriously affects the arterial endothelium on a microvascular level and is a risk factor for other vascular disease states. A meta-analysis of the available literature over the last 20 years revealed that 40% of men with ED were smokers compared with 28% of men in the general population.

ED is present in at least 50% of men with diabetes mellitus, with the onset of symptoms occurring at an earlier age than in those without diabetes. Several studies suggest that 26% to 35% of men with diabetes will develop ED. In the MMAS, the age-adjusted probability of complete ED was 3 times higher in men who had treated diabetes mellitus than in men without diabetes. There are several proposed mechanisms by which diabetes mellitus is thought to cause ED. Among these, diabetes-induced microvascular and atherosclerotic disease and diabetes-induced autonomic and somatic peripheral neuropathies seem to be the most important. Chronic renal failure (CRF) is a risk factor for ED and should be revealed during a basic urologic evaluation. Effective treatment of CRF with renal transplantation reduces the severity of ED in these patients.

A common ED patient population encountered by the urologist includes those treated for prostate cancer by radical prostatectomy (open and laparoscopic/robotic), radiotherapy (external beam radiation therapy [XRT], intensity-modulated radiation therapy [IMRT], brachytherapy), hormonal therapy, and cryosurgery. A recent report indicates that there is more than a 50% incidence of ED after radical prostatectomy, regardless of whether a nerve-sparing procedure had been performed. Other reports have shown that in younger men, bilateral nerve-sparing radical prostatectomy results in higher retention of baseline erectile function compared with the non–nerve sparing procedure. External-beam prostate radiotherapy and interstitial prostate brachytherapy also result in posttreatment ED, although typically less immediate in onset. Interstitial prostate cryosurgery is an emerging treatment modality for prostate cancer, but recent reports indicate a high likelihood of posttreatment ED. Although the medical and surgical treatment of symptomatic benign prostate hyperplasia (BPH) is generally not harmful to the cavernosal nerves, reports show that sexual function may be adversely impacted, especially after the surgical treatment of BPH.

The first office visit

Patients may present independently to the urologist’s office with a complaint of ED, may have been referred from a primary care provider, or may already have an established relationship for other urologic conditions (BPH/LUTS [lower urinary tract symptoms], calculi, and so forth). Studies have suggested, however, that the average man with ED waits up to 3 years before seeking medical evaluation (reinforcing the importance of the clinician initiating the discussion regarding ED at each elective visit). In any case, a thorough, systematic evaluation of ED should start with a complete history and physical, including the identification of any risk factors for sexual dysfunction. Remember, ED is a couple’s disease, affecting both the patients and their partners; therefore, their partners should be encouraged to be present during the office visit. Of primary importance is the building of a clinician-patient partnership established within an atmosphere of trust.

The visit should flow in a sequential manner, with each component generating and contributing information: (1) identify the chief complaint and sexual history; (2) a detailed medical and surgical history, including all comorbidities, medications and lifestyle factors; (3) a physical examination; (4) basic laboratory testing; (5) identification of the need for specialized evaluation and testing or referrals; and (6) treatment and reassessment ( Box 1 ).

Patients’ history of ED: the clinical assessment

The first step in the evaluation of ED is a complete medical, social, and sexual history, recognizing that ED may be a presenting symptom or marker of an associated disease state, such as cardiovascular disease. Any specific existing medical comorbidities, especially vascular and/or neurogenic, should be noted. A brief history of cardiovascular symptoms, including exercise tolerance, presence of angina, dyspnea, claudication, transient ischemic attacks, smoking history, and family history of cardiovascular disease, may identify patients with cardiac and vascular risk factors. A detailed urologic history should be taken, with special attention to lower urinary tract symptoms, urologic trauma, urologic malignancies, urinary tract infections, and sexually transmitted infections. Prior urologic procedures (prostatectomy, BPH-related procedures, vasectomy) should be recorded as well as ED symptoms before, surrounding, and after those surgeries. An accurate medication list should be obtained, including herbal medicines, nutritional supplements, and other alternative therapies. Attention should be given to the documentation of any allergies and confirmation of any current nitrate usage. This time is also the point to inquire about any other drug use, illicit or supplemental, especially because numerous medications can cause ED.

The foundation to confirming the diagnosis and in evaluating patients’ sexual function is a comprehensive sexual history. A validated pre-evaluation questionnaire can elucidate specific patient concerns and the need for further investigation. Assessing patients’ sexual history should encompass any concerns regarding arousal, libido, performance, ejaculation and orgasm, and overall satisfaction. Levels of desire and libido should be addressed because these can also be important in identifying some symptoms of hypogonadism. A detailed inquiry should be made into the quality of the erections themselves. Patients should be asked about their ability to attain and maintain their erection, specifically about the inconsistencies in their erections (spontaneity, ability to maintain) and the progression of their problem. The clinician’s goal in the process should be to differentiate between potential organic and psychogenic causes in a patient’s sexual problem. The practitioner should also recognize any potential overlap between organic and psychogenic etiologies.

Symptoms and quantification

It is often difficult to quantify the symptoms of sexual dysfunction because of its variable nature and complex issues involving its cause. The practitioner should incorporate the use of ED symptom scales and questionnaires for patient self-assessment whenever possible. There are many types of validated sexual questionnaires available for use. Multidimensional questionnaires, such as the International Index of Erectile Function (IIEF) or the Sexual Health Inventory for Men, are very helpful in the identification of risk factors and potential causes of male sexual dysfunction. The IIEF may be used as a 5- or 15-item version to assess male sexual function over a 4-week period. Single-item instruments have the advantage of high completion rates and low patient burden. On the other hand, multidimensional scales provide a broader and more complete assessment of disease severity. Despite such differences, similar results have been obtained across studies using these different measures. Symptom scales offer cost-efficient, validated measures for the identification of problems and also provide an assessment of past and current sexual function.

Physical examination

On the first visit for ED, routine office vital signs should be taken and recorded, in addition to height and weight. The physical examination should include a broad screening for medical comorbid conditions relevant to ED, such as body habitus and blood pressure measurements. The medical history should help direct the examination of the organ systems, including a focused cardiovascular and neurologic examination. The urologic examination should include an assessment of proper development of secondary sexual characteristics; an abdominal and inguinal examination; and scrotal examination with assessment of testicular size, consistency, and any abnormal palpable or visual scrotal findings. The examination of the penis should include an assessment of cutaneous sensation as well as screening for any cutaneous lesions, congenital anomalies, traumatic lesions, or plaques. The penis should also be examined for stretched penile length, presence of a suprapubic or pelvic fat pad affecting such length, and any evidence of phimosis or penile adhesions and scarring. A proper digital rectal examination (DRE) should document prostate size, consistency, and the presence or absence of masses. The evaluation of cutaneous sensation in the perineum is useful in identifying potential neurogenic causes of ED.

Basic laboratory evaluation

The goal of basic laboratory testing for ED is to perform cost-efficient screening for common systemic disorders. The Second International Consultation on Sexual Dysfunction (2004) Committee on Sexual Dysfunction Assessment in Men has recommended that fasting blood glucose, fasting cholesterol and lipid panel, and testosterone levels be obtained routinely as part of a basic ED evaluation. Other diagnostic laboratory values should be obtained when indicated specifically by the medical history and physical examination. These values include levels of prolactin, luteinizing hormone, follicle-stimulating hormone, prostate-specific antigen (PSA), complete blood count, and a thyroid function panel.

Vascular assessment and advanced (specialized) evaluation

Specialized evaluation of ED is often necessary to formally define its cause so that the practitioner may offer the most effective treatments. For many patients with ED, a detailed medical and sexual history, general medical examination with a focused genitourinary component, and a thorough review of all comorbidities and medications and laboratory evaluation can recognize the likely cause and allow the design of a treatment plan. Advanced or specialized evaluation is indicated if the initial treatments fail; if there is a diagnosis of PD; primary ED; history of pelvic or perineal trauma; in cases involving vascular or neurosurgical intervention; complicated endocrinopathy; complicated psychiatric disorder; complex relationship problems; when patients desire a better understanding of the underlying cause of the disease, especially as a marker of cardiovascular disease; and for medicolegal concerns.

Considerable research for the vascular assessment of ED over the past few decades has produced methods allowing for the quantitative and qualitative assessment of penile arterial and venoocclusive function. There are many tests available to evaluate penile vascular integrity, erectile function and anatomy, and venoocclusive function, including intracavernous injection (ICI) pharmacotesting, penile duplex Doppler ultrasonography (PDDU), dynamic infusion cavernosometry, and selective penile angiography, although the last two tests are typically not office based and are mentioned here for the sake of completeness.

The first-line in-office diagnostic test for vasculogenic ED has historically been the combination of ICI and visual sexual stimulation with direct assessment by an observer. This test bypasses both neurologic and hormonal influences and enables the direct evaluation of the vascular and physical status of the penis (ie, curvature). The ICI pharmacotest is simple to perform, minimally invasive, and can be done relatively quickly in the office. The most common intracavernosal vasoactive agent used for this test is prostaglandin-E1 (PGE1). The initial dose should be 10 to 20 mcg for injection. Once the intracavernosal injection is administered, a subjective assessment of response should be documented: patients should give a visual rating of their erection, comparing it with their best erection at home. This rating allows a subjective assessment to be made between an inadequate versus adequate in-office erection. Redosing of vasoactive agents may be necessary to achieve the best (or bedroom) quality erection (BQE) because patient anxiety during testing situations may prevent achieving their BQE.

A normal result produced from an ICI pharmacotest in neurologically intact patients may suggest the diagnosis of psychogenic ED. According to Rosen and colleagues, “comparison to other hemodynamic tests suggests a normal ICI pharmacotest is associated with normal veno-occlusive function (flow to maintain rigidity values of 0.5–3 mL/min).” If the response from ICI pharmacotesting is insufficient, it may be difficult to distinguish pure arterial insufficiency from venoocclusive dysfunction. An abnormal ICI pharmacotest raises several diagnostic questions that may require further study. The clinician should be aware that an ICI pharmacotest alone might be a misleading diagnostic test to exclude vascular ED unless performed in combination with PDDU. False-negative results can be found in almost 20% of patients with intermediate arterial inflow. False-positive results are also commonly known to occur. If the results are not thoroughly conclusive, or operative intervention is being considered, a second-line study is warranted.

PDDU

PDDU with vasoactive agents is the gold standard office-based diagnostic modality for determining the subtype of vasculogenic ED and in assessing the degree of its severity. The PDDU uses ICI and the assessment of penile vascular flow by color duplex Doppler ultrasound. It is the most informative and least invasive means of evaluating vasculogenic ED. This test can be performed easily in the office setting, allowing for a direct and a quantifiable evaluation of ED and a useful baseline before therapy. The test provides an objective measurement of penile hemodynamics, especially arterial inflow. Ultrasonography may reveal other penile problems or anatomic genital abnormalities, such as PD. Another indication for PDDU is in preoperative planning to provide critical data for operations involving plaque grafts, excisions, and even penile prostheses. It is also an effective test for demonstrating the classic arterial-lacunar fistula associated with high-flow arterial priapism.

To perform the study, one should have an understanding of the relevant penile anatomy and physiology of erection as well as their clinical correlations to ED. As with any procedure, a proper informed consent should be undertaken with patients outlining the purpose, alternatives, risks, and benefits of the testing process. The examination room should be comfortable and safe from intrusion and distraction. False-positive test results, displayed as a partial erection when there is no underlying vascular abnormality, may be secondary to patient anxiety, needle phobia, and/or inadequate medication dosage. Although PDDU is a noninvasive testing modality, ICIs do have potential morbidity that the examiner and patients should be aware of. Up to 20% of neurologically intact men report aching in the penis after PGE1 injections. Prolonged erection is another well-known risk and should be pharmacologically reversed with dilute intracorporeal phenylephrine injections to avoid priapism and its subsequent morbidity.

To perform the study in the office, a high-resolution ultrasonographic probe (7–10 MHz) is required for real-time ultrasonography and color pulsed Doppler, which allows the examiner to evaluate penile blood flow changes throughout the various phases of erection. With color-coded duplex sonography, the direction of blood flow is designated with red (toward the probe) or blue (away from the probe), making identification of the small cavernous vessels and recording of blood flow easier. Following intracorporeal injection of the vasoactive medication, baseline penile blood flow measurements are taken and subsequently measured at approximately 5-minute intervals until BQE is achieved, with redosing as necessary; resolution of the erection is then documented. Dosing information during the study is also useful as a basis for intracavernosal therapy. Studies have demonstrated the combination of injection plus manual self-stimulation leads to higher rates of rigid erections compared with injection alone. For recording purposes, a recent validated scale, the Erection Hardness Score (scale 1–4), can be used to standardize responses. If necessary, patients should be reexamined after self-stimulation.

The combination of oral sildenafil citrate and a visual erotic stimulation has also been studied as an effective noninvasive pharmacologic induction of erection. Studies are mixed regarding a comparable increase in the peak flow velocities as is achieved with ICI; the time frame is considerably longer, up to 90 minutes after an oral medication is given. This method may be useful in predicting treatment success with phosphodiesterase inhibitors (PDE5Is).

The important vascular parameters assessed by PDDU include cavernous artery diameters, peak systolic velocity (PSV), and end-diastolic arterial velocity. Normal cavernous arterial flow is defined as a PSV greater than 30 cm/s. A PSV measurement of less than 25 cm/s following ICI pharmacotesting and erotic stimuli has 100% sensitivity and 95% specificity in selecting patients with abnormal penile arteriography. Cavernous venous occlusive disease (CVOD) is defined as the inability to achieve and maintain adequate erections despite appropriate arterial inflow. Many investigators include another value that takes PSV into account. This value is the resistive index (RI). The formula for RI is as follows: RI = (PSV−EDV)/PSV, where EDV is the end-diastolic velocity. As the penile pressure equals or exceeds the diastolic pressure, the diastolic flow in the corpora (EDV) approaches zero and the value for RI approaches 1. During the initial tumescence phase, as well as in partial erections, the diastolic flow remains and the RI value is less than 1.0. Naroda and colleagues concluded that an RI of less than 0.75 predicts CVOD in nearly 95% of patients and that an RI greater than 0.9 to 1 is normal.

Doppler evaluations should include measurements for the evaluation of blood flow as well as any physical deformity noted (such as plaques and penile curvature). Once patients reach full tumescence (or BQE), gray-scale imaging for the presence of nonvascular abnormalities, such as plaques, curvature, and fibrosis, should be performed. At the conclusion of the testing period, it is important to ensure complete detumescence. Occasionally, this will require an intracorporeal injection of a diluted phenylephrine solution, which may be repeated at approximately 5-minute intervals as needed, until detumescence is achieved. Alternate agents, including epinephrine, have also been used, although some providers use cardiac monitoring during this process because of their potent and possibly systemic effects. These patients should be monitored for symptoms of acute hypertension, tachycardia, arrhythmias, and palpitations.

Neurologic evaluation

A patient’s medical history and physical examination develops the foundation for further neurologic evaluation of ED. Generally, many studies have shown that specialized testing for neurogenic ED is only indicated in cases of underlying neurogenic disease or when normal vascular studies and history suggest a neurologic cause. Neurogenic ED usually involves the following: known neurologic risk factors, younger age at presentation, acute onset of ED, and a normal or excellent response following ICI or oral PDE5 inhibitor pharmacotesting. Although specific neurologic tests are available, evidence suggests that they lack adequate sensitivity and reliability for routine clinical diagnosis. Various testing measures include nerve conduction velocity studies, biothesiometry, bulbocavernosus electromyography (EMG), and corpus cavernosa EMG. One study by Lefaucheur and colleagues did show a strong correlation between abnormal penile thermal sensory testing with the clinical diagnosis of neurogenic ED. However, further evaluations are necessary before this test may be brought into routine clinical practice.

Psychological evaluation

Most screening evaluations for ED can identify psychological risk factors, both independently and in coexistence with other organic risk factors. Patients (often times with their partners) with a psychogenic component or primary psychogenic sexual dysfunction should be referred to those practitioners with specific expertise (psychiatrists, clinical psychologists, and sex therapists) as part of their management.

Office treatment of ED

Once a diagnosis of ED has been made, the next step in management is to choose the appropriate treatment plan. There is no single treatment that is appropriate for every patient, and an individual treatment plan should be discussed with patients and their partners to assure the best level of satisfaction. Treatment can be considered in terms of first-, second-, and third-line therapies ( Box 2 ). First-line therapies include addressing reversible lifestyle issues (smoking cessation, healthy diet, alcohol moderation, and exercise), correcting hormonal abnormalities, and simple noninvasive therapies, such as oral medications and vacuum devices. Second-line therapies involve more invasive options, including intracorporeal injection therapy and intraurethral medication. Third-line treatments are not considered as office-based therapies, including surgical implantation of penile prosthesis and penile revascularization, and are typically reserved for those patients who cannot achieve satisfaction with less-invasive therapies (and are not discussed here).

Hormonal replacement therapy

Testosterone replacement therapy should only be used in the treatment of sexual dysfunction in the presence of symptomatic hypogonadism and is based on repeat values from early morning specimens of low serum testosterone levels ( Box 3 ). In these cases, testosterone replacement is used to maintain normal serum levels of testosterone in an attempt to restore potency and libido. In addition, maintenance of muscle mass and bone density may be achieved. Because of the potential side effects and relatively unpredictable serum levels obtained by oral administration of testosterone preparations, parenteral administration is preferred.

Currently, there are multiple testosterone formulations available for the treatment of hypogonadism. These formulations include intramuscular testosterone, buccal testosterone, topical gels and patches, and time-released testosterone pellets. Intramuscular testosterone is typically administered in dosages of 200 to 300 mg every 2 to 3 weeks. The amount and frequency of administration will vary with the individual and can be titrated. Topical and buccal administration must be used on a daily basis and may offer more stable hormone levels as compared with intramuscular therapy. Considerations of drug transference (ie, to spouse or children) and local skin reactions are issues of concern associated with topical agents. Testosterone pellets can also be placed under the skin (typically in the hip or buttocks), and their effectiveness lasts an average of 3 to 6 months. This form of treatment eliminates the need for daily treatment (improving convenience for some men) and eliminates the risk of transference.

Of note, all forms of testosterone replacement therapy may have some risks of increasing BPH symptoms, a rising PSA, and potentially increasing stroke risk. Regular close monitoring of hormone levels, PSA, CBC, and lipids is recommended. Finally, hormone replacement therapy is relatively contraindicated in men with untreated adenocarcinoma of the prostate or breast because administration may increase the rate of growth of their cancer. It would, therefore, seem prudent that before beginning testosterone replacement therapy in men older than 40 years, serum PSA levels, a DRE, and possibly transrectal ultrasound studies should be performed.

Hyperprolactinemia, another hormonal abnormality effecting sexual function, is treated by (1) cessation of medication causing hyperprolactinemia (eg, estrogens, alpha methyldopa), (2) administration of bromocriptine, or (3) surgical ablation or extirpation of a pituitary prolactin secreting tumor. Treatment with exogenous testosterone to restore the diminished levels of serum testosterone usually seen with this disorder has not been demonstrated to reverse the ED.

Oral agents: PDE5Is

In order for a normal erection to occur, an interrelated sequence of events that leads to vascular smooth muscle relaxation is necessary. Nitric oxide (NO), produced by vascular endothelial cells and nonadrenergic/noncholinergic neurons, is released and taken up by vascular smooth muscle cells. The level and activity of NO synthase is under the partial influence of testosterone. NO activates the enzyme guanylate cyclase, catalyzing the conversion of guanosine triphosphate into cyclic guanosine monophosphate (cGMP), which then acts as a second messenger with multiple intracellular effects; the most important effect with regard to erectile function is a decrease in intracellular calcium ion concentration, which facilitates smooth muscle relaxation. Unfortunately, the activity of cGMP is limited by its reconversion into GMP PDE5. PDE5Is suppress this pathway, resulting in higher intracellular levels of the second messenger, cGMP, and increased smooth muscle relaxation.

This important discovery has led to the development of specific PDE5I agents that are effective in the treatment of ED. These oral agents include sildenafil, vardenafil, tadalafil, and avanafil and are highly specific for PDE5, with efficacies approaching 60%. The pharmacokinetic properties of these agents differ, resulting in changes in their half-life (T1/2), which effects their period of efficacy. In addition, because there are differences in the degree of selectivity for the various agents, there is the possibility of cross-reactivity with different phosphodiesterases in other parts of the body, such as muscle and retina. As compared with other ED treatments, the PDE5I agents offer certain advantages: they are oral medications, and patients and partners place a high priority on this; they are well tolerated; they require stimulation; and daily agents improve spontaneity. The disadvantages include decreased efficacy in severe ED cases, as compared with other therapies; the need for systemic administration; an absolute contraindication with nitrates; delayed time of onset of action; high cost; and class-specific side effects (SEs), including headache, flushing, rhinitis, dyspepsia, occasional visual changes, and muscle pain.

Vacuum erection devices

Vacuum erection devices (VEDs) are a noninvasive and viable therapeutic option and may be offered as a first-line of treatment of patients with ED. Most VEDs have 3 common components: a vacuum cylinder, a vacuum pump that creates negative pressure within the chamber, and a constrictor or tension band that is applied to the base of the penis after the erection is achieved. The erection resulting from the vacuum device differs from the physiologically induced erection. The latter type is achieved by the initial relaxation of the corporal smooth musculature, thus allowing for engorgement of blood into the lacunar spaces. In the case of a vacuum-induced erection, corporal smooth muscle relaxation does not occur initially and blood is simply trapped in both the intracorporeal and extracorporeal compartments of the penis.

Complications associated with the use of a VED may include difficulty with ejaculation, penile pain, ecchymosis, hematomas, and petechiae (especially if the device is used for more than 30 minutes). Patients taking aspirin or warfarin sodium are more likely to develop vascular complications. Finally, only physician-prescribed, pressure-regulated VEDs should be used in the treatment of ED. Severe morbidities, including the development of PD and worsening of ED, are more likely to occur with the use of commercial, nonprescription, magazine-ad–type devices that lack the pop-off pressure mechanism that is incorporated in the prescription devices.