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Evaluation and Medical Management of Erectile Dysfunction

2006; Elsevier BV; Volume: 81; Issue: 3 Linguagem: Inglês

10.4065/81.3.385

1942-5546

Thomas J. Beckman, Haitham S. Abu-Lebdeh, Lance A. Mynderse,

Urinary Bladder and Prostate Research

Most men older than 60 years experience some degree of erectile dysfunction (ED). The physiology of erections is complex, with contributions from hormonal, vascular, psychological, neurologic, and cellular components. ED is strongly associated with cardiovascular risk factors, and this fact plays a major role in the prevention and treatment of ED. In this article, we review the evaluation of ED in terms of history, physical examination, and common laboratory studies. Additionally, we review major considerations when prescribing phosphodiesterase type 5 inhibitors and other medical treatments, including intraurethral alprostadil, penile injection therapy, and testosterone replacement. Most men older than 60 years experience some degree of erectile dysfunction (ED). The physiology of erections is complex, with contributions from hormonal, vascular, psychological, neurologic, and cellular components. ED is strongly associated with cardiovascular risk factors, and this fact plays a major role in the prevention and treatment of ED. In this article, we review the evaluation of ED in terms of history, physical examination, and common laboratory studies. Additionally, we review major considerations when prescribing phosphodiesterase type 5 inhibitors and other medical treatments, including intraurethral alprostadil, penile injection therapy, and testosterone replacement. Male sexual dysfunction includes erectile dysfunction (ED), decreased libido, anatomical abnormalities (eg, Peyronie disease), and ejaculatory dysfunction.1Morgentaler A A 66-year-old man with sexual dysfunction.JAMA. 2004; 291: 2994-3003Crossref PubMed Scopus (14) Google Scholar Erectile dysfunction is defined as the inability to achieve and maintain erections firm enough for sexual intercourse.2NIH Consensus Development Panel on Impotence NIH Consensus Conference: impotence.JAMA. 1993; 270: 83-90Crossref PubMed Scopus (1127) Google Scholar ED is common, affecting millions of men in the United States.2NIH Consensus Development Panel on Impotence NIH Consensus Conference: impotence.JAMA. 1993; 270: 83-90Crossref PubMed Scopus (1127) Google Scholar, 3Laumann EO Paik A Rosen RC Sexual dysfunction in the United States: prevalence and predictors [published correction appears in JAMA. 1999;281:1174].JAMA. 1999; 281: 537-544Crossref PubMed Scopus (4081) Google Scholar The Massachusetts Male Aging Study showed that ED increases with age; approximately 50% of men experienced ED at age 50 years, and the prevalence of ED increased to nearly 70% at age 70 years.4Feldman HA Goldstein I Hatzichristou DG Krane RJ McKinlay JB Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study.J Urol. 1994; 151: 54-61Abstract Full Text PDF PubMed Scopus (4125) Google Scholar Erectile physiology includes hormonal, vascular, psychological, neurologic, and cellular components. Testosterone is primarily responsible for maintaining sexual desire (libido), and hypogonadism is sometimes associated with ED. Other hormonal causes of ED include hyperthyroidism and prolactinomas.5Spark RF White RA Connolly PB Impotence is not always psychogenic: newer insights into hypothalamic-pituitary-gonadal dysfunction.JAMA. 1980; 243: 750-755Crossref PubMed Scopus (135) Google Scholar Penile blood supply begins at the internal pudendal artery, which branches into the penile artery, ultimately giving rise to the cavernous, dorsal, and bulbourethral arteries.6Andersson KE Wagner G Physiology of penile erection.Physiol Rev. 1995; 75: 191-236Crossref PubMed Scopus (1028) Google Scholar Psychogenic erections, triggered by fantasy or visual stimulation, are probably mediated by sympathetic input from the thoracolumbar chain (T11 to L2).6Andersson KE Wagner G Physiology of penile erection.Physiol Rev. 1995; 75: 191-236Crossref PubMed Scopus (1028) Google Scholar, 7Fowler CJ The neurology of male sexual dysfunction and its investigation by clinical neurophysiological methods.Br J Urol. 1998; 81: 785-795Crossref PubMed Google Scholar Reflex erections are caused by tactile stimulation and are mediated by the parasympathetic nervous system (S2 to S4).6Andersson KE Wagner G Physiology of penile erection.Physiol Rev. 1995; 75: 191-236Crossref PubMed Scopus (1028) Google Scholar, 7Fowler CJ The neurology of male sexual dysfunction and its investigation by clinical neurophysiological methods.Br J Urol. 1998; 81: 785-795Crossref PubMed Google Scholar Overall, parasympathetic signal is responsible for erection, and sympathetic signal is responsible for ejaculation.6Andersson KE Wagner G Physiology of penile erection.Physiol Rev. 1995; 75: 191-236Crossref PubMed Scopus (1028) Google Scholar, 8Naylor AM Endogenous neurotransmitters mediating penile erection.Br J Urol. 1998; 81: 424-431Crossref PubMed Google Scholar Sexual arousal and parasympathetic signal to the penis initiate intracellular changes necessary for erection (Figure 1).6Andersson KE Wagner G Physiology of penile erection.Physiol Rev. 1995; 75: 191-236Crossref PubMed Scopus (1028) Google Scholar, 8Naylor AM Endogenous neurotransmitters mediating penile erection.Br J Urol. 1998; 81: 424-431Crossref PubMed Google Scholar, 9Corbin JD Francis SH Webb DJ Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction.Urology. 2002; 60: 4-11Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar Endothelial cells and nerve terminals release nitric oxide,10Rajfer J Aronson WJ Bush PA Dorey FJ Ignarro LJ Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission.N Engl J Med. 1992; 326: 90-94Crossref PubMed Scopus (892) Google Scholar which in turn increases cyclic guanosine monophosphate (cGMP) levels.8Naylor AM Endogenous neurotransmitters mediating penile erection.Br J Urol. 1998; 81: 424-431Crossref PubMed Google Scholar Generous levels of cGMP cause relaxation of arterial and cavernosal smooth muscle and increased penile blood flow.9Corbin JD Francis SH Webb DJ Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction.Urology. 2002; 60: 4-11Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar As the intracavernosal pressure increases, penile emissary veins are compressed, thus restricting venous return from the penis.6Andersson KE Wagner G Physiology of penile erection.Physiol Rev. 1995; 75: 191-236Crossref PubMed Scopus (1028) Google Scholar The combination of increased arterial flow and decreased venous return results in erection. This process is reversed by the activity of type 5 cGMP phosphodiesterase (PDE), which breaks down cGMP,11Beavo JA Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms.Physiol Rev. 1995; 75: 725-748Crossref PubMed Scopus (1642) Google Scholar resulting in cessation of erection. ED is strongly associated with cardiovascular risk factors. In fact, The Health Professions Follow-up Study showed that risk factors for ED and cardiovascular disease were nearly identical and that physically active men had a 30% lower risk of ED than inactive men.12Bacon CG Mittleman MA Kawachi I Giovannucci E Glasser DB Rimm EB Sexual function in men older than 50 years of age: results from the health professions follow-up study.Ann Intern Med. 2003; 139: 161-168Crossref PubMed Scopus (626) Google Scholar Therefore, men with diabetes, hypertension, and coronary artery disease have an increased risk of ED.13Johannes CB Araujo AB Feldman HA Derby CA Kleinman KP McKinlay JB Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts Male Aging Study.J Urol. 2000; 163: 460-463Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar Not surprisingly, data from a randomized controlled trial by Esposito et al14Esposito K Giugliano F Di Palo C et al.Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial.JAMA. 2004; 291: 2978-2984Crossref PubMed Scopus (682) Google Scholar show that obese men who lose weight through diet and exercise experience significant improvements in erectile function. Certain questions should be routinely asked when taking a history from patients with ED (Table 1).15Wein AJ Van Arsdalen KN Drug-induced male sexual dysfunction.Urol Clin North Am. 1988; 15: 23-31PubMed Google Scholar Questions should elicit common ED risk factors such as cardiovascular disease, smoking, diabetes, hypertension, hyperlipidemia, prescription medications, alcohol abuse, recreational drug use, and disorders of mood and sleep. Additionally, validated questionnaires such as the International Index of Erectile Function16Rosen RC Riley A Wagner G Osterloh IH Kirkpatrick J Mishra A The International Index of Erectile Function (IIEF): a multidimensional scale for assesment of erectile dysfunction.Urology. 1997; 49: 822-830Abstract Full Text PDF PubMed Scopus (4336) Google Scholar may complement the sexual history by assessing baseline erectile function. Finally, it is important to differentiate ED from other forms of sexual dysfunction, including decreased libido and ejaculatory dysfunction.TABLE 1Essential Questions to Ask When Taking a History From Patients With Erectile Dysfunction*ED = erectile dysfunction; PDE-5 = phosphodiesterase type 5.QuestionCommentDo you have difficulty obtaining erections or difficulty with orgasms and ejaculation?Sexual dysfunction includes a variety of diagnoses, and it is important to determine whether the patient's primary complaint is ED.How often do you achieve erections?Often patients are not satisfied with the quality of their erections, but if patients can achieve erections adequately firm for vaginal penetration most of the time, their complaints are not classically defined as ED.Are your erections firm enough for vaginal penetration?Did your ED occur suddenly?The sudden onset of ED and the persistence of nocturnal erections indicate an inorganic (psychogenic) etiology. In such cases, physicians should explore the psychosocial context of the patient's sexual history, such as whether the patient feels anxious or depressed or whether the patient is experiencing difficulties in his interpersonal relationship(s).Do you have nocturnal erections?Do you feel anxious or depressed?Do you and your partner have a satisfactory relationship?Do you have a desire to engage in sexual activity?Decreased sexual desire may indicate hypogonadism; if patients are not interested in sexual activity, serum testosterone levels should be assessed. Mood disorders should also be considered.Do you have penile curvature or pain with erections?A positive response to this question may indicate Peyronie disease, which is sometimes detected on physical examination. Identifying Peyronie disease is important because it precludes intraurethral alprostadil and penile injection therapy.Can you engage in vigorous physical activity without chest pain or unusual dyspnea?PDE-5 inhibitors will be considered in most patients. Moreover, sexual activity is associated with cardiovascular stress. Hence, a history should be obtained to identify undiagnosed ischemic heart disease or to assess the stability of known ischemic heart disease.What medications are you taking?Numerous medications are associated with ED.15Wein AJ Van Arsdalen KN Drug-induced male sexual dysfunction.Urol Clin North Am. 1988; 15: 23-31PubMed Google Scholar Although it is difficult to remember all these medications, the most common ones are antihypertensives and psychotropics. Identifying the use of medications inhibiting cytochrome P-450 (eg, ritonavir) is important because these medications increase plasma levels of PDE-5 inhibitors. Identifying the use of α1-adrenergic antagonist medications is also important since combining these with PDE-5 inhibitors can cause profound hypotension. An absolute contraindication to PDE-5 inhibitors is the concurrent use of nitrates (eg, isosorbide mononitrate).How much alcohol do you consume?Substance abuse, including alcoholism, is commonly overlooked as a cause of ED.Do you use illegal drugs?Which treatments for ED have you already tried?Knowing which medications patients have tried will help physicians decide the next best therapeutic plan.Do you have a history of diseases involving your heart, blood vessels, nervous system, or hormones?It is important to identify common risk factors for ED.Do you have a history of hypertension, hyperlipidemia, diabetes, or tobacco abuse? Do you have a history of penile trauma or genitourinary surgery?Do you snore, have difficulty sleeping, or feel poorly rested?Do you ride a bicycle regularly?Prolonged and frequent bicycle riding can cause excessive pudendal pressure, leading to ED.* ED = erectile dysfunction; PDE-5 = phosphodiesterase type 5. Open table in a new tab A complete multisystem examination may reveal indicators of cardiovascular disease (eg, obesity, hypertension, or femoral arterial bruits), endocrinopathies (eg, visual field defects, thyromegaly, or gynecomastia), or neurologic abnormalities (eg, decreased sphincter tone, absent bulbocavernous reflex, or saddle anesthesia). The penis shouldbe palpated in the stretched position to detect fibrous plaques consistent with Peyronie disease, which may be present on the dorsum and base of the penis. The testicles should be evaluated for masses, decreased size, and soft consistency, indicating malignancy and hypogonadism. Examining patients with ED is a good opportunity to perform a digital rectal examination for prostate cancer screening and to assess for benign glandular enlargement. Although we favor disease-specific testing, the serum testosterone level is frequently obtained in our health practice. If a patient has hypogonadism, serum prolactin and luteinizing hormone (LH) levels should be assessed. If the prolactin level is elevated and/or the LH level is not elevated, then a magnetic resonance image of the brain should be obtained to rule out a pituitary adenoma. Additional serologies that are useful and pertain to ED risk factors include fasting glucose, fasting lipids, and thyrotropin.1Morgentaler A A 66-year-old man with sexual dysfunction.JAMA. 2004; 291: 2994-3003Crossref PubMed Scopus (14) Google Scholar When discussing treatments for ED, it is important to ensure that men and their partners have ample opportunities to ask questions and explore the risks and benefits of various treatment options. Ultimately, therapies should be tailored to individual patients through shared decision making. Phosphodiesterase type 5 (PDE-5) inhibitors are the first-line treatment for most men with ED. Phosphodiesterase type 5 inhibitors have revolutionized the treatment of ED since the introduction of sildenafil in 1998,1Morgentaler A A 66-year-old man with sexual dysfunction.JAMA. 2004; 291: 2994-3003Crossref PubMed Scopus (14) Google Scholar, 17Boolell M Gepi-Attee S Gingell JC Allen MJ Sildenafil: a novel effective oral therapy for male erectile dysfunction.Br J Urol. 1996; 78: 257-261Crossref PubMed Scopus (522) Google Scholar and experts observed that these medications have significantly affected (both positively and negatively) the sexual culture of aging people.1Morgentaler A A 66-year-old man with sexual dysfunction.JAMA. 2004; 291: 2994-3003Crossref PubMed Scopus (14) Google Scholar, 18Flower R Lifestyle drugs: pharmacology and the social agenda.Trends Pharmacol Sci. 2004; 25: 182-185Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 19Potts A Grace V Gavey N Vares T “Viagra stories”: challenging ‘erectile dysfunction.’.Soc Sci Med. 2004; 59: 489-499Crossref PubMed Scopus (104) Google Scholar, 20Low WY Zulkifli SN Wong YL Tan HM What Malaysian women believe about Viagra: a qualitative inquiry.Aging Male. 2002; 5: 57-63Crossref PubMed Scopus (11) Google Scholar Initially, there were concerns about cardiovascular risks associated with PDE-5 inhibitors, but studies have since shown that these medications are generally safe,21Morales A Gingell C Collins M Wicker PA Osterloh IH Clinical safety of oral sildenafil citrate (VIAGRA™) in the treatment of erectile dysfunction.Int J Impot Res. 1998; 10: 69-73Crossref PubMed Scopus (454) Google Scholar even in patients with stable coronary artery disease.22Arruda-Olson AM Mahoney DW Nehra A Leckel M Pellikka PA Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial.JAMA. 2002; 287: 719-725Crossref PubMed Scopus (179) Google Scholar, 23DeBusk R Drory Y Goldstein I et al.Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.Am J Cardiol. 2000; 86: 175-181Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 24Herrmann HC Chang G Klugherz BD Mahoney PD Hemodynamic effects of sildenafil in men with severe coronary artery disease.N Engl J Med. 2000; 342: 1622-1626Crossref PubMed Scopus (271) Google Scholar, 25Wysowski DK Farinas E Swartz L Comparison of reported and expected deaths in sildenafil (Viagra) users.Am J Cardiol. 2002; 89: 1331-1334Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Three PDE-5 inhibitors are currently available: sildenafil, vardenafil, and tadalafil (Table 2). These medications inhibit type 5 cGMP PDE, thereby increasing cGMP levels and tipping the physiological balance in favor of erection (Figure 1). While head-to-head comparative trials and meta-analyses are not currently available, it appears that each of these medications is equally efficacious. Nonetheless, tadalafil has a longer half-life than sildenafil or vardenafil, which affords more spontaneity to tadalafil users (up to 36 hours). Patients should be instructed to take PDE-5 inhibitors at least 1 hour before sexual activity, and sildenafil should be taken on an empty stomach. Patients should also realize that PDE-5 inhibitors will not cause erections in the absence of sexual arousal (unlike intraurethral alprostadil and penile injection therapy). Remarkably, patients in whom PDE-5 inhibitor therapy initially fails often experience success with these medications after being educated about appropriate use.26McCullough AR Barada JH Fawzy A Guay AT Hatzichristou D Achieving treatment optimization with sildenafil citrate (Viagra) in patients with erectile dysfunction.Urology. 2002; 60: 28-38Abstract Full Text Full Text PDF PubMed Scopus (156) Google ScholarTABLE 2Phosphodiesterase Type 5 InhibitorsAdapted from www.MayoClinic.com with permission from Mayo Foundation for Medical Education and Research.Generic nameStrength (mg)Onset (min)Duration (h)Common reactionsSildenafil25, 50, 10030-60, without food4Headache, flushing, dyspepsia, diarrhea, rhinitis, nausea, blue-tinged vision, dizziness, rashVardenafil2.5, 5, 10, 2030-60, with or without food4Headache, flushing, dyspepsia, nausea, rhinitis, dizziness, back pain, myalgias/arthralgiasTadalafil5, 10, 2030, with or without food24-36Headache, dyspepsia, back/limb pain, myalgias, rhinitis, flushing Open table in a new tab When prescribing PDE-5 inhibitors, we usually begin with doses in the middle range because adverse effects tend to be dose dependent. Patients are then monitored, and doses are adjusted as needed. For example, we would begin with sildenafil at the 50-mg dose. If 50 mg is only partially effective or ineffective, then the dose is increased to 100 mg; if 50 mg is effective but produces serious adverse effects, then the dose is decreased to 25 mg. Common adverse effects of the PDE-5 inhibitors, which are due to the presence of PDE throughout the body,9Corbin JD Francis SH Webb DJ Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction.Urology. 2002; 60: 4-11Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar are headache, flushing, gastric upset, diarrhea, nasal congestion, and light-headedness.9Corbin JD Francis SH Webb DJ Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction.Urology. 2002; 60: 4-11Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 27Goldstein I Lue TF Padma-Nathan H Rosen RC Steers WD Wicker PA Sildenafil Study Group Oral sildenafil in the treatment of erectile dysfunction [published correction appears in N Engl J Med. 1998;339:59].N Engl J Med. 1998; 338: 1397-1404Crossref PubMed Scopus (2034) Google Scholar A unique reaction to sildenafil is blue-tinged vision, probably related to the activity of sildenafil on PDE-6 in the retina.9Corbin JD Francis SH Webb DJ Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction.Urology. 2002; 60: 4-11Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar This reaction resolves with discontinuation of therapy. Of note, some varieties of retinitis pigmentosa have a PDE-6 gene defect. Consequently, patients with retinitis pigmentosa should not be prescribed medications from the PDE-5 inhibitor class. A contraindication to PDE-5 inhibitors is nitrate therapy.28Cheitlin MD Hutter Jr, AM Brindis RG et al.Use of sildenafil (Viagra) in patients with cardiovascular disease [published correction appears in J Am Coll Cardiol. 1999;34:1850].J Am Coll Cardiol. 1998; 33: 273-282Abstract Full Text Full Text PDF Scopus (409) Google Scholar Indeed, physicians who treat acute coronary syndromes should withhold nitrate therapy within 24 hours of initiating sildenafil28Cheitlin MD Hutter Jr, AM Brindis RG et al.Use of sildenafil (Viagra) in patients with cardiovascular disease [published correction appears in J Am Coll Cardiol. 1999;34:1850].J Am Coll Cardiol. 1998; 33: 273-282Abstract Full Text Full Text PDF Scopus (409) Google Scholar and vardenafil and within 48 hours of tadalafil. Physicians should also be cautious about prescribing PDE-5 inhibitors to patients with poorly controlled blood pressure or those receiving multidrug antihypertensive regimens.28Cheitlin MD Hutter Jr, AM Brindis RG et al.Use of sildenafil (Viagra) in patients with cardiovascular disease [published correction appears in J Am Coll Cardiol. 1999;34:1850].J Am Coll Cardiol. 1998; 33: 273-282Abstract Full Text Full Text PDF Scopus (409) Google Scholar In patients with known or suspectedischemic heart disease, cardiac stress testing is useful in stratifying the risk of PDE-5 inhibitor therapy; patients who achieve 5 to 6 metabolic equivalents without ischemia probably sustain low risk from engaging in sexual activity.28Cheitlin MD Hutter Jr, AM Brindis RG et al.Use of sildenafil (Viagra) in patients with cardiovascular disease [published correction appears in J Am Coll Cardiol. 1999;34:1850].J Am Coll Cardiol. 1998; 33: 273-282Abstract Full Text Full Text PDF Scopus (409) Google Scholar For a more detailed discussion on managing patients with coexisting ED and cardiovascular disease, we recommend the recent guidelines published by the Princeton Consensus Panel.23DeBusk R Drory Y Goldstein I et al.Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.Am J Cardiol. 2000; 86: 175-181Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar Researchers have postulated a causal relationship between benign prostatic hyperplasia (BPH) and ED. 29McVary KT McKenna KE The relationship between erectile dysfunction and lower urinary tract symptoms: epidemiological, clinical, and basic science evidence.Curr Urol Rep. 2004; 5: 251-257Crossref PubMed Scopus (65) Google Scholar Moreover, as the aging population increases, the prevalence and treatment of BPH and ED will increase. Therefore, it is important to recognize that combining PDE-5 inhibitors with medications from the α1-adrenergic antagonist class (eg, tamsulosin) can lead to profound hypotension. Considerations when combining these medications are as follows: (1) sildenafil at doses higher than 25 mg should not be taken within 4 hours of any α1-adrenergic antagonist, (2) vardenafil should not be taken with any α1-adrenergic antagonist, and (3) tadalafil should not be taken with any α1-adrenergic antagonist except tamsulosin at the 0.4-mg dose. Treatment options for patients in whom PDE-5 inhibitors have failed or for those who cannot take PDE-5 inhibitors include intraurethral alprostadil and penile injection therapy. These medications are generally more effective than PDE-5 inhibitors, but their obvious drawbacks are inconvenience. Contraindications to these treatments include blood cell dyscrasias (ie, sickle cell disease, leukemia, or multiple myeloma) and penile deformity, especially Peyronie disease. Anticoagulation is an additional contraindication to penile injection therapy. Currently, information regarding the safety of combining PDE-5 inhibitors and injection therapy is inadequate, and hence coadministration is not advised. Intraurethral alprostadil is effective in men of all ages and with a variety of causes of ED.30Padma-Nathan H Hellstrom WJ Kaiser FE Medicated Urethral System for Erection (MUSE) Study Group et al.Treatment of men with erectile dysfunction with transurethral alprostadil.N Engl J Med. 1997; 336: 1-7Crossref PubMed Scopus (502) Google Scholar Intraurethral alprostadil is inserted into the tip of the penis with an applicator. Patients should be instructed on the application technique. Because of the risk of syncope, the first dose should be observed by a health care professional. The most common adverse effect is urethral and genital pain,30Padma-Nathan H Hellstrom WJ Kaiser FE Medicated Urethral System for Erection (MUSE) Study Group et al.Treatment of men with erectile dysfunction with transurethral alprostadil.N Engl J Med. 1997; 336: 1-7Crossref PubMed Scopus (502) Google Scholar and hypotension can occur. As with all medical ED treatments, patients are educated about priapism, and they are instructed to present to an emergency department if they have erections persisting for more than 4 hours. Intracavernosal penile injection is the most effective medical therapy for ED. Penile injection therapy is efficacious and generally safe.31Govier FE McClure RD Weissman RM Gibbons RP Pritchett TR Kramer-Levien D Experience with triple-drug therapy in a pharmacological erection program.J Urol. 1993; 150: 1822-1824PubMed Google Scholar, 32Virag R Shoukry K Floresco J Nollet F Greco E Intercavernous self-injection of vasoactive drugs in the treatment of impotence: 8-year experience with 615 cases.J Urol. 1991; 145: 287-292Abstract Full Text PDF PubMed Google Scholar A study of 170 impotent men treated with triple-drug injection therapy revealed that the most frequent adverse effects were scarring (4.2%), pain (3.5%), and priapism (1.7%).31Govier FE McClure RD Weissman RM Gibbons RP Pritchett TR Kramer-Levien D Experience with triple-drug therapy in a pharmacological erection program.J Urol. 1993; 150: 1822-1824PubMed Google Scholar At the Mayo Clinic in Rochester, Minn, we use a combination of alprostadil, papaverine, and phentolamine (triple therapy). The mechanism of action of these medications is to increase penile blood flow. Specifically, alprostadil and papaverine cause relaxation of cavernosal smooth muscle and penile blood vessels, and phentolamine antagonizes α-adrenoreceptors. As for intraurethral alprostadil, patient instruction is required, and the initial dose is administered with supervision by a health care professional. Although many patients are hesitant to attempt penile injection, this method is generally associated with minimal discomfort. Various hormonal therapies, including testosterone, were once widely used to treat ED. The penile nitric oxide pathway is testosterone dependent, and thus it is necessary to screen for low serum testosterone levels in men in whom medical therapy with sildenafil fails or whose presentation suggests hypogonadism. In hypogonadal men, combining PDE-5 inhibitor therapy with testosterone is often effective. Moreover, testosterone replacement alone increases sexual interest, nocturnal erections, and frequency of sexual intercourse. Nevertheless, testosterone replacement has not been shown to improve erectile function in men with normal serum testosterone levels.33O'Carroll R Bancroft J Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study.Br J Psychiatry. 1984; 145: 146-151Crossref PubMed Scopus (145) Google Scholar Testosterone is available by injection, skin patch, topical gel, or buccal oral tablets. Testosterone therapy is associated with potential risks. For example, prolonged use of high-dose, orally active 17-α-alkyl androgens (eg, methyltestosterone) is associated with hepatic neoplasms, fulminant hepatitis, and cholestatic jaundice. Other risks of exogenous testosterone therapy include gynecomastia, alterations in lipid profile (mainly reduced high-density lipoprotein cholesterol levels), erythropoietin-mediated polycythemia, edema, sleep apnea, hypertension, infertility (via suppression of spermatogenesis) and BPH. Exogenous testosterone also increases the risk of developing prostate carcinoma. Although testosterone replacement may not cause prostate carcinoma, it could stimulate the growth of existing occult prostate cancer. Thus, all men should be carefully screened for prostate cancer with digital rectal examination and serum prostate-specific antigen (PSA) before initiating exogenous testosterone. Hypogonadism is diagnosed by the presence of hypogonadal symptoms (such as decreased libido, cognitive decline, and generalized muscle weakness) and by morning fasting total testosterone levels lower than 200 ng/dL on at least 2 separate occasions. We prefer treatment with topical testosterone (1% gel) at a starting dose of 5 g/d, applied to the shoulders, upper arms, or abdomen. A total testosterone level may be reassessed as early as 14 days after initiation of treatment. The patient's therapeutic response and testosterone level are assessed at 3 months, at which time decisions are made regarding the continuation of testosterone and possible dose adjustments. The goal of testosterone replacement is to bring serum testosterone levels into the low or middle-normal range. Although patients receiving testosterone replacement who have normal serum testosterone levels should not be at risk for adverse effects, monitoring such patients is essential. At baseline, we determine whether the patient has a history of prostate cancer, BPH, obstructive sleep apnea, liver disease, hypertension, or hyperlipidemia. Baseline testing includes serum PSA, complete blood cell count, lipids, and liver transaminases. Prostate-related symptoms and PSA should be assessed at 6 months and then annually, and patients with elevated or increasing PSA levels should not be treated with testosterone.34American Association of Clinical Endocrinologists American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update.Endocr Pract. 2002; 8: 440-456PubMed Google Scholar Hematocrit and lipids should be monitored biannually for the first 18 months and annually thereafter; testosterone therapy should be decreased or discontinued if hematocrit values are greater than 50%.34American Association of Clinical Endocrinologists American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update.Endocr Pract. 2002; 8: 440-456PubMed Google Scholar Finally, patient response to therapy and adverse effects are monitored quarterly during the first year of treatment.34American Association of Clinical Endocrinologists American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update.Endocr Pract. 2002; 8: 440-456PubMed Google Scholar For a complete review of this topic, we recommend the American Association of Clinical Endocrinologists' guidelines for the treatment of hypogonadism in adult men.34American Association of Clinical Endocrinologists American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update.Endocr Pract. 2002; 8: 440-456PubMed Google Scholar Although a detailed description of nonmedical ED treatments is beyond the scope of this review, they include topical vacuum pump devices and surgically inserted inflatable penile implants. Penile pumps work by creating a vacuum around the penis, thus drawing blood into the penis. Once the penis is engorged with blood, an elastic ring is placed over the base of the penis, and the pump is removed. Importantly, patients should use vacuum pump devices with vacuum limiters, which prevent negative pressure injury to the penis. Urologic referral for penile implants is generally not offered unless medical treatments have failed, including maximal strength injection therapy. Before electing to undergo surgery for a penile prosthesis, patients should consider the various types of prostheses, the possible consequences of surgery, and the potential for reduced effectiveness of other therapies if the prosthesis is subsequently removed. ED is very common among aging men. When evaluating patients with ED, it is important to obtain a thorough history, which will usually reveal the etiology of ED and the potential cardiovascular risk associated with taking medications from the PDE-5 inhibitor class. Sudden-onset ED and the persistence of nocturnal erections should alert physicians to the possibility of psychogenic (inorganic) ED. Although the physiology of penile erections is complex, most treatments, including PDE-5 inhibitors, intraurethral alprostadil, and penile injection, work by relaxing vascular smooth muscle and increasing penile blood flow. Phosphodiesterase type 5 medications have revolutionized the treatment of ED and are safe and effective for most patients. Penile injection therapy is generally offered to patients in whom PDE-5 inhibitors have failed or who cannot take PDE-5 inhibitors. Testosterone replacement therapy is reserved for patients with documented hypogonadism, and such patients should be counseled about the potential risks of androgen replacement.