clinical practice The new england journ l o f medicine nengl jmed 357;24 www.nejm.org 2472 december 13, 2007Erectile Dysfunction Kevin T. McVary, M.D.From Northwestern University FeinbergSchool of Medicine, Chicago. Address reprintrequests to Dr. McVary at the FeinbergSchool of Medicine, NorthwesternUniversity, Department of Urology, Tarry16-749, 303 E. Chicago Ave., Chicago, IL60611, or at email@example.com. N Engl J Med 2007;357:2472-81.Copyright © 2007 Massachusetts Medical Society. A 65-year-old man presents to an outpatient clinic, reporting that he can no longer maintain an erection sufficient for intercourse. His medical history includes wellcontrolled hypertension and stable coronary artery disease. He smokes a pack of cigarettes daily. His medications include atenolol and low-dose aspirin (81 mg daily). On physical examination, his body-mass index (the weight in kilograms divided by the square of the height in meters) is 31; the examination is otherwise unremarkable, with normal external genitalia and no loss of body hair. How should he be evaluated and treated? The Clinical Problem Erectile dysfunction is defined as the consistent inability to attain or maintain a penile erection of sufficient quality to permit satisfactory sexual intercourse.1 The prevalence of this condition increases with age. In a large cross-sectional, communitybased study,2 among men between the ages of 40 and 49 years, the prevalence of complete or severe erectile dysfunction was 5%, and the prevalence of moderate erectile dysfunction was 17%; among men between the ages of 70 and 79 years, these rates were 15% and 34%, respectively. It has been estimated that the worldwide prevalence of erectile dysfunction will be 322 million cases by the year 2025.3,4 Erectile dysfunction was once considered to be psychogenic in origin and was frequently neglected by health care providers. More recently, there has been increasing recognition of the many physiological causes of the condition and of the potential for therapy to improve a patient’s quality of life, self-esteem, and ability to maintain intimate relationships. Physiological Factors Sexual function is a complex process involving both biologic and psychological factors. Erections result from a combination of neurotransmission and vascular smoothmuscle responses that culminate in increased arterial inflow and signaling between endothelial-lined cavernosal sinusoids and the underlying smooth-muscle cells. Nitric oxide that is produced by the parasympathetic nonadrenergic, noncholinergic neurons and endothelial cells triggers a molecular cascade that results in the relaxation of smooth-muscle cells. This process occludes venous return through passive compression of the subtunical venules, resulting in an erection (Fig. 1). The ability to achieve or maintain an erection may be compromised by factors affecting any steps in this pathway . Conditions that are associated with erectile dysfunction include the metabolic syndrome,6 lower urinary tract symptoms of benign prostatic hyperplasia,7,8 cardiovascular disease,9 central neuropathologic conditions (e.g., Parkinson’s disease and This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. The New England Journal of MedicineDownloaded from nejm.org at CENTRALE FACOLTA MED E CHIRURGIA on October 25, 2012. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. clinical practice nengl jmed 357;24 www.nejm.org december 13, 2007 2473hemorrhagic or ischemic stroke), tobacco use (with the prevalence of erectile dysfunction twiceas high among smokers as among nonsmokers),10 diabetes mellitus,11 and other endocrine disorders,including hypogonadism and hyperprolactinemia (Table 1). Atherosclerosis, with associatedendothelial dysfunction, develops in the penile circulation as it does elsewhere; more than twothirds of patients with coronary artery diseasehave symptoms of erectile dysfunction before the onset of coronary symptoms.9 For patients with diabetes, the risk of erectile dysfunction increases with the duration of the condition and with increasing levels of glycatedhemoglobin.11 Medications (both prescription and nonprescription) maycause or contribute to erectile dysfunction in as many as 25% of men who present for evaluation. Strategies and Evidence EvaluationErectile dysfunction may be the presenting symptomof serious medical problems. The evaluation should begin with a review of the patient’s medical, sexual, and psychosocial history. The reviewof the medical history should include attention to previous events that may have affected vascular or neurologic function, such as pelvic trauma, surgery, or irradiation. Given the recognition of the relationship between lower urinary tract symptoms and erectile dysfunction, it is advisable to screen patients for irritative and obstructive voiding symptoms (e.g., with the International Pros- Mechanisms of Erectile Dysfunction Molecular Mechanism of Penile Smooth-Muscle Relaxation.Outflow from the parasympathetic nervous system leads to relaxation of the cavernous sinusoids in two ways, both of which increase the concentration of nitric oxide (NO) in smooth-muscle cells. First, nitric oxide is the neurotransmitterin nonadrenergic, noncholinergic (NANC) fibers; second, stimulation of endothelial nitric oxide synthase (eNOS) through cholinergic output causes increased production of nitric oxide. The nitric oxide produced in the endothelium then diffuses into the smooth-muscle cells. With the increase in nitric oxide content, the smooth-muscle cell decreases its intracellular calcium concentration through a pathway mediated by cyclic guanosine monophosphate (cGMP), which leads to relaxation. A separate mechanism that decreases the intracellular calcium level is mediated by cyclic adenosine monophosphate (cAMP). With increased cavernosal blood flow, as well as increased levels of vascular endothelial growth factor (VEGF), the endothelial release of nitric oxide is further sustained through the phosphatidylinositol 3 (PI3) kinase pathway. Active treatments (red boxes) include drugs that affect the cGMP pathway (phosphodiesterase [PDE] type 5 inhibitors and guanylyl cyclase agonists), the cAMP pathway (alprostadil), or both pathways (papaverine), along with neural-tone mediators (phentolamine and Rho kinase inhibitors). Agents that are being developed include guanylyl cyclase agonists (to bypass the need for endogenous nitric oxide) and Rhokinase inhibitors (to inhibit tonic contraction of smooth-muscle cells mediated through endothelin). Parasympathetic outflow is impaired in patients with diabetes, depression, and central and peripheral neuropathic diseases that inhibit neural output; outflow is also impaired by destruction of the nonadrenergic, noncholinergic nerves themselves. Exposure to tobacco smoke and lower urinary tract symptoms of benign prostatic hyperplasia are associated with an increase in outflow from the sympathetic nervous system that inhibits relaxation forces. Lower urinary tract symptoms may also impair the nitric oxide content in the penis, prostate, and bladder and account for the association between such symptoms and erectile dysfunction. Diabetes, the metabolic syndrome, hyperlipidemias, atherosclerosis, and moking also directly reduce the activity of nitric oxide synthase and induce apoptosis of endothelial and smoothmuscle cells. PGF denotes prostaglandin F, PGE prostaglandin E, GPCR G-protein–coupled receptor, α1 α-adrenergic receptor, and GTP guanosine triphosphate. The New England Journal of Medicine Downloaded from nejm.org at CENTRALE FACOLTA MED E CHIRURGIA on October 25, 2012. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. clinical practice nengl jmed 357;24 www.nejm.org december 13, 2007 2475obvious causes suggests a possible social or psychologicalcause. Both the patient and his sexual partner shouldbe interviewed regarding the sexual history. Erectile dysfunction should be distinguished from other sexual problems, such as premature ejaculation. Factors such as sexual orientation, the degreeto which the patient is bothered by erectile dysfunction, performance anxiety, and details regarding sexual technique should be addressed. Standardized questionnaires are available to assess erectile dysfunction, including the International Index of Erectile Function and its validated and more easily administered abridged version, the Sexual Health Inventory for Men13 (see Table 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). The five items on the latter inventory were selected in order to identify the presence or absence of erectile dysfunction and for consistency with the National Institute of Health’s definition of the disorder. On physical examination, signs of hypogonadism (including small testes, gynecomastia, and reduced growth of body hair and beard) warrant attention.14,15 In addition, a digital rectal examination and an assessment of anal sphincter tone and bulbocavernous reflex (the contraction of the bulbocavernous muscle on the perineum after compression of the glans penis) are recommended to assess the integrity of the sacral neural outflow. Peripheral pulses should be palpated for signs of vascular disease. Practice guidelines recommend the measurement of a morning serum testosterone level for men with erectile dysfunction,1,14 although it should be recognized that the threshold level of testosterone for maintaining an erection is unknown and may depend on other factors (e.g.,the level of luteinizing hormone).14,15 An unequivocally low testosterone level warrants a repeat measurement of free or bioavailable testosterone, as well as the measurement of prolactin and luteinizing hormone. Measurements of glucose and. Risk Factors for Erectile Dysfunction. Risk Factor Mechanism or Cause Treatment Metabolic syndrome Endothelial dysfunction and down-regulationof nitric oxide synthase Diet, exercise, and associated weight loss Lower urinary tract symptoms of benign prostatic hyperplasiaPossible decrease in nitric oxide in thepenis, bladder, and prostate Use of a PDE5 inhibitor Cardiovascular disease Possible endothelial dysfunction in penile vasculature Use of a PDE5 inhibitor with caution; ontraindication with nitrate use Tobacco smoking Possible endothelial dysfunction, associated atherosclerosis, and sympathetic overactivity Smoking cessationCentral neurologic conditions† Disruption of descending neural control of proerectile processes Medical treatment Spinal cord injury Dependent on the extent and location of the spinal lesion; nonsustained reflex erections commonly maintained Use of a PDE5 inhibitor (depending on the level of injury) epression or social or marital, stress Unknown Counseling, lifestyle change (e.g., weight loss, exercise), medical treatment Endocrinologic conditions‡ Disruption of testosterone-mediated up-regulation of nitric oxide synthase; low testosterone levels from hyperprolactinemia- influenced changes in the hypothalamic–pituitary axis Correction of underlying endocrine disorder; possible use of a PDE5 inhibitor Diabetes mellitus Vasculopathy from endothelial dysfunction and autonomic neuropathy Appropriate glycemic therapy PDE5 denotes phosphodiesterase type 5. Neurologic conditions include Parkinson’s disease, hemorrhagic or ischemic stroke, tumors, Alzheimer’s disease, the Shy–Drager syndrome, and encephalitis. Endocrinologic conditions include hypogonadism, hypothyroidism, hyperthyroidism, and hyperprolactinemia. The New England Journal of Medicine Downloaded from nejm.org at CENTRALE FACOLTA MED E CHIRURGIA on October 25, 2012. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. The new engl and journa l o f medicine nengl j med 357;24 www.nejm.org 2476 december 13, 2007 lipid levels, a complete blood count, and renalfunction tests are also recommended on the basis of expert consensus.16 Vascular assessments based on penile injection of prostaglandin E1, duplex ultrasonography, biothesiometry, or nocturnal penile tumescence are not recommended in routine practice but can be helpful whenever information regarding the vascular supply is needed — for example, in the choice of surgical treatment (implantationof a prosthesis vs. penile reconstruction). Treatment Therapies currently used for the treatment of erectile dysfunction include oral therapy with a phosphodiesterase type 5 inhibitor (the most commonlyused therapy), injection therapies, testosterone therapy, penile devices, and psychotherapy. In addition,limited data suggest that the treatment of underlying risk factors and coexisting illnesses — for example, with weight loss, exercise, stress reduction, and smoking cessation — may improve erectile function.17 Decisions regarding therapy should take into account the preferences and expectationsof patients and their partners. Phosphodiesterase Type 5 Inhibitors Phosphodiesterase type 5 inhibitors are considered to be the first-line therapy for the treatmentof erectile dysfunction. These agents improve erectile function by increasing penile cyclic guanosine monophosphate (cGMP), resulting in relaxation of smooth-muscle cells (Fig. 2). Several randomized trials have demonstrated the efficacy of this class of medications. A metaanalysis of 14 randomized trials involving 2283 men showed that treatment with sildenafil (at all doses tested) significantly increased the proportion of patients who had at least one episode ofintercourse (83%), as compared with placebo (45%), with a risk ratio of 1.8 in the placebo group (95% confidence interval, 1.7 to 1.9).18 Another randomized trial showed that treatment with sildenafil (at a dose of 100 mg) increased the proportion of men who had a successful episode of intercourse, as compared with placebo (51% vs. 30%, P<0.05). There are no compelling data to support the superiority of one phosphodiesterase type 5 inhibitor over another.16 Comparisons of efficacy among various agents in this class are limited because of the exclusion of patients who did not have a response to sildenafil in studies of tadalafil and vardenafil and because of differences among study subjects in such factors as smoking status, baseline erectile function, race, and age. In a meta-analysis of 11 randomized trials involving 2102 men, tadalafil (at a dose of 10 or 20 mg) led to significant improvement in erectile function (as assessed with the International Index of Erectile Function) and significant increases in the proportion of sexual attempts leading to successfulintercourse (34% with 10 mg of tadalafil, 46% with 20 mg of tadalafil, and 8% with placebo; Pin erectile function was reported in a meta-analysis of randomized trials of vardenafil (at doses of 5 mg, 10 mg, and 20 mg).21 Patients may not have a response to a phosphodiesterase type 5 inhibitor for several reasons. Figure 3 reviews potential reasons for failure of these medications, as well as common adverse events. Some patients may not be able to tolerate phosphodiesterase type 5 inhibitors because of adverse events related to vasodilatation in nonpenile tissues expressing phosphodiesterase type 5 or from the inhibition of homologous nonpenile isozymes (i.e., phosphodiesterase type 6 in the retina). Abnormal vision that is attributed to the effects of phosphodiesterase type 5 inhibitors on retinal phosphodiesterase type 6, reported only Drugs Associated with Erectile Dysfunction. Drug Class Examples Diuretics Thiazides, spironolactone Antihypertensive drugs Calcium-channel blockers, beta-blockers, methyldopa, clonidine, reserpine, guanethidine Cardiac or cholesterol drugs Digoxin, gemfibrozil, clofibrate Antidepressants Selective serotonin-reuptake inhibitors, tricyclic antidepressants, lithium, monoamine oxidase inhibitors Tranquilizers Butyrophenones, phenothiazines H2 antagonists Ranitidine, cimetidine Hormones Progesterone, estrogens, corticosteroids, luteinizing hormone–releasing hormone agonists, 5α-reductase inhibitors, cyproterone acetate Cytotoxic agents Methotrexate Immunomodulators Interferon-α Anticholinergic agents Disopyramide, anticonvulsants Recreational drugs Alcohol, cocaine The New England Journal of Medicine Downloaded from nejm.org at CENTRALE FACOLTA MED E CHIRURGIA on October 25, 2012. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine
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