Erectile Dysfunction

Release Date: June 1, 2012

Expiration Date: June 30, 2014

FACULTY:

Mariam Khan, PharmD
Medical Writer
Princeton, New Jersey

FACULTY DISCLOSURE STATEMENTS:

Dr. Khan has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy acpe
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-12-013-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

FEE INFORMATION:

Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To educate pharmacists about erectile dysfunction (ED), risk factors for ED, treatment options, and the role of clinical and community pharmacists in optimizing therapeutic options.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Identify patients at risk for developing ED.
  2. Describe the pathophysiology of ED.
  3. Review comorbid diseases associated with ED.
  4. Discuss treatment options and optimize dosing strategies.

Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance.1 The incidence increases with age and impacts intimate relationships, quality of life, and self-esteem. It is estimated that ED will have an incidence of 322 million cases by the year 2025.2

The introduction of oral phosphodiesterase type 5 (PDE 5) inhibitors has led increasing numbers of men to seek medical attention and has revolutionized how clinicians evaluate and treat ED.

PREVALENCE AND RISK FACTORS

The incidence of ED increases with age. In a study analyzing the association between age and various aspects of sexual function (i.e., overall function, desire, orgasm, and overall ability), sexual dysfunction was more likely in men older than 50 years of age. Modifiable factors such as physical activity, leanness, moderate alcohol consumption, and not smoking are associated with a decreased risk of sexual dysfunction. Some comorbid conditions associated with an increased risk of ED are diabetes, cancer, stroke, and hypertension (TABLE 1).3


tbl1

There is a connection between ED and cardiovascular disease.1 In addition, diabetes increases the risk of sexual dysfunction. The Massachusetts Male Aging Study reported that patients with diabetes had triple the incidence of ED compared with patients without diabetes. Diabetic risk factors associated with ED include hypertension, autonomic neuropathy, and gonadal dysfunction.4

PATHOPHYSIOLOGY

Vascular, neurologic, hormonal, and psychological factors interact to achieve good arterial blood flow and venous outflow, which are crucial for attaining and maintaining an erection. An erection results from a combination of neurotransmission and vascular smooth-muscle relaxation that increases arterial inflow and signaling between the endothelial-lined cavernosal sinusoids and the underlying smooth-muscle cells (FIGURE 1).2


fig1

The parasympathetic nonadrenergic and noncholinergic fibers and the endothelial nitric oxide synthase produce nitric oxide, which catalyzes a molecular cascade of chemical reactions with cyclic guanosine monophosphate (cGMP) and decreases intracellular calcium, causing smooth-muscle cell relaxation. Another pathway, which is mediated by cyclic adenosine monophosphate (cAMP), also reduces intracellular calcium and causes smooth-muscle cell relaxation.2 These chemical interactions occur in tandem and increase intracavernosal blood flow and pressure within the corpora cavernosa, producing an erection.2,5,6

ED occurs when the production of nitric oxide is impaired. One pathophysiological mechanism that hinders nitric oxide production is impaired parasympathetic neural output, which can occur in diabetes, depression, and central and peripheral neuropathic diseases. Moreover, conditions like metabolic syndrome, hyperlipidemia, atherosclerosis, diabetes, and smoking negatively affect nitric oxide synthase, thereby inducing endothelial and smooth-muscle cell death.5,6

EVALUATION

Men who are experiencing ED should seek medical evaluation. The health care provider should obtain a complete medical, sexual, and psychosocial history, which may yield adequate diagnostic information. A gradual and progressive onset suggests an organic cause, whereas acute onset in a patient without any trauma or comorbid disease may indicate a social or psychological origin (TABLE 2).2,5,6


fig1

A medical history can identify comorbid diseases that can cause ED. A sexual history provides information about the patient's erection, libido, quality and timing of orgasm, volume and appearance of ejaculate, sexually induced genital pain or Peyronie's disease, and partner's sexual function.1,2,5 The International Index of Erectile Function Questionnaire may be used to assess the severity of the patient's symptoms. ED is classified as mild, mild-to-moderate, moderate, or severe (TABLE 3).1


fig1

The physical examination should assess cardiovascular, neurologic, and genitourinary systems, and penile, testicular, and digital rectal examination should be performed.

Other tests may include fasting serum glucose concentration, lipid panel, thyroid-stimulating hormone test, and morning testosterone concentration.1 It should be noted that the diagnostic value of measuring testosterone remains controversial, but is warranted in certain patients. Peripheral pulses should be palpated for signs of vascular disease.2,6 The patient's use of medications (including OTC and/or illicit drugs) and alcohol should be reviewed.1,2,5,6

TREATMENT

Lifestyle changes and pharmacotherapy can alleviate ED. The first steps in treating ED are to quit smoking, increase physical activity, and (in obese patients) lose weight.

Treatment options for ED include PDE 5 inhibitors (first-line); intraurethral alprostadil, intracavernosal agents, and vacuum pump devices (second-line); and surgically implanted penile prosthesis (third-line). Trazodone and herbal products are some other therapies.1,5,8

PDE 5 Inhibitors

The PDE 5 inhibitors sildenafil, tadalafil, vardenafil, and avanafil (TABLE 4) increase cGMP, thereby reducing the calcium concentration and relaxing the penile smooth-muscle cells. Trials evaluating superiority of one of these drugs over another are lacking. All of the PDE 5 inhibitors have similar efficacy, but they exhibit different pharmacokinetic profiles.7,8 Moreover, as a class, PDE 5 inhibitors do not affect the libido, and sexual stimulation is essential to a successful outcome.9


fig1

In general, PDE 5 inhibitors are well tolerated; the more common adverse effects include headache, flushing, dyspepsia, rhinitis, and abnormal vision. Other adverse effects are dizziness, syncope, and nonarteritic anterior ischemic optic neuropathy (NAION).7 Factors associated with NAION and ED include hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, smoking, and age over 50 years.7,8

PDE 5 inhibitors should not be taken with nitrates because both of these agents can reduce blood pressure.1,2 In an emergent situation, a patient who has taken sildenafil may be given a nitrate after 24 hours; for tadalafil, after 48 hours.5,10 Vardenafil does not have a suggested time interval, but blood pressure and heart rate did not change when the drug was taken 24 hours before nitrate administration.5

The following procedure is recommended in a patient who develops hypotension: Place the patient in the Trendelenburg position, attempt aggressive fluid resuscitation, and—if necessary—administer an alpha agonist (phenylephrine), beta agonist (norepinephrine), and intra-aortic balloon.5

The use of PDE 5 inhibitors is a concern in patients with coronary artery disease because the physiological response that occurs during intercourse increases the blood pressure and heart rate. The risk of intercourse-induced myocardial infarction is estimated to be 20 chances per million per hour in patients with ischemic heart disease.2,5

Another clinically important drug interaction involves PDE 5 inhibitors and alpha-blockers, whose concomitant use results in orthostatic hypotension. The American Urological Association recommends that PDE 5 inhibitors be used with caution and initiated at the lowest recommended dose in patients taking alpha-blockers.7

Sildenafil, the first PDE 5 inhibitor, is rapidly absorbed after oral administration, and onset of activity is optimal if the drug is taken on an empty stomach. Patients should be advised to take sildenafil 1 hour before sexual intercourse, with a maximum administration frequency of once daily.9

Vardenafil is another potent and selective PDE 5 inhibitor. In vitro studies suggest that vardenafil exhibits high selective inhibition of PDE 5 compared with other PDE isoenzymes. A high-fat meal reduces the absorption rate of vardenafil, which is metabolized by the hepatic isoenzyme CYP3A4. Although PDE-5 inhibitors have minimal effects on QTc interval, vardenafil is not recommended in patients who take type 1A or type 3 antiarrhythmics or in patients with congenital prolonged QT syndrome.8

Tadalafil is 9,000-fold more selective for PDE 5 inhibition than other PDEs. Patients should be instructed to take tadalafil approximately 2 hours before sexual activity, with a maximum frequency of every other day, because its activity is maintained for at least 36 hours.9 Tadalafil is metabolized via CYP3A4, and food and alcohol do not affect its absorption.9 Tadalafil also may be clinically useful in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia.

Avanafil was recently approved by the FDA for the treatment of ED. This agent has a rapid onset of action and a short half-life.11 In a multicenter, double-blind, phase III trial, 646 patients were randomized to receive avanafil (50 mg, 100 mg, or 200 mg) or placebo for 12 weeks. Patients taking avanafil experienced significant improvements in sexual functioning. In the trial, avanafil's onset of action was 15 minutes or less, and the pharmacodynamic effect persisted 6 hours postdose.12 The recommended dose is 100 mg thirty minutes prior to sexual activity.13 If the patient does not respond to initial therapy, then a different PDE-5 inhibitor may be initiated. If the patient still fails to respond to therapy, the following parameters should be thoroughly evaluated: hormonal abnormalities, lack of adequate stimulation, food or drug interaction, timing and frequency of dosing, heavy alcohol use, and the patient's relationship with his partner.5

Transurethral Alprostadil

Alprostadil transurethral suppositories may be an appropriate alternative for patients who fail to respond to PDE 5 inhibitors or are not candidates for PDE 5 inhibitor therapy. Alprostadil is a synthetic vasodilator identical to prostaglandin E1 (PGE1) that is formulated as a suppository for transurethral delivery, an approach known as medicated urethral system for erection (MUSE).2 The medication is absorbed into the corpus cavernosa via intercommunicating veins.11 Approximately 80% of the drug is absorbed into the systemic circulation and is metabolized as it passes through the lungs.14

A study that assessed the safety and efficacy of two different starting doses (250 mcg vs. 500 mcg) of transurethral alprostadil found that the 500-mcg dose resulted in a sufficient response and satisfaction.15 Regardless, the starting dose of alprostadil (MUSE) ranges from 250 mcg to 1,000 mcg.8,15 The patient should void first, as this lubricates the urethra and facilitates administration of the suppository.15 The patient should then stand while the medication is being absorbed, in order to minimize leakage and promote absorption. Because of the risk of urethral bleeding, vasovagal reflex, hypotension, and priapism (erection lasting >4 hours), the first dose must be administered under the supervision of a clinician.8

Postmarketing studies found less successful results with monotherapy, and consequently alprostadil has been further evaluated in combination with other agents, such as penile vacuum devices or oral PDE 5 inhibitors, which have increased efficacy compared with alprostadil alone.5,15 A cohort study of 28 patients demonstrated that MUSE-sildenafil combinations were well tolerated, with excellent patient and partner satisfaction.16

Intracavernous Vasoactive Drug Injection

Alprostadil, papaverine, and phentolamine are vasoactive drugs used for intracavernous injection (ICI) therapy, which is an effective nonsurgical alternative for patients with neurogenic or psychogenic ED.5,8,14 ICI therapy, which mimics natural erectile physiology, provokes a rapid, predictable, and reliable erection when appropriately administered.8 The initial trial dose of ICI should be administered under a clinician's supervision, and the patient should be educated as to proper technique. The effective dose should be determined, and the patient should be monitored for adverse effects. ICI may be used only once in 24 hours.5

Alprostadil (PGE1), the most popular vasoactive agent, results in erection in more than 70% of patients.8,17 The most common adverse effect is painful erection. Papaverine, a nonspecific PDE inhibitor, increases cAMP and cGMP in penile erectile tissue. Major drawbacks include priapism, corporal fibrosis, and alterations in liver function. Phentolamine, an alpha-adrenergic antagonist, weakly induces corporeal smooth-muscle relaxation and is used in combination with papaverine.8,14 One combination drug, Bi-Mix, comprises 30 mg papaverine and 0.5 mg to 1 mg phentolamine; another combination, Tri-Mix, contains papaverine, phentolamine, and alprostadil. The dosage of Tri-Mix solution typically ranges from 0.1 mL to 0.5 mL.8 It is important to note that drugs such as papaverine and alprostadil are available commercially, but combinations such as Bi-Mix and Tri-Mix are available only from specialty pharmacies.5

The disadvantages of ICI therapy are its invasiveness and the potential for priapism and fibrosis.5,8 Of particular concern in ICI-induced priapism is the potential for corporeal tissue damage.5 Patients should be informed of this important adverse effect and be instructed to immediately seek medical attention should priapism occur. Intracavernosal phenylephrine is used to treat priapism.14 Fibrosis is a complication that can be prevented by compressing the injection site for 3 to 5 minutes after injection (up to 10 minutes in patients taking anticoagulants).8

Because of the risk of priapism, ICI therapy is contraindicated in patients with a history of sickle cell anemia and in schizophrenic patients taking antipsychotics.

Vacuum Erection Devices (VEDs)

These pump devices apply negative pressure to the penile shaft and glans, which causes the sinusoidal tissue to fill with blood. The advantages of VEDs are that they are economical, few contraindications are associated with therapy, no systemic adverse effects exist, and therapy is efficacious. The disadvantages are that VEDs are cumbersome and produce an unnatural erection.1,8 VED therapy is preferred for older patients in stable relationships and is contraindicated in patients with sickle cell anemia or blood dyscrasias and in those taking anticoagulants.1,8

Trazodone

Trazodone antagonizes alpha-2 adrenergic receptors in the penile vascular and corporeal smooth muscle, which relaxes the tissue and increases arterial blood inflow. A meta-analysis concluded that, at higher doses, trazodone may be beneficial in patients with psychogenic ED.5,18 Currently, the role of trazodone in the treatment of ED is limited, and more well-designed studies are needed to explore the drug's utility for this condition.5

Topical Therapies

A randomized, double-blind, placebo-controlled, 2-week crossover trial was conducted to evaluate treatment of ED with a topical cream containing three vasodilators: aminophylline, isosorbide dinitrate, and co-dergocrine mesylate. The cream was found to be particularly effective in patients with erectile dysfunction of psychogenic origin.19

Topical products consisting of alprostadil, organic nitrates, minoxidil, papaverine, or yohimbine are not approved by the FDA for the treatment of ED. They may be available from specialty pharmacies.5

Dietary Supplements and Alternative Medicine

Despite pharmacologic advances, alternative medicine is popularly used in the treatment of ED. The utility of acupuncture in treating ED may have benefits, but evidence is lacking, and further research is needed.20,21 Androstenedione and dehydroepiandrosterone, which are testosterone precursors, can increase estradiol and testosterone levels; however, studies demonstrated decreased levels of HDL and insignificant increases in serum testosterone. In addition, androstenedione's effects on estrogen include gynecomastia, pancreatic cancer, and other conditions. The use of these agents should be discouraged, and patients should be advised to seek professional medical advice for the use of testosterone to treat ED.20

Ginkgo biloba has also been utilized in the treatment of ED. While ginkgo extract may improve vascular perfusion, its utility in the treatment of ED has not been demonstrated in well-designed studies. Limited data are available on its use for the treatment of ED following prostate cancer treatment.20 Another supplement, L-arginine, is an amino acid precursor to nitric oxide; it provides little to no benefit in the treatment of ED.

Yohimbine, an indole alkaloid, is similar to an alpha-2 adrenoreceptor antagonist, with some central and peripheral effects. Yohimbine exhibits is pharmacologic effects in the brain center associated with libido and erection. OTC yohimbine should be discouraged, as the amount of yohimbine in such products cannot be ascertained. Patients should be encouraged to discuss the use of yohimbine with their health care provider.20

Korean red ginseng was evaluated for the treatment of ED in a double-blind, placebo-controlled, crossover study involving 45 patients. The group taking Korean red ginseng experienced positive changes in erectile parameters (i.e., penile rigidity, penile girth, libido, and patient satisfaction) compared with the other groups. More studies are needed to assess the use of Korean red ginseng in the treatment of ED.20,22

Surgical Therapies

Inflatable penile prostheses mimic physiological flaccidity and erection, but they are associated with complications, such as mechanical failure, pump displacement, and autoinflation. Modern prostheses allow for antibiotic impregnation and elution, which reduce the risk of infection. Regardless, the presence of infection is a serious complication that must be managed.5,8

Penile arterial reconstructive surgery can help healthy younger men (age <55 years) whose ED is due to focal arterial occlusive disease. More studies are needed to determine the role of reconstructive surgery in ED.5

ROLE OF TESTOSTERONE IN ED

The relationship between low testosterone levels and ED has not been elucidated. It is hypothesized that testosterone exhibits a stronger effect on libido than on erection. Evidence regarding testosterone's role in penile erection is conflicting; nonetheless, hypogonadal patients may benefit from testosterone therapy.2,23 The addition of testosterone may improve some patients' response to conventional therapy (e.g., PDE 5 inhibitors, ICI, or intraurethral therapy).5,23 Hypogonadal patients should have the following parameters monitored: serum testosterone, hemoglobin, hematocrit, and prostate-specific antigen.1,2,23,24

CARDIOVASCULAR DISEASE AND ED

ED is strongly associated with cardiovascular disease (i.e., hypertension and atherosclerosis).1 It is believed that vascular dysfunction and atherosclerosis affect both the coronary arteries and the penile vasculature.4,5 A study investigating the association between ED and subsequent cardiovascular disease found that patients with ED have a greater risk of cardiovascular disease than men without ED; consequently, patients who present with ED should be screened for cardiovascular risk factors.25

There are three risk categories for patients with ED and cardiovascular disease: low risk, intermediate risk, and high risk (TABLE 5). Patients should be stratified based upon their risk factors, with their treatment modified accordingly.26,27


fig1

FUTURE TREATMENTS

Udenafil is a new PDE 5 inhibitor that is available in Korea and Russia. It is not available in the United States. In clinical trials conducted in Korea, udenafil was found to be safe and effective in treatment of ED.

The role of gene therapy in the treatment of ED is being explored. The defective gene in the corporeal tissue can be restored via injection of the therapeutic material directly into the penis. Moreover, the tunica albuginea has a slower cell turnover rate, which prolongs the effect of therapy. Additional studies are warranted to determine the role of this type of therapy in ED.11

CASE DISCUSSIONS
Case 1

Presentation: Patient M.A., aged 57 years, presents with the inability to maintain an erection upon penetration of his partner. M.A. has type 2 diabetes mellitus and hypertension, and he had a myocardial infarction 7 months ago. M.A. also recently quit smoking cigarettes. His current medications include metoprolol, atorvastatin, metformin, pioglitazone, fluoxetine, and varenicline. M.A. is looking for a drug treatment that he can take within 1 hour of planned intercourse, that will take effect within 20 minutes of ingestion, and that will last for at least 5 hours.

Plan: M.A. has many risk factors for ED, including diabetes, hypertension, and history of smoking. M.A. appears to have vasculogenic ED, given that he has atherosclerosis. As M.A. is new to treatment, initiation of PDE 5 inhibitor therapy would be appropriate. Based upon M.A.'s preferences for therapy, the most appropriate agent would be tadalafil. Pertinent counseling points would be to query M.A. as to whether he feels healthy enough for sexual activity, considering his history of myocardial infarction. M.A. must also be cautioned not to take medication in conjunction with nitrates, because both drugs can reduce blood pressure.

Case 2

Presentation: Patient O.K., who is 46 years old, presents with the inability to develop an erection. O.K. has partial-onset seizures and atrial fibrillation. He is currently talking the following medications: lamotrigine, carbamazepine, warfarin, amiodarone, atenolol, and digoxin. O.K. had previous ineffective responses to sildenafil and tadalafil and is wondering whether other oral agents are available, as he is uneasy about administering injections. His condition is making it difficult for him to be intimate with his partner, causing him to have doubts about his self-worth.

Plan: O.K. has one risk factor for ED: seizure disorder. Therefore, he appears to have neurogenic ED. O.K. is not new to therapy, as he has failed two PDE 5 inhibitors. Based upon O.K.'s pathophysiology, further treatment with PDE 5 inhibitors is not recommended. Although O.K. expresses an aversion to injections, ICI therapy should be recommended, since vacuum devices are contraindicated in patients taking anticoagulants and there is a paucity of information on the use of other oral agents. O.K. must be reassured that ICI therapy provides a rapid, predictable, and reliable erection and has been shown to be effective in his particular type of ED. Pertinent counseling points would be to advise O.K. to learn the proper administration technique and to caution him about the potential for priapism and fibrosis. Attention must also be paid to O.K.'s depressive state regarding his ED, and psychiatric consultation should be considered.

ROLE OF THE PHARMACIST

Patients are increasingly seeking medical attention for ED, as the management of this condition with oral PDE 5 inhibitors is an acceptable option. Community pharmacists can play an integral role in optimizing therapy and encouraging patients to seek medical attention. Furthermore, other treatment options may be discussed with the patient to help with the management of ED.

REFERENCES

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  2. McVary KT. Erectile dysfunction. N Engl J Med. 2007;357:2472-2481.
  3. Bacon CG, Mittleman MA, Kawachi I, et al. Sexual function in men older than 50 years of age: results from the Health Professionals Follow-up Study. Ann Intern Med. 2003;139:161-168.
  4. Felman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994;151:54-61.
  5. Montague DK, Jarow JP, Broderick GA, et al. Chapter 1: the management of erectile dysfunction: an AUA update. J Urol. 2005;174:230-239.
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  7. Briganti A, Salonia A, Deho F, et al. Clinical update on phosphodiesterase type-5 inhibitors for erectile dysfunction. World J Urol. 2005;23:374-384.
  8. Brant WO, Bella AJ, Lue TF. Treatment options for erectile dysfunction. Endocrinol Metab Clin North Am. 2007;36:465-479.
  9. Hatzimouratidis K, Hatzichristou DG. A comparative review of the options for treatment of erectile dysfunction: which treatment for which patient? Drugs. 2005;65:1621-1650.
  10. Kloner RA, Hutter AM, Emmick JT, et al. Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol. 2003;42:1855-1860.
  11. Alwaal A, Al-Mannie R, Carrier S. Future prospects in the treatment of erectile dysfunction: focus on avanafil. Drug Des Devel Ther. 2011;5: 435-443.
  12. Goldstein I, McCullough AR, Jones LA, et al. A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction. J Sex Med. 2012;9:1122-1133.
  13. Stendra (avanafil) product information. Mountain View, CA: Vivus, Inc; April 2012.
  14. Manecke RG, Mulhall JP. Medical treatment of erectile dysfunction. Ann Med. 1999;31:388-398.
  15. Ekman P, Sjögren L, Englund G, Persson BE. Optimizing the therapeutic approach of transurethral alprostadil. BJU Int. 2000;86:68-74.
  16. Nehra A, Blute ML, Barrett DM, Moreland RB. Rationale for combination therapy of intraurethral prostaglandin E(1) and sildenafil in the salvage of erectile dysfunction patients desiring noninvasive therapy. Int J Impot Res. 2002;14(suppl 1):S38-S42.
  17. Linet OI, Neff LL. Intracavernous prostaglandin E1 in erectile dysfunction. Clin Investig. 1994;72:139-149.
  18. Fink HA, MacDonald R, Rutks IR, Wilt TJ. Trazodone for erectile dysfunction: a systematic review and meta-analysis. BJU Int. 2003;92:441-446.
  19. Gomaa A, Shalaby M, Osman M, et al. Topical treatment of erectile dysfunction: randomised double blind placebo controlled trial of cream containing aminophylline, isosorbide dinitrate, and co-dergocrine mesylate. BMJ. 1996;312:1512-1515.
  20. Moyad MA. Dietary supplements and other alternative medicines for erectile dysfunction. What do I tell my patients? Urol Clin North Am. 2002;29:11-22.
  21. Lee MS, Shin BC, Ernst E. Acupuncture for treating erectile dysfunction: a systematic review. BMJ. 2009;104:366-370.
  22. Choi HK, Seong DH, Rha KH. Clinical efficacy of Korean red ginseng for erectile dysfunction. Int J Impot Res. 1995;7:181-186.
  23. Shabsigh R. Hypogonadism and erectile dysfunction: the role for testosterone therapy. Int J Impot Res. 2003;15(suppl 4):S9-S13.
  24. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004;350:482-492.
  25. Thompson IM, Tangen CM, Goodman PJ, et al. Erectile dysfunction and subsequent cardiovascular disease. JAMA. 2005;294:2996-3002.
  26. DeBusk R, Drory Y, Goldstein I, et al. Management of sexual dysfunction in patients with cardiovascular disease: recommendation of The Princeton Consensus Panel. Am J Cardiol. 2000;86:175-181.
  27. Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am J Cardiol. 2005;96:313-321.

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