Continuing Education Activity

Erectile dysfunction (ED) is a prevalent and multifaceted condition that predominantly afflicts males beyond 40 years, with its prevalence escalating globally. This condition is characterized by the consistent or recurrent inability to attain and maintain an erection sufficient for satisfactory sexual performance. The etiology of ED is diverse, encompassing organic, psychogenic, and mixed factors, often interwoven with comorbidities such as diabetes, cardiovascular disease, and neurologic disorders. This complexity underscores the significance of discerning the root causes to guide appropriate management.

The psychological and emotional ramifications of ED can be profound, impacting not only the afflicted individuals but also their partners. Unaddressed, it may precipitate anxiety, depression, diminished self-esteem, and strained interpersonal relationships. Thus, the comprehensive evaluation and management of ED carry substantial importance.

Fortunately, a plethora of therapeutic modalities is at the clinician's disposal. These range from the administration of oral phosphodiesterase type 5 inhibitors, hormone replacement therapies, and external vacuum devices to the application of urethral suppositories, intracavernosal injections, topical gels, and sex therapy. This activity reviews the evaluation and treatment of ED and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Apply evidence-based treatments for erectile dysfunction, including oral phosphodiesterase type 5 inhibitors, hormone replacement therapies, and other therapeutic modalities as indicated.

• Implement a comprehensive evaluation, including medical and psychosocial history, to discern the etiological factors contributing to erectile dysfunction.

• Differentiate between organic and psychogenic causes of erectile dysfunction to guide appropriate diagnostic and treatment approaches.

• Coordinate interdisciplinary care when managing erectile dysfunction (ED), involving urologists, psychologists, and sexual health specialists to optimize patient outcomes and well-being.

Introduction

Erectile dysfunction (ED), formerly termed impotence, is defined as the failure to achieve or maintain a rigid penile erection suitable for satisfactory sexual intercourse.[1] While no specific time is part of this definition, some have suggested that the condition needs to persist for six months. ED is a common condition in men who are 40 years and older; prevalence increases with age and other co-morbidities.[2] 

ED can be a symptom of a wide range of underlying pathologies and is an essential but underutilized cardiovascular risk factor.[3][4][5][6][7] Any disease process that affects penile arteries, nerves, hormone levels, smooth muscle tissue, corporal endothelium, or tunica albuginea can cause erectile dysfunction. This condition is closely related to cardiovascular disease, diabetes mellitus, hyperlipidemia, and hypertension, among other disorders. Endothelial dysfunction appears to be the other common pathway in patients with this condition.[8] 

While the vast majority of patients with ED will have organic disease, some may have a primary psychological issue, particularly younger men. Even when the underlying cause is organic, there are almost always psychological consequences to ED regarding marital and relationship issues, cultural norms and expectations, loss of self-esteem, shame, anxiety, and depression, among others. ED can cause considerable emotional damage to the patient and their partner, as well as have a significant impact on their quality of life. Fortunately, ED is almost always treatable.

Etiology

The cause of ED is often multifactorial. Distinguish whether the condition has an underlying psychological cause or an organic etiology. Depression, performance anxiety, and other sexual disorders can be strong contributing factors even when organic causes also exist. Aging is an essential factor contributing to ED. As patients age, cardiovascular diseases, hypertension, and other co-morbidities play an increasingly significant role in this condition. Diabetes mellitus and metabolic syndrome can affect several organ systems, resulting in the accelerated deterioration of erectile function, and can disrupt the mechanisms underpinning erections on a molecular level.[8][9]

Other causes of ED include neurological diseases (such as multiple sclerosis), hormonal causes (hypogonadism, thyroid), traumatic (eg, pelvic fractures, spinal cord injuries), hyperlipidemia, stroke, sleep apnea, COPD, glaucoma, multiple sclerosis, sequela of priapism, depression, prostatic hyperplasia with lower urinary symptoms (BPH with LUTS), iatrogenic (eg, post transurethral resection of the prostate) and a variety of medications (antidepressants, antihypertensives, antipsychotics, opioids, and recreational drugs).[10][11][12][13][14][15][16][17][18]

Cardiovascular Disease and Erectile Dysfunction

Cardiovascular disease is a very significant risk factor for ED. Almost 50% of men with known coronary artery disease proven by cardiac catheterization have significant ED.[19] Part of the reason for this is that the coronary arteries and the penile cavernosal arteries are similar in size and tend to develop atherosclerotic problems similarly. Since the cavernosal arteries are small, they can develop blockages from atherosclerotic plaques earlier, resulting in vasculogenic ED years before the clinical appearance of coronary artery disease. Both cardiovascular disease and ED involve endothelial cell dysfunction in their pathophysiology.[20] 

Patients will often demonstrate subclinical atherosclerosis long before any overt ED by as much as 10 years. The cavernosal arteries being of smaller diameter means that vasculogenic ED often precedes coronary artery disease, myocardial infarctions, and strokes by up to 5 years.[3][21] Younger men who present with unexplained ED appear to have a very significant increase, up to 50-fold, of their cardiovascular risk in later life compared to an age-matched control group.[4][22] Inform patients that ED is a significant indicator of underlying heart disease and refer them for further cardiovascular risk screening and treatment.[3][4][5][6][7][22]

The Prostate Cancer Prevention Trial database showed that having ED increased a patient's cardiovascular risk roughly equivalent to the risk of smoking or having a family history of myocardial infarctions.[23] A meta-analysis of 14 studies totaling over 90,000 men with ED found that these patients had 44% more cardiovascular events, 62% more myocardial infarctions, 39% more strokes, and a 25% increased risk of death compared to patients presenting without ED.[24] 

ED has useful independent predictive value for future cardiovascular events; therefore, screen all patients with ED for cardiovascular risks.[21] If cardiovascular risk is intermediate, perform non-invasive testing for subclinical atherosclerosis and an exercise stress test, but if the patient has a high risk, recommend a formal cardiology referral.[4][25][26][27]

Besides cardiovascular disease, there are strong correlations between ED, hypertension, hyperlipidemia, diabetes, hypogonadism, obesity, smoking, alcoholism, benign prostatic hyperplasia (BPH) with lower urinary symptoms (LUTS), depression, and premature ejaculation.

• About 40% of men with ED will have hypertension, while 35% of all hypertensive men will also have ED [28][29][30] 
• Hyperlipidemia is in about 42% of men with ED
• Undiagnosed diabetes is up to 3 times as likely in men with erectile dysfunction (28%) compared to non-diabetic men with normal erections (10%)[28][31][32]
• Among men over 50 years of age, people with diabetes are roughly twice as likely to have ED (46%) compared to those without (24%).[33]
• The longer a patient has diabetes and the more severe the disease state, the greater the risk of ED.[33]
• One-third of diabetic men will have hypogonadism, which may partly explain the high correlation between diabetes and ED [34]
• Up to 35% of all men with ED will also have hypogonadism, and about 6% will have abnormal thyroid function.[35][36] While testosterone deficiency can negatively impact erectile function, vascular disease and diabetes are far more likely causes of ED.[37] 
• Obesity is associated with a 50% increase in ED compared to men of normal weight.[38] One-third of the obese men with ED who enrolled in a weight loss program resolved their ED symptoms in 2 years [39]
• In smokers who quit, erectile quality improved by 25% after one year [40] 
• Heavy alcohol users also report an increased risk of ED compared to the general population.[31] The precise cause is uncertain but is thought to be due to direct alcoholic toxicity to the corporal endothelium, loss of corporal smooth muscle tissue, and early neuropathy [41] 
• There is a strong correlation between BPH with LUTS and ED. The majority of men with symptomatic BPH, up to 72%, will also have ED [42][43][44] 
• Patients with depression are almost 40% more likely to have ED than men without depression. Conversely, the incidence of depression in men with ED is almost 3 times greater.[45]
• Obesity and morbid obesity are significant risk factors for ED. Treatment of obesity with bariatric surgery can significantly improve sexual performance.[46][47][48]
• At least 30% (and up to 60%) of patients with ED will also have premature ejaculation.[28][49] Successful treatment of the ED will often alleviate premature ejaculation due to reduced performance anxiety. ED treatment usually alleviates premature ejaculation.

Prescription medications are thought to cause one-quarter of all cases of ED. Of the 12 most commonly prescribed medications in the US, 8  list erectile dysfunction as a possible side effect.[35][50] These drugs would include most antidepressants (especially selective serotonin reuptake inhibitors), cimetidine, ketoconazole, spironolactone, sympathetic blockers (methyldopa, clonidine, and guanethidine), thiazide diuretics, and other antihypertensives. (Angiotensin-converting enzyme [ACE] inhibitors and calcium channel blockers are the least likely to cause ED.) Beta-blockers are only a minor contributor to ED, while alpha-blockers improve erectile function.[51][52]

Of the prostate cancer patients who undergo radical prostatectomy surgery, 85% can expect ED post-operatively, compared to an ED rate of only 25% for men who received definitive radiation therapy.[53][54] (This data refers to patients who did not have ED prior to their prostate cancer treatment.) Interestingly, the use of robotic surgery for radical prostatectomies has not changed the post-operative incidence of ED.

The role of bicycle riding in ED is controversial. Traditional racing bicycle seats place considerable pressure directly on the perineal nerves as well as the pudendal and cavernosal arteries, which suggests it could be a potential problem for cyclists.[55][56] A 2020 meta-analysis of 3330 cyclists compared to 1524 non-cycling controls indicated a significantly increased risk of ED in cyclists.[57]

Epidemiology

Many patients fail to seek medical attention, and many physicians are reluctant to ask patients about their sexual health; therefore,  obtaining accurate values for the true prevalence of ED is difficult. The best available data indicate that 52% of men in the US between 40 and 70 years of age have erectile dysfunction.[1][31][58] Further, it is estimated that at least 30 to 50 million men in the US and at least 150 million men globally have ED.[59][60] These values are likely a gross underestimation of the actual number of men with ED due to reporting bias, cultural factors, a general failure by many physicians to inquire about their male patient's sexual health and embarrassment issues.[58] The prevalence of ED is closely related to age and the presence of other co-morbidities such as diabetes, hypogonadism, and cardiovascular disease.[58] The best available data from the Massachusetts Male Aging Study indicates an overall prevalence of 52%, with the incidence increasing with age.[31] At age 40, about 40% of men are affected, while 70% will report having ED by age 70.[31] The National Health and Social Life Survey and similar studies confirmed these findings.[61][62] 

Estimates suggest that erectile dysfunction will affect 322 million men worldwide by 2025.[60]

Pathophysiology

The critical process in penile erection activity is the relaxation of the intracavernosal smooth muscle.[63] This process permits increased blood flow into the corpora cavernosa, which fills with blood and compresses the emissary veins, reducing venous outflow.[63] The paraventricular and medial preoptic nuclei of the hypothalamus control this process.[63] Signals travel through the parasympathetic nervous system to the parasympathetic nerves of the S2-S4 sacral plexus and then to the penis via the cavernosal nerves. Nitric oxide released by the cavernous nerve terminals initiates the erectile process, while nitric oxide from endothelial cells acts to maintain it.[63]

Nitric oxide stimulates the production of cyclic guanosine monophosphate (GMP) when it enters the smooth muscle.[64] Cyclic GMP activates protein kinase G, which opens potassium channels and closes calcium channels. Low intracellular calcium causes the intracavernosal smooth muscle tissue to relax, increasing arterial flow with simultaneous veno-occlusive activity.[63] This results in a rigid erection with minimal blood flow into or out of the corpora once the erection is established. When penile phosphodiesterase degrades cyclic GMP, the corporal smooth muscle contracts again, and the process reverses.[63] Pathology arising from any of the above processes can result in erectile dysfunction.[63][65]

History and Physical

Before embarking upon any treatment or further investigations, clinicians must conduct a thorough medical history, detailed sexual history, and physical examination. It is also essential to obtain a complete medication list, including supplements, mainly if targeting prostate problems, as they often contain anti-androgens.[66]

We have found it helpful to give the patient a scoring system so they can better communicate the degree of their erectile rigidity, with 100% being the best and hardest they ever had, 0% being flaccid, and 50% being just barely hard enough for penetration. This simple scoring system has made it much easier for patients to indicate how rigid their erections are and track their progress after treatment. Alternatively, a questionnaire, such as the International Index of Erectile Function Questionnaire (IIEF), can be given to the patient to fill out privately. The questionnaire has been validated and found helpful for monitoring the severity of erectile dysfunction and treatment efficacy.[67]

Typical sexual history questions include:

• How hard or rigid an erection can you now get (with 50% being just barely enough for penetration)?
• What is the best or most rigid erection you can get right now?
• How long can that erection last?
• Does the penis feel numb or in any way unusual?
• Does the penis lose rigidity during foreplay?
• Does the penis lose rigidity only when attempting vaginal penetration?
• Does the penis stay erect and rigid until immediately after penetration? (This could be from anxiety or a venous leak.)
• Do you still get morning erections? 
• If so, are the morning erections any better or longer-lasting than the erections you get when having intercourse?
• If not, when was the last time you had a good morning erection?
• Any overnight erections? If so, how hard are they?
• Does the hardness of the erection vary much from one day to the next?
• Has there been any time or recent circumstance when the erection worked any better, such as with masturbation or an alternate partner?
• How is erectile rigidity with masturbation compared to when attempting intercourse?
• When was the last time your erections worked normally and you had sexual intercourse?
• When did the erection trouble begin?
• Did it start suddenly or gradually? (sudden, unexplained onset of ED is almost always psychogenic)
• Was there any significant change in your life that happened at about the same time as the erection trouble started? New relationships or medications?
• Is the main problem insufficient rigidity or maintenance?
• Is the problem stable or getting worse?
• Is there any history of a particularly traumatic sexual event in your past?
• What do you use for contraception?
• Have you already tried any treatments? If so, what?
• Are ejaculation and orgasm normal even if the erections are not?
• How hard does the erection get at ejaculation?
• Do you feel your general interest in sexual activity is roughly normal?
• If ED was not an issue, how often would you desire to have sexual intercourse?
• Does your partner agree with that frequency?
• Does your partner know you are here seeking treatment? If so, are they encouraging?
• Would your partner be willing to become involved in treatment?
• How often do you and your partner currently attempt intercourse?
• Which of you usually initiates sexual activity and how?
• If not successfully treated, what will happen to your relationship?
• Are the erections straight or curved?
• Is there a problem with libido, interest, ejaculation, or orgasm? If so, when did these other symptoms start?
• Would you be satisfied if we could get the erections up to 65% or 75%, and they would last for 10 or 15 minutes? If not, what would you consider a successful treatment?

Other helpful things to elicit in the patient history include vascular risk factors (eg, hypertension and diabetes), lifestyle factors (such as smoking, activity level, alcohol intake, and the use of any recreational drugs), and general medication history.[68] With the patient's permission, the partner should also be present for history as they can give a different perspective on the relationship; their views help measure the response to therapy. Having the sexual partner involved in the treatment process can greatly improve the outcome. The partner may also provide a different perspective on the nature of sexual dysfunction as well as relationship issues not otherwise forthcoming directly from the patient.

Complete a general cardiovascular examination, as erectile dysfunction could be the first symptom of underlying vascular or heart disease.[66] Check peripheral pulses and measure blood pressure. The genitalia should be carefully inspected, looking at the testicular size (hypogonadism), signs of infection (such as redness and discharge in acute balanoposthitis), the presence of penile fibrosis or plaques (as in Peyronie disease), and phimosis (the inability to retract the foreskin). Hair distribution, breast size (gynecomastia), and a detailed neurological examination are helpful. Evaluate the cremasteric reflex by gently scratching or stroking the upper inner thigh while observing the scrotum. A normal reflex would be a retraction or elevation of the ipsilateral testicle. This reflex activates if the thoracolumbar erection center is intact.[66] 

Erectile dysfunction can be the first symptom of otherwise silent cardiac or vascular disease, so a full cardiovascular workup should be completed in all patients without an apparent cause of their ED.[22][66][69]

Evaluation

Many clinicians often find it challenging and uncomfortable to initiate discussions about their patient's sexual health, a sentiment that is rooted in cultural norms and the potential for embarrassment.[70] 

The following phraseology is very acceptable when vocalized to patients in a way that indicates, by intonation, that the questioner is expecting that everything will be fine and normal. If you ask, "How is your sex life? Everything working OK for you?" men without any sexual problems or issues are likely to respond with a quick "everything is fine" response. If the patient hesitates with their response or indicates that things are "not like they used to be," this should suggest that there is a potential sexual disorder that warrants further inquiries and investigation.

Psychogenic ED and Mental Health

It is beneficial to distinguish between obvious psychological and organic causes of ED as well as to verify that the patient has erectile dysfunction and not another type of sexual disorder, such as premature ejaculation. Careful questioning should be able to determine if the patient has actual, organic erectile rigidity failure or some other sexual problem.[71] Items in the history that point towards a psychological etiology include sudden onset of erectile dysfunction (primarily if related to a new partner or a major life-changing event), situational ED, normal erections with masturbation or a different partner, the presence of good morning erections and high daily variability in erectile rigidity.[71] Refer obvious cases of psychogenic ED to an appropriate mental health professional.[66] Even without obvious psychological issues, involving mental health experts can help deal with associated problems, such as reducing performance anxiety, promoting treatment adherence, improving relationship issues, identifying interpersonal conflicts, and setting realistic expectations for the couple.[66][72][73]

Recommendations for a mental health evaluation can be complex and uncomfortable for a clinician, particularly during a patient's initial visit. Here are some strategies to clarify and support the need for a mental health consultation, making it more readily accepted by patients:

• A mental health assessment is just part of our routine evaluation; we recommend it for everyone with ED.
• It is just a one-time evaluation, an opinion. If we do not find any problems, we cross that off our list and move on.
• The assessment is like a blood test; if everything is normal, we go on, and if not, we deal with it.
• We take vital signs (blood pressure and temperature) at every office visit for the same reason because problems in these areas are not always obvious, yet if not diagnosed and treated, they can cause severe harm.
• Identifying any emotional, anxiety, or relationship issues earlier means they can be dealt with properly, and if we find nothing, we proceed.  

Most patients with ED will not have an underlying psychological cause, but just having ED will damage relationships, increase stress, diminish self-esteem, and create anxiety, all of which interfere with a successful outcome. 

Blood Testing

There are no specific tests required for the initial evaluation of ED. However, many clinicians will order routine blood testing to include a complete blood count (CBC) and electrolytes, baseline renal and liver function tests, HgbA1c to screen for diabetes mellitus, and a lipid profile. Checking a morning testosterone level is recommended by the 2018 AUA Guidelines on Erectile Dysfunction. However, some experts feel it is not necessary unless there are other symptoms suggestive of hypogonadism, such as loss of sexual desire or testicular atrophy on physical examination.[66] If not measured initially, check morning testosterone levels to rule out hypogonadism if patients fail oral PDE-5 ED therapy.[66] Other blood tests that may be requested include LH and prolactin (if hypogonadism is present) and sickle cell testing in patients of African/Caribbean descent. Measure thyroid function (TSH) and prostate-specific antigen in appropriate patients (optionally). We refer patients with abnormal laboratory test results to their primary healthcare providers for further evaluation and treatment. 

A standard laboratory workup might include CBC, a comprehensive metabolic panel (CMP, which includes liver and renal function), a lipid profile, TSH level, HgbA1c, and a morning testosterone assay on all new patients presenting for evaluation of their ED.

Shared Decision Making 

According to the 2018 AUA Guidelines Statement on ED, the recommended approach to patients with ED involves shared decision-making. In this approach, the clinician informs and educates the patient and his partner using the best available evidence about the various appropriate treatment options available to them; further diagnostic testing may be reasonable or advisable.[66][74] A frank discussion about the pros and cons of testing and treatment ultimately leads to an informed patient choice that corresponds to the couple's values and preferences.[75] This is similar to the older "goal-oriented" approach of famed urologist Dr. Tom Lue, who urged healthcare professionals to focus on realistically discussing therapeutic options with patients to facilitate their personal treatment selection rather than pursuing extensive testing, which ultimately does not significantly affect outcomes. 

The basis for this approach is that, with the possible exception of psychotherapy for purely psychogenic ED, there is no effective cure; identification of the underlying cause is only helpful in detecting other potential health issues and comorbidities. Given this fact, the focus changes from expensive diagnostic testing that will not significantly affect the outcome to facilitating patient treatment selection after a detailed discussion on reasonable therapeutic options. With this in mind, no other investigations are generally required for patients with ED, although specialized testing may be helpful in selected individuals.[66] 

Further Testing (Optional)

All of the following tests for patients with ED should be considered optional for selected patients only.

Penile biothesiometry involves a straightforward office screening test for penile neuropathy utilizing skin vibrational threshold sensitivity. The process entails placing a blunt-tipped vibrating probe on the right and left shaft, as well as the glans. Patients are required to indicate when they first sense the tip vibrating, determining their threshold vibrational sensitivity. This value is compared to age-based normal standards after obtaining 5 separate readings at each site and averaging the results.[76] While it does not directly examine erectile nerves, it is a reasonable, safe, and cost-effective office test for penile neuropathy. Patients who test positive may undergo more specialized nerve testing.[76][77][78]While not confirmed, some have suggested that individuals with an abnormal biothesiometry test might display hypersensitivity to intracavernosal injection therapy due to denervation hypersensitivity.

Nocturnal tumescence testing (NPT) proves valuable in distinguishing psychogenic from organic erectile dysfunction. Testing involves measuring the frequency, tumescence (circumference changes), duration, and maximal rigidity of nocturnal erections. Nocturnal erections require complete functioning of the neurovascular axis and typically occur during REM sleep. An average functioning man has between 3 and 6 erections a night, with a mean duration greater than 30 minutes, maximal rigidity greater than 70% at both base and tip, as well as an increase in circumference of over 3 cm at the base and 2 cm at the tip.[79] This process is then repeated, usually for 3 nights. Men with purely psychogenic ED will typically demonstrate normal NPT tracings, while those with organic problems will show abnormal nocturnal erectile activity. Hypogonadism will often cause a decrease in rigidity while maintaining some tumescence in NPT studies.[80][81] Today, NPT monitoring is rarely used or considered necessary to distinguish psychogenic from organic erectile dysfunction reliably. A careful and detailed personal and sexual history typically allows for the determination of significant psychogenic factors.[71]

Penile duplex Doppler ultrasound measures arterial vascular flow and checks for cavernous veno-occlusive dysfunction (venous leak).[82] This test may also be helpful after penile trauma, post-priapism, Peyronie disease, and in patients with ED who fail to respond to oral agents.[82] The ultrasound is typically done by giving the patient an intracavernosal injection of a vasoactive drug, usually 20 μg of prostaglandin E1. (This also serves as a clinical trial of penile injection therapy.) Following the injection, the peak systolic velocities (PSV) are measured. A normal value is > 35 cm/s, while a reading of < 25 cm/s suggests arterial insufficiency. The value of < 25 cm/s was found to have 100% sensitivity and 95% specificity for patients with abnormal pudendal arteriography.[83] Hypertensive patients who have vasculogenic ED, as demonstrated by a significantly reduced cavernosal arterial flow on duplex ultrasound, should be referred for a complete cardiac evaluation due to their increased cardiovascular risk.

Ultrasound can also demonstrate cavernous veno-occlusive dysfunction, often called "venous leak" by patients; this finding represents the failure of penile corporal rigidity despite adequate arterial inflow. Venous leak becomes evident when rapid detumescence occurs despite normal peak systolic and end-diastolic velocities (EDV > 5 cm/s).[84] Measuring the vascular resistive index (RI) can aid in the diagnosis of veno-occlusive dysfunction. Calculate RI using the formula: RI = (PSV-EDV)/PSV. An RI < 0.75 is consistent with veno-occlusive dysfunction.[85] The main benefits of this investigation are its non-invasiveness and its ability to exclude both penile arterial and venous dysfunctions accurately. However, the results are very user-dependent, and abnormal anatomy can give erroneous readings. Further, the information provided would remain the same treatment for most patients. Refer hypertensive patients who have vasculogenic ED and demonstrate significantly reduced cavernosal arterial flow on duplex ultrasound for a complete cardiac evaluation.

Use dynamic infusion cavernosometry and cavernosography for patients in whom a site-specific venous leak is suspected--usually for patients who have suffered pelvic/perineal trauma or those who have primary erectile dysfunction (ie, have never been able to achieve an erection). These tests usually precede corrective vascular surgery.[86][87] Two needles are placed in the penis to infuse saline simultaneously and measure intracavernous pressure. The inability to raise intracavernous pressure to match the mean systolic blood pressure with the saline infusion or the sudden fall in intracavernous pressure after stopping the saline infusion demonstrates veno-occlusive dysfunction.[86][87] Cavernosography shows the site of the veno-occlusive dysfunction.[88] 

Pudendal arteriography provides a clear visualization of the penile arterial vasculature. This test is reserved for young patients with erectile dysfunction resulting from trauma in cases where revascularization surgery is a potential consideration.[89] The anatomy of the internal iliac, internal pudendal, and penile arteries are carefully studied.[89] The inferior epigastric arteries are also examined for potential use in penile revascularization.[89]   

Endothelial cell dysfunction can be tested by various means, such as the penile nitric oxide release test, peripheral arterial tonometry, and flow-mediated dilation. There are also different serum markers such as C reactive protein, endothelin 1, vascular cell adhesion molecule-1, as well as the presence of endothelial progenitor cells and microparticles.[90] None of these tests for endothelial cell function has much current clinical utility, and they are of research interest only at present.

Treatment / Management

Initial treatment involves improving general health status through lifestyle modifications. This treatment not only improves erectile function but reduces cardiovascular risk. Recommended lifestyle modifications would include the following:

• Increased physical activity
• Switching to a Mediterranean diet or nutritional counseling
• Stopping smoking, drugs, and alcohol
• Gaining reasonable control of diabetes, lipids, and cholesterol

Carefully review the patient’s drug history to remove or alter the doses of offending medications. Offer men who have a psychological cause psychosexual counseling. With the patient’s consent, this counseling should be offered to the partner as well. 

L-arginine is an amino acid supplement that is the essential substrate for producing nitric oxide synthase, the enzyme that produces nitric oxide in the body. Supplemental L-arginine increases nitric oxide synthase levels, theoretically improving erection function. Several studies have shown some efficacy in treating mild to moderate ED with L-arginine supplementation (1500 mg to 5000 mg).[91]

Eroxon is a proprietary topical gel and the only OTC product with an FDA recommendation for treating ED. The gel contains carbomer, ethanol, glycerine, propylene glycol, and potassium hydroxide. After applying the gel to the glans penis, which takes about 15 seconds, the gel quickly evaporates and provides an immediate cooling effect on the glans. This rapid cooling stimulates the nerves and induces tissue warming, resulting in the relaxation of smooth muscles. Consequently, this process enhances blood flow to the corpora and relaxes intracavernosal smooth muscles, promoting erectile function and rigidity.

The gel has successfully treated ED in about 60% of men, typically within just 10 minutes. At 20 minutes, the success rate increased to 75%, equivalent to the reported efficacy of prescribed oral agents. This efficacy was maintained over 12 and 24 weeks in studies, with minimal side effects. Unfortunately, there are only a few studies with a limited number of individuals available on this gel. Only one of the studies was double-blinded, and none were placebo-controlled. It is unclear how this new gel might work with existing ED therapies, such as phosphodiesterase-5 inhibitors like sildenafil and tadalafil. The gel is currently available in the UK and Belgium. When it will be available in the US is still undetermined. While the expected cost in the US is unknown, in the UK, a single application cost is equivalent to $8.

Oral phosphodiesterase-5 inhibitors (PDE-5 inhibitors), such as sildenafil and tadalafil, are usually the first-line treatment of ED. They are effective in a wide range of etiologies, including cardiovascular disease, diabetes, hypertension, and hypogonadism.[92] PDE-5 inhibitors act by decreasing the degradation of cyclic GMP via phosphodiesterase inhibition, which increases the relaxation of cavernosal smooth muscle and intracavernosal arterial blood flow. It is important to note that PDE-5 inhibitors do not initiate the erectile response. Sexual stimulation is required to release nitric oxide from the vascular endothelium and penile nerve endings to commence the erectile process. PDE-5 inhibitors are highly effective and have an overall success rate of up to 76%.[93] Patients on sildenafil should remember to take it on an empty stomach, or it will not be absorbed. 

Adverse events will occur in about 40% of patients but are usually mild. The most common side effects are headache, indigestion, nasal stuffiness, and mild visual changes such as temporary light sensitivity or bluish coloration to vision. There have been rare reports of permanent blindness from non-arteritic anterior ischemic optic neuropathy with PDE-5 inhibitors.[94][95] There are also rare reports of unilateral deafness, typically starting within 24 hours of ingestion, related to these drugs.[96][97][98] Fortunately, these reactions are rare, but patients should be appropriately informed. 

Different PDE-5 inhibitors have varying half-lives, which can influence the patient’s final selection. Note the importance of using these drugs with antihypertensives and alpha-blockers with caution. They should not be used at all with nitrates due to potentially dangerous, profound hypotension. 

Patients who fail PDE-5 inhibitor therapy should try at least one other PDE-5 medication, as up to 50% of initial treatment failures will respond to a different PDE-5 drug. (Check testosterone levels in patients who fail PDE-5 therapy if this was not measured earlier.) Those who are hypogonadal might benefit by adding testosterone supplementation to their PDE-5 inhibitor therapy.[99] 

Instructing patients on how to take their medication correctly is essential. For example, sildenafil is poorly absorbed and might be ineffective if taken with food, and it also frequently requires several therapeutic tries before it begins working successfully.

Results from studies on adding daily L-arginine supplements to sildenafil or tadalafil therapy demonstrated a significant improvement in IEFF scores and erectile function compared to sildenafil or tadalafil monotherapy.[91][100][101]

Testosterone supplementation appears to be more effective as a treatment for low libido than for ED.[102][103] Recommend starting with oral PDE-5 inhibitors as the initial therapy for most patients with both ED and hypogonadism. Testosterone supplementation is reasonable in those with proven hypogonadism and ED who have already failed PDE-5 inhibitor therapy or who also have low libido. Patients with hypogonadism with borderline erectile rigidity are most likely to benefit from testosterone supplementation. The patients with ED who received the most significant benefit from testosterone supplementation were those with the most severe level of hypogonadism.[104] Overall, only 35% of all patients with hypogonadism with ED will show significant improvement in their erectile function from testosterone supplementation.[105] Testosterone monotherapy is not considered an effective treatment for ED.[66]

External vacuum devices are an excellent, non-surgical option for many patients with ED. The outer cylinder of the device is placed over the penis and pressed to the body to create an airtight seal. The patient then uses a small, hand-operated (or battery-powered) vacuum pump to create negative pressure around the penis, which engorges the corpora with blood. Placing an elastic band around the base of the penis maintains the artificial erection. The vacuum can then be released, leaving the artificial erection maintained for up to 30 minutes. Practice with the device seems to improve outcomes, and manual dexterity is required. The efficacy rates of these devices have been high, at about 70% to 80%, but the patient satisfaction rates are low.[106][107] 

External vacuum device therapy is a cost-effective, safe, and highly efficient long-term treatment for ED, suitable for frequent use if desired. However, using the device initially requires practice for optimal performance. It remains a good, safe, and effective noninvasive option for patients who deem it practically acceptable.

Intraurethral prostaglandin E1 (alprostadil) pellets (also called medicated urethral system for erection or MUSE) are available for use as urethral suppositories. The pellets are small, about the same size as a grain of rice. The patient first voids and then places the tip of the insertion device inside the urethral meatus and pushes the plunger to deposit the prostaglandin E1 pellet into the pre-moistened distal urethra, where it will dissolve with a gentle hand massage. The medication is absorbed through the urethra and makes its way to the corpora cavernosa, where it causes muscle relaxation, resulting in an erection. Overall efficacy is reportedly good, generally at about 50% to 65%.[108][109] Results from a large, double-blinded, placebo-controlled study of over 1500 men with chronic ED found that two-thirds responded to intraurethral prostaglandin E1 pellet therapy sufficiently to have intercourse.[109] 

Intraurethral prostaglandin E1 pellets are commercially available in 4 different strengths, but the 2 largest dosages are used most often (500-1000 mcg.) Side effects include urethral burning and somewhat variable efficacy even from the same dosage, possibly depending on the precise site of pellet application. This therapy is used relatively infrequently due to its high cost, the variability of efficacy, and the frequent need for patients to purchase at least 6 doses at a time.

Intracavernosal Injections with prostaglandin E1 are frequently the next choice of therapy if oral PDE-5 inhibitors are unsuccessful.[106] Intracavernosal injections of papaverine (an alpha-blocker and vasodilator) as a therapy for ED were first described in 1988 and have delivered good results.[110] Since then, several agents have been found that can cause smooth muscle relaxation, vasodilation, and erections when injected (alone or in combination) into the corpora cavernosa. These include papaverine, prostaglandin E1, phentolamine, and atropine.[111][112][113]  

The single agent used most frequently today is prostaglandin E1, which has fewer systemic adverse events and good efficacy while offering reduced priapism risk and less fibrosis compared to other agents. This agent works via its effects to increase cavernosal cyclic AMP, the body’s most effective, natural smooth muscle relaxant and is the only FDA-approved agent for intracavernosal injection therapy of ED.[66]

A single injection, which is sufficient as the corpora cavernosa shares vascularity, is done on the side of the penile shaft near the base to avoid the urethra (ventrally) and the dorsal neurovascular bundle.[114][115] Patients should switch sides to minimize scarring. Typically, use short, 27 to 30-gauge needles with 1 cc syringes of insulin type. Intracavernosal injection therapy has demonstrated high effectiveness in up to 94% of patients.[116] However, prostaglandin E1 is relatively expensive and somewhat painful when injected into the corpora. Combination therapy has become popular using a relatively standard combination of papaverine 30 mg, phentolamine 1 mg, and prostaglandin E1 20 mcg/cc (known as “TriMix”) or by adding 0.2 mg of atropine to make “QuadMix.” These combinations need to be prepared by a compounding pharmacy. In general, they are about twice as effective as prostaglandin E1 alone, tend to cost less, and usually avoid the discomfort associated with intracavernosal prostaglandin E1 injections when used alone. Dosages and concentrations can be adjusted to double strength levels if needed. Only prostaglandin E1 is recommended by the FDA for intracavernosal injection therapy for ED.[66]

Usually, the initial trial dosage is 0.2 to 0.25 cc, which increases slowly to give the patient a rigid erection for a reasonable time; no more than 90 minutes and optimally only about 45 minutes. If the corpora cavernosa are healthy with good vascularity, intracavernosal injections are almost always going to be successful. Failure of intracavernosal injection therapy is a good diagnostic indicator of vasculogenic ED. Side effects from intracavernosal injections include pain, priapism, bleeding or bruising at the injection site, and scarring of the tunica. 

Patients need to be carefully counseled not to exceed the recommended dosage for them as it is highly tempting to inject more medication “just to be sure” or because the initial effect appeared sub-optimal. Be prepared to offer a priapism antidote (usually a diluted phenylephrine solution) either in their office or in the emergency department.[117]

Patients must be warned not to increase the injected dosage without the approval of their clinician, not to mix it with other ED agents such as PDE-5 inhibitors, and to go to the nearest emergency department for reversal therapy if their erection lasts longer than 4 hours to prevent permanent damage to the corpora. 

Combined therapy with intracavernosal injections (or intraurethral prostaglandin pellets) plus the addition of a PDE-5 inhibitor can be very effective if neither treatment alone is successful.[112][118][119][120] The two treatments use different chemical mediators (cyclic AMP for injections, cyclic GMP for PDE-5 inhibitors), which synergistically enhances their combined activity. While effective, the risk of priapism increases, and experience with this type of combined therapy is limited.[121][122][123] Nevertheless, it may be worth a clinical trial before considering penile prosthesis surgery or giving up entirely on those who are not surgical candidates.[124]

Penile prostheses are a surgically invasive treatment typically offered when all other, less intrusive measures fail or are otherwise unacceptable. These devices are surgically inserted into the corpora cavernosa to restore erectile function artificially. There are 2 main types available: malleable and inflatable. The malleable prosthesis is physically manipulatable into a straight or bent position per the patient’s wishes. The inflatable type becomes erect by activating a small pump in the scrotum, which fills the inflatable penile balloon cylinders from a hidden fluid reservoir surgically implanted in the lower abdomen. Older men with limited manual dexterity or mental health issues find the malleable prostheses more manageable. In contrast, most men, especially from younger generations, typically prefer inflatable devices due to their more natural operation and function. Patients with diminished pelvic or penile sensation might have better outcomes with inflatable devices to avoid painless ulcers and erosions due to excessive pressure from the malleable rods on the skin.

Complications from these devices include erosion, leakage, infection, and possible mechanical failure. Early inflatable penile prostheses had many problems, including infections, penile deformities, aneurysm formation, leakage, pump failures, and other mechanical issues. Current devices have resolved these problems and are mechanically reliable. The current mechanical failure rate for inflatable prostheses is <5% over 5 years.[125][126] Other improvements include antibiotic or hydrophilic coatings that further reduce the risk of infection.[127][128][129][130][131] The overall infection rate for penile prostheses is now only about 3% but might be as high as 10% in patients with prior implants, diabetes, or spinal cord injuries.[132][133]

Although many patients with this condition will not wish to have surgery, penile prosthesis implantation procedures tend to have very high patient satisfaction scores (about 90%).[134][135] Long-term results are not quite as good, with only 41% of patients indicating they are still using their penile prosthesis after 20 years.[134][136]

Penile revascularization surgery is performed only in a small subgroup of patients, with an estimated occurrence rate of 5% in all patients with ED.[137] This is ideally considered for younger patients (less than 30 years) with ED following pelvic/perineal trauma who have sustained an isolated vascular injury. Arterial insufficiency must be demonstrated on penile Doppler ultrasound and then identified on a formal arteriogram. Perform the revascularization operation by anastomosing the inferior epigastric artery to the dorsal artery of the penis or directly to the corpus cavenosum. Long-term results are only marginal.

Arterial balloon angioplasty has been done successfully for focal arterial stenosis of the pudendal or penile arteries. However, improvement does not usually last due to recoil arterial narrowing and restenosis unless using drug-eluting stents. This therapy is not yet the standard of care and is only helpful in patients with focal, identifiable arterial stenosis in vessels large enough to accept a stent.[138][139][140]

Venous ligation surgery for veno-occlusive dysfunction involves embolizing or ligating the penile veins (eg, the deep dorsal vein). This surgery is not recommended as long-term results do not show lasting efficacy.[66][138][141]  

Low-intensity shockwave therapy has shown efficacy, particularly in patients with severe ED not responding to PDE-5 inhibitors.[142][143][144][145][146] Its presumed mechanism of action is through improved cavernosal hemodynamics, induction of endothelial cell proliferation, and activation of endogenous stem cells as well as from penile revascularization. Shockwave therapy increases angiogenic factors that promote neovascularization, restore smooth muscle activity, and attract stem cells. This therapy also increases vascular endothelial growth factor, neuronal nitric oxide synthase, and other natural bioactive agents.[147] The exact mechanism of action of shockwave therapy is not well understood, but it does seem that the effect is dose-dependent, as 3000 pulses per session give better results than 1500 or 2000 pulses.[143]

While early results appear promising in optimal candidates, some study results have shown no effect.[148] Meta-analysis of all the currently available studies has demonstrated that low-intensity shockwave therapy generally provides a clinically significant short-term improvement in erection rigidity and function. However, the lack of long-term data makes it difficult to recommend at this time.[149] Overall, low-intensity shockwave therapy appears to be a reasonable, safe, and moderately effective initial therapy for relatively healthy patients with mild to moderate ED, with an overall success rate of 30 months in about 40% of patients.[146][149][150] Negative risk factors that limited successful outcomes include advanced age, hypertension, smoking, obesity, hyperlipidemia, high pre-therapy SHIM (Sexual Health Inventory for Men) scores, and lengthy duration of ED. Low-intensity shockwave therapy is relatively useless in men with severe ED.[151] The therapy is still considered investigational in the US and is not recommended by the FDA.[66]

Intracavernosal stem cells and platelet-rich plasma therapy are promising but experimental, requiring more investigation.[66][152][153][154][155][156][157]

Several studies are looking at penile rehabilitation therapy after radical prostatectomy surgery that suggests a benefit, but there is no consensus on the exact treatment selection, duration, or timing. The majority of the published studies suggest a combination of PDE-5 inhibitors together with external vacuum device therapy offers the best results, although intraurethral pellet therapy and intracavernosal injections have been successful.[158] Tadalafil offers a theoretical benefit over sildenafil based on its longer half-life and pharmacokinetics, but there is insufficient data to make any formal recommendation.[159][160][161][162] Early use of penile rehabilitation treatment is recommended lasting up to 1 year after surgery, but the exact timing has not been adequately studied.[159][160][161][162]

Though there is currently insufficient data to support any recommendation, it seems reasonable that penile rehabilitation techniques should also help prostate cancer patients who select definitive radiation therapy.[163] Nevertheless, with sildenafil and tadalafil now being generic and low-cost, there seems to be little harm in recommending their early use after definitive prostate cancer treatment.

Differential Diagnosis

The primary differential diagnoses for ED would be hypogonadism, loss of libido, depression with low mood, and other psychological conditions. This condition may be the first manifestation of diabetes or cardiovascular disease, as well as depression. Differentiating between true erectile dysfunction and other sexual disorders, such as premature ejaculation, is essential and usually easily accomplished by obtaining a good sexual history of the patient.

Prognosis

The prognosis of ED is dependent on the cause. Psychosexual causes generally have a good response to counseling, and most other causes of ED respond favorably to oral PDE-5 inhibitors.[164] If not, there are multiple other options for treatment, including external vacuum devices, intraurethral prostaglandin pellets, intracavernosal injections, and combined therapy. Patients rarely fail all of these non-surgical options; there is still penile prosthesis implantation surgery, which remains highly successful. Almost every patient with ED can be treated successfully with the currently available therapies.

Complications

Complications of ED can cause a strain on relationships and negatively impact the quality of life of these patients. The cardiovascular pathologies and diabetic complications that may accompany this condition are correlated with other health issues as well.

Priapism from PDE-5 inhibitor medications is relatively uncommon at only about 3% of all priapism cases despite the widespread use of these drugs. Penile injection therapy is involved in about 8.8% of priapism cases and trazodone in about 6%, while second-generation antipsychotic drugs are responsible for 33.8%.[165]  

Treatment for drug-induced priapism is intermittent intracavernosal injections of diluted phenylephrine solution, 200 μg at a time, about 5 to 10 minutes apart until detumescence or when a maximum dose of 1 mg of phenylephrine is delivered. If this fails, a surgical shunting procedure will be necessary. Treatment should begin quickly, as permanent corporal fibrosis can occur with delayed therapy.[166][167]

Deterrence and Patient Education

One of the most important messages to the public would be that this condition is treatable and men should seek help if they suffer from erectile dysfunction. To prevent the condition, positive, healthy, basic lifestyle choices should be addressed such as smoking, diet, and exercise.[168] It is also paramount to aggressively treat existing medical conditions, such as diabetes, obesity, and hypertension, properly.

Pearls and Other Issues

Extensive and expensive diagnostic testing for ED is not warranted as there are no curable organic causes. Basic blood tests for testosterone level, lipids, HgbA1c, thyroid, renal, and kidney function are reasonable, but more extensive testing is unnecessary for most patients. Instead, the focus of treatment is generally to assist the patient in selecting the optimal therapy for him and then giving it a clinical trial. Penile prosthesis surgery is usually for patients who have failed all other treatment options and are still highly motivated to have erectile function restored. 

When oral PDE-5 agents do not work, make sure they are correctly taken and check the testosterone level of the patient.

While mechanical and obvious, external vacuum devices are reliable and work reasonably well for most patients. In one study, where 1500 ED patients were carefully taught, counseled, and followed, the success rate in achieving an adequate erection was an astonishing 94.5%.[107]

Yohimbine is a tree bark that has been used for decades as an oral therapy for ED, primarily before the advent of PDE-5 inhibitors, by having a central and peripheral effect on erectile function and blocks presynaptic alpha-adrenergic receptors, which decrease adrenergic tone while increasing cholinergic effects. Yohimbine is safe and inexpensive, with no significant adverse events noted. Yohimbine poses challenges as it requires 3 times daily dosing, and clinical studies did not show significant efficacy compared to a placebo. Consequently, the 2018 AUA Guidelines on Erectile Dysfunction did not include a recommendation for this therapy. There is, however, renewed interest in using yohimbine in combination with PDE-5 inhibitors, but there is insufficient data to recommend it.[169][170][171]

Trazodone is a sedative and antidepressant that is often still used as a sleep aid.[172] A high risk of priapism was noted in patients taking trazodone, so some practitioners began using it off-label to treat ED.[173][174][175] While this therapy has clearly shown some good activity in treating ED, particularly in patients with psychogenic erectile dysfunction, its effectiveness when used in combination with PDE-5 inhibitors and the optimal dosage is unestablished, although a dose of 150 to 200 mg has been suggested.[176]

In a patient who has failed all other treatments short of penile prosthesis surgery, consider a trial of combined therapy with a full dose intracavernosal injection, such as 1 cc of "TriMix" or "QuadMix," together with a PDE-5 inhibitor. While data is limited and the risk of priapism increases, there is a reasonable chance this will work and prevent the need for surgery.

Venous leak surgery is unrecommended due to poor outcomes.

Many other ED treatments are investigational only. Such experimental treatments include low-intensity extracorporeal shockwave therapy, intracavernosal stem cell installation, endovascular revascularization with angioplasty of the pudendal or penile arteries, and platelet-rich plasma therapy.[138][147] Of these, stem cell therapy appears to be the most promising and is being actively investigated.[177]

Warn patients about the dangers of taking dietary supplements that claim to improve sexual performance, confidence, or stamina. Many of these products, from one-third to half, have been found to contain PDE-5 inhibitors, which can be dangerous for patients taking nitrates for cardiovascular disease.

Evaluation and Treatment Summary

• Inquire about sexual health in all adult patients. Use a non-threatening, non-judgmental intonation and use phraseology such as, "How is your sex life? Is everything working OK for you?"
• Be aware that if the patient gives a qualified or hesitant answer, it probably indicates he has a sexual problem.
• The next step is a careful medical and sexual history, together with a comprehensive physical examination.
• Clues to possible psychological causes include sudden onset of ED, high erectile variability, good morning erections, and good erections with masturbation or alternate partners.
• Refer psychogenic sexual disorders to appropriate mental health providers.
• No specific testing for ED is required, but a blood panel consisting of a morning testosterone level, CBC, CMP, liver and renal function, lipid panel, HgbA1c, and TSH would not be unreasonable.
• No other tests are required or recommended for most patients with ED.
• Employ "shared decision making" by carefully discussing the pros and cons of all the various treatment options that are not contraindicated with the patient and their partner if possible.
• First-line therapy is usually with oral PDE-5 inhibitors. Make sure the patient takes them correctly.
• Try at least 2 different oral agents before moving on to another therapy. Check serum and morning testosterone levels in all patients who fail oral PDE-5 therapy.
• Intracavernosal injections are usually the subsequent treatment, but remember intraurethral suppositories and external vacuum devices.

If even 1 full cc of double strength "TriMix" or "QuadMix" injections are not working, and all other non-surgical therapies, such as external vacuum devices, have been tried unsuccessfully, consider a trial of combined therapy by asking the patient to take an oral PGE-5 inhibitor about an hour before the "Trimix" injection—before going on to penile prosthesis surgery. Tell patients to be cautious when using combined therapy of this type, as it carries a high risk of inducing priapism. This therapy is a consideration only for patients who have failed all other treatment options and are considering a penile prosthesis or just giving up. Failure of this combined therapy to work indicates severe damage to the corpora cavernosa, which may only be relieved by a penile prosthesis implant.

Enhancing Healthcare Team Outcomes

ED is managed in the community with the help of primary healthcare providers, specialist nurses, pharmacists, and psychologists. However, patients who are unresponsive to initial management should be referred to secondary services, classically urologists, for further investigations and management.[66] Prompt diagnosis and treatment can reduce the emotional stress felt by patients and their partners.

Effective management of ED demands a collaborative approach involving various healthcare professionals to optimize patient-centered care, outcomes, and safety. Physicians lead by diagnosing underlying causes, devising treatment strategies, and ensuring interprofessional communication. Advanced practitioners contribute by conducting assessments, discussing treatment options, and offering patient education. Nurses play a crucial role in patient education, providing emotional support, and monitoring treatment adherence. Pharmacists ensure accurate medication selection, dosage, and potential interactions. Team communication among these professionals fosters comprehensive care and minimizes medication errors. Care coordination involves streamlining appointments, facilitating referrals, and monitoring patient progress. The synergy of these roles ensures a holistic approach, enhances patient safety, and improves team performance, resulting in optimized outcomes for individuals with ED.