AUA & CUA: Erectile Dysfunction (2021 CUA, 2018 AUA)

See Original 2018 AUA Guidelines

See Original 2021 CUA Guidelines

Diagnosis and Evaluation

UrologySchool.com Summary

	2018 AUA§	2021 CUA§
Mandatory	History and physical exam Diabetes screen (fasting glucose or HbA1c) Serum testosterone	History and physical exam
Recommended	Questionnaire	Diabetes screen (fasting glucose AND HbA1c) in patients with either suspected vasculogenic or idiopathic ED Fasting lipids in patients with either suspected vasculogenic or idiopathic ED Serum testosterone in patients with symptoms of testosterone deficiency or failure of PDE5 inhibitor
Optional	Fasting lipids Serum BUN/Cr Specialized testing	Questionnaire

History and Physical Exam

History (medical, sexual, and psychosocial)

• May identify the medical condition and also specify reversible or treatable factors associated with ED
• Determine that the problem is ED versus other aspects of the sexual response cycle (desire, ejaculation, orgasm) or from other causes (Peyronie’s disease, lifestyle factors including illicit drug use, quality of partners relationship)
  • See Campbell's 11th edition Tables 27-2 and 27-3
• Because of the complexity of sexuality and the impact of a sexual relationship on a man’s life, it is strongly advised that a male’s partner be invited to participate in this process whenever possible and clinically appropriate.
• Signs and Symptoms
  • Onset of symptoms (the timing of specific symptoms should be ascertained in relation to the onset of ED as these symptoms may be primary causes of ED or secondary effects of the ED condition)
  • Symptom severity
  • Whether symptoms have been stable or are progressive (worsening symptoms may suggest progressive underlying comorbidities, particularly cardiovascular comorbidities)
  • Degree of bother
  • Changes in libido, orgasm, ejaculation, genital pain and penile morphology (possible presence of Peyronie’s disease)
  • Situational factors (e.g., occurring only in specific contexts, only when with a partner, only with specific partners), circumstances that facilitate or hinder erectile function
  • Presence of nocturnal and/or morning erections (suggests, but does not confirm, a psychogenic component to ED symptoms that would benefit from further investigation), masturbatory erections
• Risk factors
  • Comorbid medical conditions: hypertension, peripheral vascular disease, diabetes, obesity, and renal disease
  • Pelvic surgery, radiation or trauma
  • Medications
  • Prior use of erectogenic therapy
  • Comorbid sexual conditions: premature ejaculation, anorgasmia, low libido, and Peyronie's
  • Evaluation of psychological factors (i.e., depression, anxiety, relationship conflict, stressors at home or work) and psychosexual issues addresses psychogenic contributions to clinical presentations.
    • Patients may not appreciate that depression, anxiety, stress, and relationship conflicts can interfere with the physiological processes necessary for erectile function. Thoughtful discussion of these issues with men and their partners is a key component of patient education and can promote acceptance of incorporating a mental health/sexuality expert into the treatment plan.
      • In situations in which sudden or severe ED is likely to develop (e.g., men considering definitive therapy for pelvic cancers) early inclusion of psychosexual expertise on the treatment team is critical to development of an effective and feasible treatment plan
  • Lifestyle factors: smoking, substance use/abuse, sedentary lifestyle
• Questions that may help to differentiate psychogenic from organic erectile dysfunction (5):
  1. Presence of nocturnal erections?
     • Psychogenic ED: often present
     • Organic ED: reduced
  2. Presence of erection during masturbation or with alternate partners?
     • Psychogenic ED: often present
     • Organic ED: reduced
  3. Significant recent psychosocial stress?
     • Psychogenic ED: strong impact
     • Organic ED: minimal impact
  4. Feelings of performance anxiety around sexual activity?
     • Psychogenic ED: strong impact
     • Organic ED: minimal impact
  5. Situational variability of erectile dysfunction (improved while on vacation)?
     • Psychogenic ED: potential for wide variability
     • Organic ED: minimal variability

Physical exam (5)

1. General exam
   • Vitals
     • May identify hypertension which may contribute to ED
   • Body habitus (waist circumference, BMI)
   • Signs of testosterone deficiency (2):
     • Gynecomastia
     • Virilization (under-developed facial/pubic/axillary hair)
2. Genitals
   • Penile length and girth, presence of penile plaques, phimosis, frenular tether, meatal stenosis,
     • Examination of the penis for occult deformities or plaque lesions should occur with the penis held stretched and palpated from the pubic bone to the coronal sulcus.
3. Scrotum
   • General assessment of the scrotal skin
   • Palpation of the testicles to assess for size, consistency, and location.
4. Groin for quality of femoral pulses
5. Neurological exam
   • Sensory evaluation should be an integral part of the evaluation for ED in all patients with or without an apparent neurologic disorder, to identify potential neurogenic cause of ED

• Digital rectal examination is NOT required for evaluation of ED; however, BPH is a common comorbid condition in men with ED and may merit evaluation and treatment.

Labs

Guideline Recommendations

• 2018 AUA§
  • All males (2):
    1. Fasting glucose or hemoglobin A1c (screen for occult diabetes)
    2. Morning total testosterone
  • Optional
    • Fasting lipids
    • Serum BUN/Cr
    • Other: optional testing such as thyroid-stimulating hormone (TSH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH), prolactin, complete blood count (CBC), and urinalysis are added when dictated by clinical context.
• 2021 CUA§
  • Fasting glucose or hemoglobin A1c in patients with either suspected vasculogenic or idiopathic ED
  • Fasting lipids in patients with either suspected vasculogenic or idiopathic ED
  • Morning total testosterone if (2):
    1. Symptoms of testosterone deficiency
    2. Failure of phosphodiesterase type-5 inhibitors

Serum testosterone

• Typical range for total testosterone measurement is 250 to 1000 ng/dL
  • Because of individual variability, the normal range for which replacement therapy should be initiated remains unknown
• If the testosterone level is below or at the low limit of normal, blood draw should be repeated for confirmation; a mildly abnormal testosterone level might be found to be normal in 30% of patients on repeat testing.
• When proceeding with a second total testosterone determination, assessment of LH and prolactin should also be included.
  • Measurement of serum gonadotropin will help to localize the source of the hypogonadism.
    • Elevated serum LH and FSH releases are appropriate pituitary responses to the low serum testosterone levels, which is consistent with testicular failure (primary hypogonadism).
      • See Causes of Primary Hypogonadism
    • Normal or low serum LH and FSH releases in the setting of low serum testosterone levels indicate an inappropriate response and suggest a central disorder (secondary hypogonadism), such as hyperprolactinemia.
      • See Causes of Secondary Hypogonadism
      • Hyperprolactinemia
        • Associated with ED
          • Identifying and addressing the underlying cause of hyperprolactinemia may improve ED
        • Causes hypogonadism by suppression of gonadotropin-release hormone from the hypothalamus, which impairs the pulsatile LH secretion required for serum testosterone production by the gonads.
        • Should be suspected if low serum testosterone and low or inappropriately normal LH.
        • Generally accepted guidelines provide indications for pituitary imaging: cases of severe central hypogonadism (testosterone <150 ng/dL) and suspicion of pituitary disease (i.e. panhypopituitarism, persistent hyperprolactinemia, or symptoms of tumor mass effect).
        • Management
          • A prolactin-secreting adenoma should be treated radiologically and if necessary surgically. Bromocriptine, a dopamine agonist that lowers prolactin level and restores testosterone to normal, serves to reduce the size of the tumour.
          • Neurological ablation becomes necessary if the therapeutic response to medication does not occur or visual effects are noted in association with optic-nerve compression.

Validated questionnaires

Uses (3)

1. Assess severity of ED
2. Measure treatment effectiveness
   • Greater improvements in IIEF-EF score necessary for satisfactory results in patients with more severe ED
3. Guide future management

Options (3)

1. Sexual Health Inventory of Men (SHIM)
   • Subjective patient-reported assessment of erectile dysfunction
   • 5 questions, minimum score 1, maximum score 25
     • Confidence
     • Firmness
     • Maintained erection after penetrated
     • Maintained erection to completion
     • Satisfaction
   • Links
     • Sexual Health Inventory for Men (SHIM) (pdf)
       • SHIM in Spanish (pdf)
2. International Index of Erectile Function (IIEF)
   • Consists of 15 questions that quantify 5 domains (follows typical sequence):
     1. Sexual desire
     2. Erectile function
     3. Intercourse satisfaction
     4. Ejaculatory/orgasmic function
     5. Overall sexual satisfaction
   • Validated in heterosexual population, but has been shown to be efficacious in men who have sex with men (MSM) population
   • International Index of Erectile Function (IIEF) (pdf)
3. Erection Hardness Scale (EHS)
   • Self-reported assessment of penile hardness
   • Scale of 0 (no engorgement) to 4 (complete rigidity)

Guideline Recommendations

• 2018 AUA: recommended
• 2021 CUA: can be useful

Specialized testing

Uses

• Can be used to differentiate between organic and non-organic causes of ED when the patient’s history is conflicting and in medico-legal cases
• Situations that may require more detailed evaluation include men with ED who are
  1. Young
  2. Strong likelihood of primary psychogenic etiology
  3. Strong family history of cardiac illness
  4. Concomitant PD
  5. History of pelvic trauma
  6. Failed prior ED therapies
  7. Lifelong ED

Options

• Nocturnal Penile Tumescence and Rigidity (NPTR) testing
• Audiovisual and vibratory stimulation
• In-office testing (3)
  1. Intracavernosal injection (ICI)
  2. Penile duplex ultrasound
  3. Biothesiometry

• Invasive testing (2)
  1. Cavernosometry and cavernosography
  2. Selective internal pudendal angiography

Nocturnal Penile Tumescence and Rigidity (NPTR) testing

• Quantifies the number, duration, and rigidity of nocturnal erections
• Involves placement of two strain gauges on the penile shaft to measure radial rigidity during sleep; the device is used over several nights’ sleep
• Historically used to differentiate psychogenic from organic causes of ED, with the presumption that men with psychogenic ED would have preservation of nocturnal penile erections.
  • Test is prone to false negatives and may be less useful in men with impaired sleep schedules.
• Recommended criteria for normal NPTR include:
  1. 4-5 erectile episodes per night
  2. Mean duration >30 minutes
  3. Increase in circumference >3cm at the base and >2cm at the tip
  4. Maximal rigidity >70% at both base and tip
• Limited availability in Canada and costs are not covered by most provinces

Audiovisual and vibratory stimulation

• Erotic stimulation by explicit videotape material with monitoring
• Has been used as a reliable as well as a time- and cost-effective alternative to NPTR to differentiate psychogenic from organic causes of ED

Intracavernosal injection (ICI)

• An erectogenic agent (e.g., prostaglandin E1, papaverine, and/or phentolamine) is injected into the corpora cavernosa of the penis. Erectile response is assessed 5-10 minutes post injection and typically after sexual stimulation (e.g. masturbation, exposure to audiovisual sexual stimulation). The erectile response is observed and rated by an independent assessor.
• The test is designed to bypass neurologic and hormonal influences involved in the erectile response and evaluates veno-occlusive function of penis. A normal test, based on the assessment of a sustainably rigid erection, signifies normal erectile hemodynamics. Alternative diagnoses of psychogenic, neurogenic, or endocrinogenic ED may then be considered.
• For some men, the sympathetic tone and anxiety involved with in-office penile injection may override the injection agent’s activity, leading to a false positive diagnosis of ED. Repeat dosing is recommended in such cases.
• In addition to providing information on penile vascular status, ICI may be useful to assess for penile deformities such as Peyronie’s disease

Penile duplex ultrasound

• Currently the gold-standard (most reliable, least invasive) in penile vascular evaluation
• Evaluates both cavernous arterial inflow and the veno-occlusive capacity of the penis
• Used to localize and measure the size and flow through the cavernous vessels, pre- and post-vasoactive injection which allow a more refined assessment of penile circulation. The test adds an imaging dimension and a quantification component to the evaluation of blood flow in the penis, distinct from the ICI evaluation, which relies on the assessor’s judgment alone
• Uses (4):
  1. Differentiation of primary psychogenic vs. organic etiology for ED
  2. Identification of males with severe veno-occlusive dysfunction resulting in ED who are unlikely to respond to medical therapy
  3. Identification of young males who may be candidates for penile revascularization procedures
  4. Assessment of arterial function in males who may warrant assessment by a cardiologist (i.e., males with predominantly vascular ED)
• Key parameters derived from penile duplex ultrasound include peak systolic velocity ([PSV], cavernosal artery blood flow rate at start of systole) and end diastolic velocity ([EDV], cavernosal artery blood flow rate at the end of diastole)
  • PSV <25-30 cm/s is considered evidence of arterial insufficiency (arteriogenic or vascular ED)
    • PSV consistently > 35 cm/s defines normal cavernous arterial inflow
  • EDV >5 cm/s is consistent with veno-occlusive dysfunction, though different cut-points have been applied.
  • Resistive Index (PSV – EDV) / PSV) <0.80 is indicative of veno-occlusive dysfunction

Biothesiometry

• Non-specific term for testing intended to assess for peripheral neuropathies
• Has been applied to the penis, most commonly by applying a device that administers vibrations of controlled and consistent intensity

Cavernosometry and cavernosography

• Cavernosometry quantifies intracorporal pressure after ICI and is useful primarily for establishing a diagnosis of veno-occlusive dysfunction.
• Typically, cavernosometry is performed in conjunction with cavernosography (intracorporal installation of radio-opaque dye) which permits detailed localization of any area(s) of leak
• Previously used in select patients who were suspected of having a site-specific vasculogenic leak resulting from perineal or pelvic trauma or who have had lifelong ED (primary ED). Rarely performed in the modern era since surgery for veno-occlusive dysfunction is not recommended, making anatomical localization from cavernosography largely irrelevant.

Selective internal pudendal angiography

• Accurately defines the arterial inflow of the penis
• Commonly reserved for
  1. Young patient with ED secondary to a traumatic arterial disruption or the patient with a history of penile compression injury, who is being considered for penile revascularization surgery
  2. Non-ischemic priapism

Guideline Recommendations

• 2018 AUA: For some men with ED, specialized testing and evaluation may be necessary to guide treatment. Specialized testing should only occur if findings will affect management
• 2021 CUA: rarely required in the routine assessment of patients with ED

Management

Options (6)

1. Conservative treatment
   1. Psychosexual counselling
   2. Medication change
   3. Lifestyle modifications
2. Phosphodiesterase type 5 inhibitors (PDE5i)
3. Vacuum erection device
4. Intraurethral alprostadil
5. Intracavernosal injections
6. Surgery

• Treatment approach as per 2021 CUA guidelines:
  1. First-line: PDE5Is
  2. Second-line: ICI or intraurethral alprostadil or vacuum device
  3. Third-line: surgery

Conservative treatment

Psychosexual counselling

• May represent a spectrum of approaches from a simple open discussion with the primary care physician to psychologist, sexual therapists and/or psychiatrists
• Consider referral to a mental health professional to promote treatment adherence, reduce performance anxiety, and integrate treatments into a sexual relationship
  • Many men avoid using ED treatments or discontinue using effective ED treatments because of beliefs about loss of masculinity and distress related to possible failure in a sexual situation.
  • Psychogenic ED is generally driven by a man’s anxiety related to the ability to achieve an erection. Medical treatments can be effective in these situations, but the addition of psychotherapy or psychosexual counseling may help men to use the medications more effectively and ultimately transition off medical ED therapies.

Medication change

• Certain medications are associated with ED. If this is found, consider changing to a different dose or type of medication entirely, this may reverse ED in some patients
• Offending drugs such as estrogens, morphine, sedatives, and neuroleptics should be discontinued

Lifestyle modifications

• Changes in diet, discontinuation of cigarette smoking, reducing alcohol, increased physical activity, improve overall health and may improve erectile function
• A change to a no-nose saddle from a conventional saddle has been shown to recover erectile function, presumably by alleviating perineal trauma, in a short-term interventional study of men with ED associated with occupational bicycle riding.
• Physical activity
  • 2023 Systematic Review and Meta-Analysis of RCTs evaluating Impact of Aerobic Exercise on Erections
    • 11 RCTs included
    • Results
      • Mean increase in the IIEF-EF score of ≈3 with aerobic exercise
        • The effect of aerobic exercise on erectile function was greater in men with lower baseline IIEF-EF scores
    • Khera, Mohit, Samir Bhattacharyya, and Larry E. Miller. "Effect of aerobic exercise on erectile function: systematic review and meta-analysis of randomized controlled trials." The Journal of Sexual Medicine 20.12 (2023): 1369-1375.

Oral medication

Phosphodiesterase type 5 inhibitors

Mechanism of action

• Inhibits the phosphodiesterase type 5 (PDE5) enzyme from breaking down cyclic guanasine monophosphate (cGMP) to 5’GMP, resulting in increased concentration of penile cavernosal cGMP
  • Increasing penile cavernosal cGMP then causes smooth muscle relaxation in the corpus cavernosum vasculature.
    • Smooth muscle relaxation results in increased erection hardness and duration in men with ED who have sufficient intact vasculature
• Augments but does not induce the erectile response
  • Initiation of erection requires the release of nitric oxide from penile nerve endings and vascular endothelium under the influence of sexual stimulation

Metabolism

• Metabolized by the cytochrome P450 3A4 enzyme
  • Dose increase required with concomitant use of (inducers of this enzyme):
    • Rifampin
  • Dose reduction required with concomitant use of (inhibitors of this enzyme):
    1. Ketoconazole, itraconazole, fluconazole
    2. Ritonavir, indinavir
    3. Cimetidine
    4. Macrolide antibiotics (e.g. erythromycin)
• Dose adjustment may be needed if (3)§:
  1. Age >65
  2. Hepatic impairment
  3. Renal impairment (creatinine clearance <30 mL/min)

Options

• FDA-approved oral PDE5i available for management of ED (4):
  1. Sildenafil
  2. Tadalafil
  3. Vardenafil
  4. Avanafil
  • All have similar efficacy and tolerability, though limited data available on avanafil
    • Mean change in IIEF-EF scores is similar (≈7 points) across drugs, slightly higher with tadalafil§)
    • In general, these agents effectively result in successful sexual intercourse rates of ≈70%.
    • There is no sustained erectile function improvement after discontinuing PDE5i
  • Only tadalafil is currently FDA-approved for daily dosing
    • On-demand dosing versus daily dosing for tadalafil appears to produce the same level of efficacy
    • Potential advantages of daily dosing (6)§
      1. Increases sexual spontaneity
      2. Improves sexual self-confidence
      3. Less concern regarding timing of medication
      4. Female partners preferred daily dosing compared to on-demand regimens.
      5. In patients experiencing co-morbid lower urinary tract symptoms, daily tadalafil (5 mg) is an approved treatment option and has been shown to decrease symptom scores significantly more than on-demand dosing
      6. May be more cost-effective than on-demand dosing, depending on the dosing and frequency of use
    • 2021 CUA Guidelines conditionally recommend against preferentially prescribing daily tadalafil for patients presenting with erectile dysfunction.
      • No meaningful difference in side effects or discontinuation rates between either dosing regimen

Characteristics of PDE5is

PDE5i	Onset of action	Duration of action (T1/2)	Available doses (maximum)	Effect of food intake
Sildenafil	30-60 min	Up to 12 hours (4 hours)	25 mg, 50 mg, 100 mg PRN (100mg daily)	High-fat meal decreases efficacy
Vardenafil	30-60 min	Up to 10 hours (4 hours)	10 mg oral dissolvable tablet 2.5 mg, 5 mg, 10 mg, 20 mg PRN (20mg daily)	High-fat meal decreases efficacy
Tadalafil	60-120 min	Up to 36 hours (17.5 hours)	2.5 mg, 5 mg daily 5 mg, 10 mg, 20 mg PRN (20mg daily)	Not affected
Avanafil	15-30 min	Up to 6 hours (5 hours)		Not affected

Advantage of sildenafil and vardenafil over tadalafil: faster onset

Advantages of tadalafil over sildenafil and vardenafil: longer duration of action and not affected by meals

• Instructions regarding onset and duration of action and effect of food intake should be provided to maximize benefit/efficacy.
  • Studies of men who report non-response to PDE5i indicate that incorrect use (e.g., lack of sexual stimulation, medication taken with a large meal) accounts for 56-81% of treatment failures
  • Patients with an unsatisfactory response to PDE5is should first be counselled regarding proper use of the medication and may require a potential dose adjustment

• The dose should be titrated to provide optimal efficacy
  • Given that men with diabetes or post-prostatectomy often present with more severe levels of ED, consider initiating therapy at a higher dose.
  • Dose-response effects across PDE5i medications are small and non-linear (i.e., doubling the dose does not double the effect)
  • As part of the process of identifying the optimal dose, males may be offered dosing frequency changes or different PDE5i.
• Few studies focused on special populations (diabetes, metabolic syndrome, post-prostatectomy, etc.), but in general, findings are similar to those reported in the general ED population. For example, for males with diabetes, sildenafil, tadalafil, and vardenafil appear equally effective with limited data reported for avanafil.

Contraindications

• Absolute (2):
  1. Concomitant use of nitrate-containing medications (e.g., sublingual nitroglycerin, isosorbide dinitrate, other nitrate preparations used to treat angina, amyl nitrite, and amyl nitrate “poppers”)
     • Combination of a nitrate-containing medications with a PDE5i can cause a precipitous drop in blood pressure
     • If angina occurs during sex when using a PDE5i, patients should stop having sex and seek emergency care immediately. They should inform medical personnel that a PDE5i was taken and should avoid nitroglycerin use for a period of 24 hours for sildenafil and vardenafil and 48 hours for tadalafil
     • No pharmacologic antidote to the PDE5i/nitrate interaction exists
  2. Known hypersensitivity to any component of the tablet
• Relative (5):
  1. Severe renal or liver disease
     • In males with mild to moderate hepatic or renal impairment or men with spinal cord injury, dose adjustment should be considered given the potential for delayed metabolism
     • CUA guidelines do not include severe renal or liver disease as contraindication, but do suggest dose adjustment
  2. Severe cardiac disease
     • Controlled and post-marketing studies have shown that PDE5i do not cause an increase in myocardial infarction or death rates when compared with expected rates in study control populations.
     • Caution is advised for the use of PDE5i in patients with certain conditions: aortic stenosis, left ventricular outflow obstruction, hypotension, and hypovolemia.
     • FDA recommends against use in patients with MI in last 6 months
  3. Concomitant use of non-selective alpha blockers
     • Caution is advised when PDE5i are co-administered with α-adrenergic blockers, because both agents are vasodilators with blood pressure lowering effects.
     • There is a potential risk of significant hypotension when using non-selective alpha blockers (terazosin, alfuzosin, doxazosin)
     • Concomitant use of selective alpha blockers (silodosin, tamsulosin) does not present a risk for significant hypotension.
  4. Concomitant use of anti-arrhythmics
     • Vardenafil is not recommended in (2):
       • Patients who take type 1A (e.g., quinidine or procainamide) or type 3 (e.g., sotalol or amiodarone) anti-arrhythmics
       • Congenital prolonged QT syndrome
  5. Known hereditary degenerative retinal disorders
     • FDA recommends against use in patients with known hereditary degenerative retinal disorders, such as retinitis pigmentosa

Adverse events

• Most AEs associated with the administration of PDE5i are mild to moderate and improve over time
  • Out of 1000 patients taking the drug on average 8 will experience a serious adverse event with sildenafil, 7 with tadalafil and 8 with vardenafil§
• Side effects prompt discontinuation only in a few patients
  • The most common reason for discontinuation of PDE5i is lack of treatment efficacy (e.g., hardness of erection)
• Most AEs follow a dose-response pattern
  • Generally, daily dosing associated with lower rates of AEs
• The most frequently reported AEs (occurring in ≥2% of patients): HARD DICK F***S MY NIGHT DAMN VISION
  1. Headache (7-16%)
  2. Dyspepsia (4-10%)
  3. Flushing (4-10%)
  4. Myalgia/back pain (0-3%)
  5. Dizziness
  6. Nasal congestion (3-4%)
  7. Visual disturbances (e.g., photophobia, blue vision) (0-3%)
  • Sildenafil and vardenafil associated with higher rates of visual disturbance
    • Sildenafil and vardenafil cross-react to a greater extent with PDE type 6, which is expressed in the retina, than tadalafil and avanafil.
  • Tadalafil associated with higher rates of back pain and myalgia
  • Vardenafil associated with higher rates of nasal congestion
• Non-arteritic Anterior Ischemic Optic Neuropathy (NAION)
  • A rare visual condition characterized by the sudden onset of loss of vision in one eye
    • Several studies have suggested that PDE5i use is associated with an increased risk of NAION, although the absolute risk is small (3 additional cases per 100,000 men age ≥ 50).
  • Men in higher-risk groups (e.g., older males, males of Caucasian ethnicity, males with vascular risk factors) should be counseled about this small increased risk, including the fact that the absolute risk of NAION is extremely low with or without the use of PDE5i, and that the association does not imply causation.
  • Patients should be advised to stop use of PDE5i and to seek immediate medical attention as a safety measure in the event of a sudden loss of vision
• No increased risk of skin cancers or prostate cancer recurrence after prostate cancer treatment

Vacuum erection device

Mechanism of action

• Standard vacuum erection device consists of a plastic suction cylinder and vacuum-generating source (manual or battery-operated pump) in one piece. It is placed directly over the flaccid penis and operated, and after the penis is erected an elastic constriction ring or band is positioned at the base of the penis which can be maintained safely for up to 30 minutes; then the vacuum is released and the device is removed.
  • To avoid extremely high negative pressures which can injure the penis, only vacuum constriction devices containing a vacuum limiter should be used
• Principle is to mechanically create negative pressure surrounding the penis to engorge it with blood and then restrain outflow from the organ to maintain the erection-like effect.
  • Although the treatment does not produce a truly physiologic erection and the engorged blood predominantly consists of venous blood, the effect resembles a normal erection and is sufficient for coitus.

Advantages

• Effective and low-cost treatment option for select men with ED
  • Effective in the general ED population as well as in men with diabetes, spinal cord injury, post-prostatectomy, and other conditions
• Associated with high rates of patient and partner satisfaction
• Useful in patients with glanular insufficiency

Disadvantages

• Considered a more cumbersome and labour-intensive way to achieve an erection

Indications

• Reasonable option for those who cannot tolerate or have contraindications to other medical or surgical options
• May have a role as a “rescue” device in men who are PDE5i non-responders

Contraindications

• No absolute contraindications

Adverse events (4):

1. Penile numbness
2. Pain
3. Bruising
4. Painful ejaculation

Intraurethral (IU) alprostadil

• Known as MUSE (Medicated Urethral System for Erection)

Mechanism of action

• Alprostadil (prostaglandin) suppository inserted into into the distal urethra
  • Relies on the absorption of the medication into the surrounding corpus spongiosum, with passage via small vascular channels into the corpora cavernosa, the main erectile bodies

Efficacy

• Inferior efficacy compared to PDE5 inhibitors and ICI

Indications (2):

• Patient prefers to avoid oral medication and avoid needles required for ICI medications
• PDE5i are contraindicated
• The main indications are patients who are non-responsive to PDE5 inhibitors resulting from damage of the autonomic penile nerve supply (e.g., radical prostatectomy, cystectomy, and trauma) or those who wish to use the therapy in combination with PDE5 inhibitors.

Contraindications (5):§

1. Known hypersensitivity to alprostadil
2. Abnormal penile anatomy (urethral stricture, balanitis (inflammation/infection of the glans of the penis), severe hypospadias and curvature, and in patients with acute or chronic urethritis)
3. Increased risk of priapism (patients who are prone to venous thrombosis or who have a hyperviscosity syndrome (sickle cell anemia or trait, thrombocythemia, polycythemia, multiple myeloma))
4. Patients for whom sexual activity is inadvisable
5. Used for sexual intercourse with a pregnant woman unless the couple uses a condom barrier

Drugs and Dosages

• Semisolid pellet 1x3mm
• Alprostadil (125, 250, 500, and 1000mcg dosages)
• Dispensed into the distal urethra, 3cm from the external urethral meatus
• For patients considering the use of IU alprostadil, an in-office test should be performed.★
  • Most studies proceeded with chronic treatment only in men who had erections firm enough for intercourse in response to in-office testing. The success rates among men who used the medication chronically, therefore, are relevant to responsive intra-office testing – not men with ED in general.
  • IU alprostadil should not be prescribed until a man has undergone instruction in the method, an initial dose-titration in the office, and detailed counseling regarding possible adverse events and actions to take in response to potentially serious adverse events.
• Onset of effect is within 5-10 minutes after administration§
• Duration of effect is approximately 30-60 minutes§

Adverse events

• Most common (5):
  1. Genital pain
  2. Minor urethral trauma/bleeding
  3. Urethral pain or burning
  4. Dizziness
• Episodes of hypotension or syncope are rare.
• No reports of priapism
  • Although episodes of priapism were not reported in IU alprostadil trials, the man should be thoroughly educated about priapism and instructed on safe responses and maneuvers in a prolonged erection situation.
• MUSE seems safe for female partners, producing only a 5.8% incidence of vaginal burning or itching
• Should be used with a condom for intercourse with a pregnant woman

Intracavernosal injections (ICI)

• First pharmacologic treatment available for ED
• Involves the delivery of vasoactive agents directly into the corpus cavernosum prior to intercourse

Options

• Drugs commonly used in clinical practice (4) PAPA: Papaverine, Alprostadil, Phentolamine, and Atropine
  • Papaverine
    • MOA: non-specific PDE inhibitor that prevents the degradation of cAMP and cGMP thereby promoting tissue relaxation; decreases venous outflow
    • Advantages: inexpensive and stable at room temperature
    • Disadvantages: commonly observed liver enzyme elevations, priapism risk (up to 35%), and penile fibrosis risk (1-33%) have led to its abandonment as monotherapy
  • Alprostadil
    • MOA: synthetic form of prostaglandin E1 and induces tissue relaxation via increased cAMP
    • Advantages: lower incidences of prolonged erection, systemic side effects, penile fibrosis
    • Disadvantages: higher incidence of painful erection, higher cost, has a shortened half-life if not refrigerated after reconstitution into liquid from powder.
    • Rare systemic side effects that include vasodilation, inhibition of platelet aggregation and stimulation of intestinal activity.
  • Phentolamine
    • MOA: non-selective, reversible, competitive, α1-blocker (stimulation of α1-adrenergic receptor inhibits erection), no effect on venous outflow
    • Advantages: limited success when administered intracavernosally as a sole agent, short half-life
    • Disadvantages: systemic hypotension, reflex tachycardia, nasal congestion, and gastrointestinal upset.
  • Atropine
    • MOA: anti-cholinergic
  • Only alprostadil is FDA and Health Canada approved for ICI injection and is the only medication typically used as a single agent.
  • Combination therapy (trimix is alprostadil + papaverine + phentolamine) offers a synergistic mechanism of the vasoactive agents to elicit maximal erectile responses, particularly among patients who have failed monotherapy
    • Shown to be even more efficacious than alprostadil monotherapy while maintaining an acceptable side effect profile and less penile pain
  • VIP in combination with phentolamine is currently being sought for regulatory approval in the US

Indications

• Treatment option for males who
  • Have contraindications to the use of PDE5i
  • Prefer not to take an oral medication
  • Find that PDE5i are inadequate or ineffective

Contraindications (5):

• My Direct Pinches Cause Instant Priapism

1. Use of Monoamine oxidase inhibitors (risk of precipitating a life-threatening hypertensive crisis if an intracavernosal α-adrenergic agonist is used to reverse a priapic episode)
2. Reduced manual Dexterity (although the partner can be trained in the injection technique)
3. Psychological instability
4. Severe Coagulopathy or unstable Cardiovascular disease
   • Anti-coagulation therapy is not a contraindication
5. Infection (systemic, cutaneous, or urinary tract infection)
6. History or risk for Priapism
7. Obesity (relative, from 2019 AUA Update on ICI)

Adverse Events

• Most serious adverse event is priapism.
  • Patients should be thoroughly educated about priapism and instructed in actions to take in a prolonged erection situation.
    • Commonly-used strategies (but for which there is no evidence) include attempting ejaculation and, if unsuccessful, then oral pseudephedrine followed by the application of an ice pack to the penis for 30 minutes to an hour. If a painful, non-bendable erection persists after these strategies, then the man should proceed to the emergency room within 2-4 hours of medication administration.
    • ICI with PGE1 alone appears to have lower rates of priapism but is associated with more pain and higher risk of complications.
• Other adverse events include prolonged erection (does not require treatment, unlike priapism), pain, ecchymosis, penile fibrosis, plaque, or curvature and other deformities (injection site nodules)
  • Repeated penile trauma from ICI inevitably causes penile fibrosis
    • ICI should be limited to 10 injections monthly to reduce risk of penile fibrosis
    • ICI induced fibrosis appears to be partially reversible, is often unnoticed by patients and does not contribute significantly to the development of meaningful penile curvature.
• AUA: in-office injection test should be performed for men with ED considering ICI therapy
  • Men should first have an in-office injection test to determine the appropriate dose and medication(s) to produce sufficient duration of response and to minimize adverse events. Start with a small dose of medication

Application

• Injections should be conducted at 3 and 9 o’clock positions to avoid neurovascular structures on the dorsum of the penis and the urethra ventrally
  • Injections should be at 90° to the penile surface

Outcomes

• Effective in all subtypes of ED.
• Effective in the general ED population as well as in men with diabetes, cardiovascular risk factors, men post-prostatectomy, and men with spinal cord injuries
• Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) scores were not significantly different between ICI and oral therapy. However, EDITS scores were significantly higher with implants than with ICI or oral therapy
  • Patient satisfaction is often measured using EDITS (Erectile Dysfunction Inventory of Treatment Satisfaction) with higher EDITS scores correlating to greater satisfaction.
    • EDITS scores must be distinguished from the IIEF questionnaire, as EDITS scores tend to vary depending on comfort of the patient towards therapy.
• Patient attrition from ICI has been reported as 30-60% by 6 months and up to 80% beyond that time.
  • A majority of men who discontinued use were younger.
  • Attrition has been attributed to modifiable issues, such as inadequate penile rigidity and anxiety, and unmodifiable issues, such as lack of spontaneity, unnaturalness, lack of interest and health concerns.
    • Such high attrition rates in the modifiable category could be due to inadequate medication titration, injection technique or perhaps high expectations and anxiety that may be alleviated by psychological intervention.

Surgery

Indications (4):

1. Penile injury resulting from genital or pelvic trauma
2. Penile structural deformity occurring in association with Peyronie disease
3. Cavernosal fibrosis secondary to prolonged ischemic priapism or infection
4. Medical therapy for ED is contraindicated, unsuccessful, or undesirable

Options

1. Penile Prosthesis
2. Vascular Reconstruction
   1. Penile Arterial Reconstruction
   2. Penile Venous Reconstruction

Penile Prosthesis

• See Surgery of Erectile Dysfunction Chapter Notes
• Effective in men from the general ED population as well as men from a variety of special populations
  • Satisfaction rates are high for both implant naïve patients and those undergoing surgical revision of an existing device
• Patients should understand that this treatment choice is best conceptualized as irreversible
  • Although prostheses can be removed, it is unlikely that a man’s penis will be reliably responsive to other ED therapies after prosthesis explant.
  • While not all nonsurgical options need to be attempted prior to considering placement of a penile prosthesis, all nonsurgical options should at least be discussed with the patient prior to considering surgical intervention.
• 2019 AUA Best Practice Policy on Antibiotic Prophylaxis recommend an aminoglycoside with either a first- or second-generation cephalosporin or vancomycin 1 hour before surgery and up to 24 hours after surgery for implanted prosthetic devices (AUS, penile prosthesis, sacral neuromodulators)
• The potential risks of prosthesis surgery include (5):
  1. Risks inherent in the surgical procedure (penile edema or hematoma, corpus injury, urethral injury, acute urinary retention, and crura injury)
  2. Possible changes in the appearance of the penis
     • When objective measures are used, small length decreases may be documented
     • Glans will remain flaccid post implant
  3. Infection
     • A serious adverse event that typically occurs within the first 3 months after surgery and usually requires removal of the prosthesis
       • In select cases, an infected prosthesis can be removed, the location of the device washed out using an antibiotic salvage procedure and a new device immediately placed.
         • This approach should be restricted to men without evidence of sepsis or severe local infection.
       • More typically, the infected device is removed, the infection is addressed with antibiotics, and the tissues are allowed to heal (for 6 weeks to 6 months).
     • No evidence that diabetic men are at higher risk of prosthesis infection
  4. Erosions
  5. Device malfunction or failure
     • Almost 50% will still be functional after 20 years of use

Vascular Reconstruction

Penile arterial reconstruction

• May be considered for young men with (3):
  1. ED and
  2. Focal pelvic/penile arterial occlusion  and
  3. Without documented generalized vascular disease or veno-occlusive dysfunction
• Usually used for internal pudendal artery stenosis

Penile venous reconstruction

• Not recommended; overall, data indicate that penile venous ligation surgery is unlikely to result in long-term successful management of ED for the overwhelming majority of men and delays treatment with other more reliable options such as penile prosthesis surgery

Investigational (2)

• Low-intensity extracorporeal shock wave therapy (ESWT)
  • Proposed treatment option for patients with mild to moderate ED
  • Administered with a wand-like device delivering low intensity shockwaves to different areas of the penis in multiple sessions.
  • Hypothesized to work by inducing angiogenesis through growth factor activation and inducing nerve regeneration
  • Randomized sham-controlled trials that have evaluated low-intensity ESWT do not clearly indicate that benefits outweigh risks/burdens for men with ED
  • Not Health Canada or FDA approved for clinical use for ED
  • 2018 AUA: Should only be used in investigational settings in the context of a clinical trial
  • 2021 CUA: conditionally recommends against low-intensity shockwave treatment (Li-SWT) as a treatment for patients with ED
• Intracavernosal stem cell therapy

Experimental

• Platelet-rich plasma (PRP) therapy
• Amniotic fluid matrices

Cardiology referral

• 2018 AUA
  • Men should be counseled that ED is a risk marker for underlying cardiovascular disease (CVD) and other health conditions that may warrant evaluation and treatment
  • ED is as strong of a risk factor for CVD as is smoking and family history
  • Sexual activity has been associated with increased risk for cardiac events, although the absolute risk is small, particularly in men who regularly engage in other physical activities
    • Low-risk patients (men without cardiac disease who are able to exercise with no to minimal cardiac symptoms, men with diagnosed cardiac disease who have undergone successful revascularization procedures (e.g., coronary artery stenting, coronary artery bypass graft), men with controlled asymptomatic hypertension, and men with low grade heart failure (i.e., New York Heart Association Class I and II heart failure) may be treated for ED without additional cardiovascular evaluation.
    • All other men with cardiovascular conditions require a cardiology consultation and additional cardiac evaluation; if there is uncertainty regarding a man’s exercise tolerance and fitness for sexual activity, then he should be referred for in-depth evaluation of cardiac reserve by a cardiologist
• 2021 CUA
  • Controversial whether a diagnosis of ED alone should initiate a more thorough cardiovascular evaluation

Special scenarios

Erectile function recovery after radical treatment for prostate cancer

• Radical prostatectomy (RP)
  • Erectile function may improve over time
    • The interval of spontaneous erectile function recovery usually occurs 12-24 months after RP, although recovery may still be possible as much as 36 months after surgery.
    • Relatively few men recover baseline erectile function, particularly those age > 60 at the time of surgery
  • A meta-analysis of studies with >12 months follow-up post-RP reported that use of a bilateral nerve-sparing technique was associated with a 60% erectile function recovery rate compared to a rate of 47% for use of a unilateral nerve-sparing technique.
• Radiotherapy (RT)
  • Erectile function may worsen over time
    • Onset of ED is delayed and may occur 24-36 months after treatment
• Penile rehabilitation
  • Refers to the concept of using interventions to promote the natural recovery of erectile function after an insult to the erectile mechanism which occurs after radical prostatectomy (RP), external beam radiation therapy (EBRT), brachytherapy and other localized prostate cancer treatments.
    • Majority of studies focus on scheduled PDE5is for variable periods of time leading up to and following RP.
  • Meta-analysis of 5 RCTs found that in every 1000 patients who receive penile rehabilitation with scheduled PDE5is, 28 more patients experienced ED resolution compared to placebo§
  • 2018 AUA: men who desire preservation of erectile function after treatment for prostate cancer (by RP or RT) should be informed that early use of PDE5i post-treatment may NOT improve spontaneous, unassisted erectile function
  • 2021 CUA
    • Conditionally recommends against penile rehabilitation with scheduled PDE5is following RP
    • Insufficient evidence to make any recommendation for penile rehabilitation following treatment with EBRT and brachytherapy for prostate cancer.
      • Limited evidence suggests that scheduled PDE5is taken around the time of radiation therapy (EBRT and/or brachytherapy) do not offer any long-term protective effects against future ED.

Hormonal therapy in patients with hypogonadism

• Testosterone monotherapy
  • Unlikely leads to a clinically significant improvement in erectile function
    • Meta-analysis found that testosterone monotherapy increases IIEF-EF score by 2.65 compared to placebo§
  • Not recommended for the purpose of treating ED in patients with hypogonadism and ED
• Dual PDE5i and testosterone therapy
  • Some evidence to supports its use as a combination therapy to salvage patients who have failed PDE5is
  • Should be considered in patients with hypogonadism and ED
    • Current recommendations suggest that a short (e.g. 3-month) therapeutic trial of testosterone is justified in men with hypogonadism, and in the absence of a response, testosterone administration should be discontinued
    • Once treatment with exogenous testosterone is initiated, ongoing follow-up is mandatory.
  • Alternative hormonal replacement therapies have been suggested, but because of insufficient evidence they are not currently recommended for use

Questions

1. What are the mandatory investigations in a patient with erectile dysfunction as per the AUA/CUA?
2. What are the recommended investigations in a patient with erectile dysfunction as per the AUA/CUA?
3. As per the 2021 CUA Guidelines on Erectile Dysfunction, what are the indications to measure serum testosterone?
4. What are the 5 domains of the International Index of Erectile Function (IIEF)?
5. List potential specialized testing options in the evaluation of erectile dysfunction
6. List the FDA-approved PDE5 inhibitors for the treatment of ED
7. What are the contraindications to PDE5 inhibitors?
8. Which PDE5 inhibitor is not recommended in patients who take type 1A antiarrhythmics (e.g., quinidine or procainamide) or type 3 antiarrhythmics (e.g., sotalol or amiodarone) or in patients with congenital prolonged QT syndrome?
9. What are potential adverse events related to the use of a PDE5i?
10. Which PDE5 inhibitors have higher rates of visual disturbances? Myalgia?
11. What is the onset of action, T1/2, and effect of food intake on the different PDE5 inhibitors?
12. What are the non-surgical treatment options for erectile dysfunction?
13. What are the contraindications to intraurethral alprostadil?
14. What are the typical medications in intracavernosal injection?
15. What are the contraindications to intracavernosal injections?
16. What are potential complications of penile prosthesis surgery?

Answers

1. What are the mandatory investigations in a patient with erectile dysfunction as per the AUA/CUA?
   • AUA: history, physical, diabetes screen (fasting glucose or HbA1c), serum testosterone
   • CUA: history, physical
2. What are the recommended investigations in a patient with erectile dysfunction as per the AUA/CUA?
   • AUA and CUA: questionnaire
   • CUA: diabetes screening in select patients, serum testosterone in selected patients
3. As per the 2021 CUA Guidelines on Erectile Dysfunction, what are the indications to measure serum testosterone?
   1. Symptoms of hypogonadism
   2. Failure of PDE5 inhibitor treatment
4. What are the 5 domains of the International Index of Erectile Function (IIEF)?
   1. Sexual desire
   2. Erectile function
   3. Intercourse satisfaction
   4. Ejaculatory/orgasmic function
   5. Overall sexual satisfaction
5. List potential specialized testing options in the evaluation of erectile dysfunction
   1. Nocturnal Penile Tumescence and Rigidity testing
   2. Intracavernosal injection
   3. Penile duplex ultrasound
   4. Biothesiometry
   5. Cavernosometry and cavernosograophy
   6. Arteriography
6. List the FDA-approved PDE5 inhibitors for the treatment of ED
   1. Sildenafil
   2. Tadalafil
   3. Verdenafil
   4. Avanafil
7. What are the contraindications to PDE5 inhibitors?
   • Absolute:
   1. 1. Hypersensitivity
      2. Concomitant use of nitrates
   • Relative:
   1. 1. Severe liver disease
      2. Concomitant use of alpha-blocker
      3. Severe cardiac disease
      4. Concomitant use of antiarrhythmics
      5. Known hereditary degenerative retinal disorders
8. Which PDE5 inhibitor is not recommended in patients who take type 1A antiarrhythmics (e.g., quinidine or procainamide) or type 3 antiarrhythmics (e.g., sotalol or amiodarone) or in patients with congenital prolonged QT syndrome?
   • Vardenafil
9. What are potential adverse events related to the use of a PDE5i?
   1. Headache
   2. Dyspepsia
   3. Flushing
   4. Myalgia
   5. Nasal congestion
   6. Visual disturbances
   7. NAION
10. Which PDE5 inhibitors have higher rates of visual disturbances? Myalgia?
    • Sildenafil and vardenafil
    • Tadalafil
11. What is the onset of action, T1/2, and effect of food intake on the different PDE5 inhibitors?
    • Sildenafil: 30-60 mins, 4 hours, high-fat meal decreases efficacy
    • Verdenafil: 30-60 mins, 4 hours, high-fat meal decreases efficacy
    • Tadalafil: 60-120 mins, 17.5 hours, no effect
    • Avanafil: 15-30 mins, 5 hours, no effect
12. What are the non-surgical treatment options for erectile dysfunction?
    1. Oral PDE5 inhibitors
    2. Vacuum erection device
    3. Intraurethral alprostadil
    4. Intracavernosal injections
13. What are the contraindications to intraurethral alprostadil?
    1. Patients with known hypersensitivity to alprostadil
    2. Abnormal penile anatomy
    3. Conditions that increase the risk of priapism
14. What are the typical medications in intracavernosal injection?
    • Papaverine (PDE5 inhibitor)
    • Alprostadil (prostaglandin)
    • Phentolamine (alpha-blocker)
    • Atropine (anticholinergnic)
15. What are the contraindications to intracavernosal injections?
    1. Concomitant use of monoamine oxidase inhibitors
    2. Reduced manual dexterity
    3. Psychological instability
    4. Severe coagulopathy and/or unstable cardiovascular disease
    5. History or risk of priapism
16. What are potential complications of penile prosthesis surgery?
    • Intra-operative: corpus injury, urethral injury, crura injury, bleeding
    • Early post-operative: infection, urinary retention
    • Late post-operative: erosion, change in appearance of penis, device malfunction

Additional references

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, vol 1, chap 26
• Burnett, Arthur L., et al. "Erectile dysfunction: AUA guideline." The Journal of urology 200.3 (2018): 633-641.
• Domes, T., et al. "Canadian Urological Association guideline: Erectile dysfunction." Can Urol Assoc J 2021 August 17; Epub ahead of print. http://dx.doi.org/10.5489/cuaj.7572