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Campbell’s Chapter 22. Evaluation and Nonsurgical Management of Erectile Dysfunction and Premature Ejaculation. Brent Zamzow DO January 14, 2008. ED - Historical. Before 1970 – Psychotherapy 1970’s - Penile prosthesis & psychotherapy, sleep lab

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campbell s chapter 22

Campbell’s Chapter 22

Evaluation and Nonsurgical Management of Erectile Dysfunction and Premature Ejaculation

Brent Zamzow DO

January 14, 2008

ed historical
ED - Historical
  • Before 1970 – Psychotherapy
  • 1970’s - Penile prosthesis & psychotherapy, sleep lab
  • 1980’s - Yohimbine, intracavernous & transurethral therapy, vacuum device, testosterone, ultrasound
  • 1990’s to present - oral PDE-5 inhibitors
  • ED treatment
    • Psychologist → Urologist → Primary Care
ed historical1
ED - Historical
  • 1999 - 1st International Consultation on Sexual Medicine (ICSM)
    • ED redefined as consistent or recurrent inability to attain and/or maintain penile erection sufficient for sexual performance
    • ED is a symptom of many medical problems
      • requires physician involvement
      • internet prescribing condemned
    • Goal-directed approach
ed historical2
ED - Historical
  • 2nd ICSM - 2004
    • Patient-centered & evidence-based
    • See illness through patient’s eyes
    • Holistic approach - biologic, psychologic & social aspects
    • Flexible & individualized approach
    • Let patient choose his best therapy
  • 3rd ICSM - July 10-13, 2009
self administered questionnaires
Self-Administered Questionnaires
  • International Index of Erectile Function (IIEF)
    • most common questionnaire
    • addresses erectile function, orgasmic function, desire, intercourse satisfaction, overall satisfaction
  • Male Sexual Function Scale
    • 2nd ICSM
  • Doesn’t take into account partner
history taking
History Taking
  • Medical
    • atherosclerosis, DM, depression
    • organic vs. psychogenic
    • medications, pelvic surgery?, trauma?
  • Sexual
    • severity, onset, duration
  • Psychosocial
    • social, occupational, family, financial
    • Don’t assume everyone’s involved in monogamous, heterosexual relationship
exam labs
Exam & Labs
  • Physical Exam
    • General screening for risk factors
      • body habitus, cardiovascular, neurologic, genital
  • Labs
    • Fasting glucose, lipids, hormonal profile, thyroid function
  • Findings
    • Educate patient on modifiable risk factors
      • stress, marital conflict, smoking, EtOH, obesity, bicycle riding, prescription drugs
vascular evaluation
Vascular Evaluation
  • Goal - diagnose & quantify arterial & veno-occlusive dysfunction
  • Options:
    • Combined intracavernous injection & stimulation (CIS)
    • Duplex ultrasound
    • Dynamic infusion cavernosometry & cavernosography (DICC)
    • Selective penile angiography
evaluation of penile blood flow 1 st line
Evaluation of Penile Blood Flow 1stline
  • Combined Intracavernous Injection & Stimulation (CIS)
    • Inject vasodilator, stimulate, assess
    • Most commonly performed diagnostic procedure for ED
    • Bypasses neurologic & hormonal influences to evaluate vascular status
    • Use:
      • alprostodil 10-20ug
      • papaverine & phentolamine (Bimix 0.3 mL)
      • Trimix 0.3 mL
    • 27 or 29g needle, compress for 5 min after injection
1 st line cis
1st line - CIS
  • Normal results = normal venous occlusion
  • False negative up to 20% w/ borderline arterial flow
evaluation of penile blood flow 2 nd line
Evaluation of Penile Blood Flow 2nd Line
  • Duplex Ultrasonography
    • Penile blood flow study (CIS & blood flow measurement by US) is most reliable & least invasive evidence based assessment of ED
      • Red = towards probe
      • Blue = away from probe
    • Can visualize dorsal & cavernous arteries in real time
    • Can diagnose high flow priapism
2 nd line ultrasound
2nd line - Ultrasound
  • Technique
    • Measure flow velocities 5-10 min after injection
    • Rate erectile quality
    • Look at both cavernous arteries & diameters
    • Asymmetric cavernous arterial flow >10cm/s or reversal of flow across a collateral may mean atherosclerotic lesion
2 nd line ultrasound1
2nd line - Ultrasound
  • Doppler Waveform
2 nd line ultrasound2
2nd line - Ultrasound
  • Peak Systolic Velocity (PSV)
    • PSV < 25 correlates with abnormal pudendal arteriography
    • Severe unilateral arterial insufficiency >10 cm/s asymmetry
    • Severe vascular ED, diameter increase is <75%, diameter rarely exceeds 0.7 mm
  • Be aware of variant vessel anatomy
2 nd line ultrasound3
2nd line - Ultrasound
  • Veno-occlusive Dysfuntion
    • Need to trap blood & limit venous outflow
    • Venogenic impotence
      • High systolic flow (>25 cm/s)
      • Persistent end-diastolic flow (EDV) (>5 cm/s)
    • Resistive Index (RI)
      • RI = PSV – EDV/PSV
        • Measure 20 min after injection & stimulation
      • RI > 0.9 normal
      • RI < 0.75 venous leakage
iscm recommendations on us
ISCM Recommendations on US
  • Intracavernosal injection with color duplex Doppler ultrasound
    • Most informative diagnostic test
    • Least invasive for vascular ED, high vs. low flow priapism, Peyronie’s plaque
    • Useful measurements
      • PSV, cavernous artery diameter, EDV, RI
      • PSV <25 = severe cavernous artery insufficiency
      • PSV >35 = normal inflow
      • Negative relationship between age & PSV
evaluation of penile blood flow 3 rd line
Evaluation of Penile Blood Flow3rd line
  • Cavernous arterial occlusion pressure
    • Basically penile blood pressure measurement – 1989
    • Technique
      • Inject vasodilator
      • infuse saline into corpora to get pressure > systolic BP
      • apply Doppler to penile base
      • Pressure when cavernous arterial flow becomes detectable is cavernous artery systolic occlusion pressure (CASOP)
    • Gradient between cavernous & brachial artery pressure <35 & equal pressure on L & R is normal
3 rd line penile blood flow
3rd line – Penile Blood Flow
  • Pharmacologic Arteriography
    • Technique
      • Inject vasodilator
      • Cannulate internal pudendal artery
      • Inject contrast
      • Look at anatomy of iliac, internal pudendal, penile arteries
    • Aberrant anatomy in 50% of normal volunteers
    • Useful for anatomy, not function
    • Indication:
      • Young pt w/ ED due to traumatic arterial disruption or perineal compression injury. Essential for planning reconstruction
3 rd line penile blood flow1
3rd line – Penile Blood Flow
  • Pharmacologic Cavernosometry & Cavernosography
    • Cavernosometry
      • Saline infusion while monitoring intracavernous pressure
      • Assesses penile outflow
    • Cavernosography
      • Infusion of contrast into corpora after vasodilator induced erection
    • Good for young men who may be candidates for penile vascular operations
historical investigational
Historical & Investigational
  • Penile Brachial Pressure Index
    • Inaccurate
  • Penile Plethysmography
    • Penile pulse volume recording
  • Infrared Spectrophotometry
  • Radioisotopic Penography
  • MRA
  • Cavernous Smooth Muscle Content
nocturnal penile tumescence npt
Nocturnal Penile Tumescence (NPT)
  • 80% NPT during REM sleep
  • Total tumescence time
    • 20% of night at puberty
    • Adults – 27 minutes/night
  • RigiScan - 1985
    • Monitors radial rigidity, tumescence, number, duration of erectile events
    • Portable – can use at home
    • Can record 3 different nights up to 10 hrs each
    • Results
      • Radial rigidity >70% = good erection
      • <40% = flaccid penis
      • Normal = 3-6 erections/night, 10-15 minutes per episode
slide23
NPT
  • NEVA device
    • Uses electrobioimpedance to assess volumetric changes in penis during nocturnal erections
    • Undetectable alternating current from glans to hip electrodes
    • Penile base electrode measures impedance & changes in penile length
    • Mean volume change in controls = 213% increase (14.4 mL)
npt summary
NPT Summary
  • Freedom from psychological influences & its ability to detect sleep-related abnormalities
  • Full erection = neurovascular axis is functionally intact & cause is likely psychogenic
  • Disadvantages
    • Age dependent
    • Costly
  • Not recommended as routine test for ED
  • Indications:
    • Suspected sleep disorder
    • Obscure cause
    • Nonresponse to therapy
    • Planned surgical treatment
    • Legally sensitive case
    • Measurement of drug effects in placebo-controlled drug trials
    • Suspected psychogenic cause
psychological evaluation
Psychological Evaluation
  • ED associated with:
    • Anxiety
    • Depressive symptoms
    • Low self-esteem
    • Negative outlook on life
    • Emotional stress
    • History of sexual coercion
  • General vs. Situational?
  • Primary vs. Acquired
    • Substance abuse, psychiatric illness
  • Noncoital erections
    • ?Masturbatory, nocturnal, morning
hormonal evaluation
Hormonal Evaluation
  • Hypogonadism increases with age
    • Decrease or absence of hormonal secretion from the gonads in men
    • Draw testosterone between 8-11am
    • For screening – total testosterone
    • If testosterone low or low-normal
      • Confirm with 2nd draw + LH + prolactin
testosterone
Testosterone
  • Men produce 4-8 mg/day in pulsatile manner
  • Peaks in morning, nadir in evening
  • Converts to DHT by 5α-reductase in skin, liver, prostate
  • Metabolized to estradiol by aromatase in brain, fat, liver, testes
  • 2% unbound – free testosterone
  • 30% bound to SHBG
  • Rest bound to albumin & other serum proteins
  • Bioavailable testosterone = free + albumin bound
  • SHBG made by liver – downregulated by androgens, upregulated by estrogens
  • Estrogens, thyroid hormone, aging increase serum SHBG & decrease bioavailable testosterone
  • Exogenous androgens, growth hormone, obesity depresses SHBG & increases free testosterone
lifestyle change ed
Lifestyle Change & ED
  • Obesity
    • Decreased BMI = improvement in ED
  • Physical Activity
    • Sedentary = highest risk
  • Cigarette Smoking
  • Statin to lower cholesterol may improve ED
  • Long distance bicycle riding
  • No Effect
    • Education level
    • Marital status
    • Urban vs. Rural
    • Coffee
    • EtOH
medications ed
Medications & ED
  • Nonspecific alpha-blockers have most severe effect on erectile function
  • Methyldopa & Reserpine
  • Thiazide diuretics
  • Spironolactone interferes with testosterone synthesis
  • SSRI’s – ED & ejaculation problems
  • Calcium channel blockers & ACE inhibitors don’t cause ED
  • Alpha-1 blocker is protective
    • Doxazosin reduces incidence of ED
herbal supplements for ed
Herbal Supplements for ED
  • 25-50% placebo response
  • Acupuncture – psychogenic ED
  • Androstenedione – may benefit men w/ low testosterone, lowers HDL 10%
  • Ginko biloba – may have blood-thinning effect
  • Korean red ginseng – may benefit
  • L-Arginine – precursor to Nitric Oxide, may lower BP
  • Yohimbine – most supplements contain little or none, can have serious side effects
  • Zinc – good if low zinc, can be immunosuppressive
testosterone therapy
Testosterone Therapy
  • Injectable (IM)
    • Least expensive
    • 200-250mg q2wks
    • Do not replicate normal circadian rhythm
    • Testosterone “rush” for 72 hrs, then low by 10-12 days
  • Transdermal
    • Can simulate normal circadian levels if applied in AM
    • Patch – 2.5-5 mg/day
      • Applied daily to arm, back, or upper butocks
      • Side effects – itching, chronic irritation, contact dermatitis
    • Gel – 50, 75, or 100 mg packs
      • Applied daily to arms, abdomen, or shoulders
      • Wash hands after application
    • Pellet – 75mg/pellet
      • 2-6 pellets implanted subQ q3-6months
    • Buccal – 30mg tablet BID
    • Oral – 200mg/d
      • Become metabolically inactive after 1st pass through liver
      • Large doses toxic to liver
hormonal therapy
Hormonal Therapy
  • DHT
    • Cannot be aromatized to estradiol – pure androgen
    • Good for hypogonadal men w/ gynecomastia, boys w/ delayed puberty
  • Dehydroepiandrosterone (DHEA)
    • Controversial
  • End Points
    • General well-being, mood, sexual interest, sexual activity
adverse effects of testosterone replacement
Adverse Effects of Testosterone Replacement
  • Infertility
    • Suppresses LH, FSH
  • Breast tenderness & gynecomastia
  • Erythrocytosis
    • Mean Hct increases from 42-47% after 3 months
  • Induce or worsen sleep apnea
  • May increase PSA
  • ? Exacerbates prostate cancer
  • Prostate or breast cancer = contraindication
  • Monitoring
    • DRE & PSA q6months
    • Periodic H&H, LFT’s, lipid profile
    • Efficacy of testosterone determined by clinical response
  • If hyperprolactinemia – testosterone does not improve sexual function
phosphodiesterase type 5 inhibitors
Phosphodiesterase Type-5 Inhibitors
  • Sildenafil (Viagra)
    • FDA approved 1998
  • Vardenafil (Levitra)
    • FDA approved 8/2003
  • Tadalafil (Cialis)
    • FDA approved 11/2003
arousal pathway
Arousal Pathway
  • Sexual arousal stimulates NO release at penile nerve endings
  • NO diffuses into vascular & cavernous smooth muscle cells
  • Stimulation of guanylyl cyclase & elevation of cGMP
  • Hyperpolarization & lowers cytoplasmic calcium
  • Smooth muscle relaxation & erection
  • PDE-5 inhibitors potentiate NO’s effect
    • Do not increase NO levels
    • Need sexual stimulation for PDE-5 inhibitors to work
pde 5 inhibitors
PDE-5 Inhibitors
  • Sildenafil & Vardenafil cross-react slightly w/ PDE-6
    • ? Reason for visual disturbances
  • Tadalafil minimally cross-reacts with PDE-11
    • Consequences unknown
  • Other side effects:
    • Headache, flushing, low BP, dyspepsia due to PDE-5 inhibition in vascular or GI smooth muscle
  • Sildenafil 20mg TID FDA approved in 2005 for pulmonary HTN
pde 5 inhibitors1
PDE-5 Inhibitors
  • Very effective at enhancing erectile function
    • Good for different patient subgroups, ED causes, outcomes measured
  • Difficult to Treat Patients
    • All effective in ED + DM
    • All improve ED following prostate cancer
      • Nerve sparing pts respond better
      • Daily PDE-5 inhibitor may be beneficial
    • Sildenafil + testosterone if ED & low testosterone
    • Cumulative probability of success increases w/ 1st 9-10 attempts
  • Tadalafil – less planning, longer half-life, more convenient for some
pde 5 inhibitors2
PDE-5 Inhibitors
  • Side effects peak at first 2wks of use
  • Package Insert Warnings
    • MI within 90 days
    • Unstable angina, or angina w/ intercourse
    • NY Heart Association class II or greater heart failure in last 6 months
    • Uncontrolled arrhythmias, hypotension (<90/50), or HTN (>170/100)
    • Stroke in past 6 months
    • Known hereditary degenerative retinal disorders, including retinitis pigmentosa
    • Tendency to develop priapism (sickle cell, anemia, leukemia)
    • Impairs metabolic breakdown
      • Ketoconazole, itraconazole, protease inhibitors (ritonavir) – lower dose
    • Enhances breakdown
      • Rifampin – increase dose
pde 5 inhibitors3
PDE-5 Inhibitors
  • Recommended starting dose
    • 50mg sildenafil
    • 10mg vardenafil & tadalafil
  • Cardiovascular safety
    • They do not worsen cardiac events
    • Vardenafil not recommended w/ type IA antiarrythmics (quinidine or procainamide) or type 3 (sotalol or amiodarone), or congenital prolonged QT syndrome
    • Use w/ caution in aortic stenosis, left ventricular outflow obstruction, hypotension, hypovolemia due to vasodilator effects
    • Nitrates – absolute contraindication
      • Use >2 wks ago, not contraindication
      • Don’t take nitrate for at least 24 hrs after (48hrs for tadalafil)
    • Alpha-blocker – use caution due to vasodilation & hypotension
intracavernous injection
Intracavernous Injection
  • 1983 AUA meeting, Brindley personally demonstrated erection after injection of phenoxybenzamine
  • 1985 – papaverine & phentolamine injection use reported
  • Papaverine
    • Isolated from opium poppy
    • Inhibitory effect on PDE, increased cAMP & cGMP, blocks calcium channels
    • 1-2 hr half-life
    • Good
      • Low cost
      • Stable at room temp
    • Bad
      • Priapism (up to 35%)
      • Corporal fibrosis (1-33%) due to acidity
    • <55% effective
    • Not FDA approved
intracavernosal injection
Intracavernosal Injection
  • Phentolamine (alpha1 & alpha2-antagonist) (Regitine)
    • Side effects
      • Hypotension
      • Reflex tachycardia
      • Nasal congestion
      • GI upset
    • 30 min half-life
    • Increases corporal blood flow, but does not cause significant increase in intracavernous pressure
intracavernosal injection1
Intracavernosal Injection
  • Alprostadil (Caverject & Edex 2-40mcg) - Prostaglandin E1
    • Exogenous form of a naturally occurring fatty acid
    • Causes smooth muscle relaxation, vasodilation, inhibition of platelet aggregation by elevating cAMP
    • Metabolized by prostaglandin-15-hydroxydehydrogenase in corpora cavernosa
    • 96% locally metabolized after 60 min
    • Side effects
      • Pain at injection site or during erection
      • Hematoma
      • Priapism
    • Much lower incidence of fibrosis
    • Once reconstituted into liquid from powder, has shortened half-life if not refrigerated
intracavernosal injection2
Intracavernosal Injection
  • Combinations
    • Papaverine + Phentolamine
    • Papaverine + Phentolamine + Alprostadil
      • Lower incidence of painful erection
      • As effective as alprostadil alone
      • Good for failed therapy or painful erection w/ PGE1
  • Serious side effects
    • Priapism
      • Alprostadil 1.3%
      • Papaverine 10%
      • Papaverine/phentolamine 7%
    • Fibrosis
      • Alprostadil 1%
      • Papaverine 12%
      • Papaverine/phentolamine 9%
intracavernosal injection3
Intracavernosal Injection
  • Contraindications
    • Sickle cell
    • Schizophrenia
    • Other severe psychiatric disorders
    • Severe systemic illness
    • If on anticoagulant, compress injection site for 7-10 min
    • Poor manual dexterity – have partner inject
intraurethral therapy
Intraurethral Therapy
  • Alprostadil (Muse)
    • Absorbed in spongiosum & transported to cavernosa through venous channels (circumflex & emissary veins)
    • 3mm x 1mm pellet
    • 500 mcg Muse = 10 mcg injected alprostadil
    • 2/3 respond
    • Side effects
      • Penile pain/dull ache in penis, scrotum, legs
central acting drugs
Central Acting Drugs
  • Yohimbine
    • Alpha2-antagonist from bark of yohim tree
    • Good for psychogenic ED
    • Side effects
      • GI upset, anxiety, HA, agitation, palpitations, HTN
    • AUA stance – no efficacy of yohimbine over placebo with organic ED
  • Trazadone
  • Apomorphine
    • Dopaminergic agonist
vacuum constriction device
Vacuum Constriction Device
  • Plastic cylinder connected to vacuum-generating source
    • Place constriction ring after engorgement
    • Remove ring within 30 min
    • Satisfaction rate 68-83%
premature ejaculation pe
Premature Ejaculation (PE)
  • DSM-IV
    • Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration and before the person wishes it
  • Short ejaculatory latency, lack of control, sexual dissatisfaction
    • Latency <2 min suggests possible PE
  • Excludes PE secondary to EtOH, substance abuse, medication
premature ejaculation
Premature Ejaculation
  • Etiology
    • Penile Hypersensitivity
    • 5-Hydroxytryptamine-Receptor Sensitivity
    • Hyperarousability
    • Hyperexcitable ejaculatory reflex
    • Genetic predisposition
    • Psychogenic
      • Poor control techniques
      • Early sexual experience
      • Anxiety
      • Infrequent sex
premature ejaculation1
Premature Ejaculation
  • Treatment
    • Psychological/Behavioral
    • Drugs
      • SSRI’s
        • Paroxetine (Paxil) exerts strongest ejaculatory delay
          • Daily or 3-4 hrs prior to intercourse
        • Sertraline (Zoloft), Fluoxetine (Prozac)
        • Side effects
          • Fatigue, yawning, nausea, loose stool, perspiration
        • Ejaculatory delay starts to occur at end of 1st or 2nd week
      • Nonselective Serotonin Reuptake Inhibitor
        • Clomipramine (Anafranil)
          • Daily or 3-4 hrs before intercourse
other pe treatment
Other PE Treatment
  • Topical anesthetic
    • Effective at retarding ejaculation
  • PDE-5 Inhibitors
    • Unlikely to have role