Transcript Campbell`s Chapter 22 - Detroit Medical Center

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
 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 - 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 - 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
 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
 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
 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
ED Treatment Options
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
st
1 line
 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
st
1
line - CIS
 Normal results = normal venous occlusion
 False negative up to 20% w/ borderline arterial flow
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
nd
2
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
nd
2
line - Ultrasound
 Doppler Waveform
nd
2
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
nd
2
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
 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
3rd 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
rd
3
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
rd
3
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
 Penile Brachial Pressure Index
 Inaccurate
 Penile Plethysmography
 Penile pulse volume recording
 Infrared Spectrophotometry
 Radioisotopic Penography
 MRA
 Cavernous Smooth Muscle Content
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
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
 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
 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
 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









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
 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
 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
 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
 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
 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
 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
 Sildenafil (Viagra)
 FDA approved 1998
 Vardenafil (Levitra)
 FDA approved 8/2003
 Tadalafil (Cialis)
 FDA approved 11/2003
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
 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
Sildenaf Vardenafi
il
l
Tadalafil
Onset of Action
15 min - 1 hr
15 min – 1 hr
15 min – 2 hr
Half-life
3-5 hr
4-5 hr
17.5 hr
Bioavailability
40%
15%
Not tested
Fatty Food
↓↓
Absorption
↓↓ Absorption
No effect
HA, flushing,
dyspepsia
Yes
Yes
Yes
Bachache, Myalgia
Rare
Rare
Yes
Blurred/Blue vision
Yes
Rare
Rare
Precaution w/
antiarrhythmics
No
Yes
No
Contraindication w/
nitrates
Yes
Yes
Yes
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
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
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
 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
 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 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 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 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
 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
 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
 Plastic cylinder connected to vacuum-generating
source
 Place constriction ring after engorgement
 Remove ring within 30 min
 Satisfaction rate 68-83%
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
 Etiology
 Penile Hypersensitivity
 5-Hydroxytryptamine-Receptor Sensitivity
 Hyperarousability
 Hyperexcitable ejaculatory reflex
 Genetic predisposition
 Psychogenic

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

Poor control techniques
Early sexual experience
Anxiety
Infrequent sex
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
 Topical anesthetic
 Effective at retarding ejaculation
 PDE-5 Inhibitors
 Unlikely to have role
 END