erectile dysfuntion epidemiology and pathophysiology

Erectile Dysfuntion Erectile Dysfuntion EPIDEMIOLOGY AND EPIDEMIOLOGY AND PATHOPHYSIOLOGYPATHOPHYSIOLOGY

Dr. Anmar Nassir, FRCS(C)Dr. Anmar Nassir, FRCS(C)

Canadian board in General UrologyCanadian board in General Urology

Fellowship in Andrology Fellowship in Andrology (U of Ottawa)(U of Ottawa)

Fellowship in EndoUrology and Laparoscopy Fellowship in EndoUrology and Laparoscopy (McMaster Univ)(McMaster Univ)

Assisstent Prof Assisstent Prof Umm Al-QuraUmm Al-Qura

Consultant Urology Consultant Urology King Faisal Specialist HospitalKing Faisal Specialist Hospital

Before age 40 Before age 40 1- 9% 1- 9% from 40 to 59 from 40 to 59 5-30% 5-30% from 60 to 69 from 60 to 69 20- 40% 20- 40% men in their 70s and 80smen in their 70s and 80s50-75%50-75%

24 international studies between 1993 and 2003

Males : 40 and 70 years Males : 40 and 70 years 52% reported some degree of ED. 52% reported some degree of ED. 40 40 70 the probability of: 70 the probability of:

complete impotence tripled from 5.1% complete impotence tripled from 5.1% 15% 15% moderate impotence doubled from 17% moderate impotence doubled from 17% 34% 34% minimal impotence remained constant at 17%.minimal impotence remained constant at 17%.

By the age of 70 years 68 % have ED.By the age of 70 years 68 % have ED.

Males : 40 and 70 years Males : 40 and 70 years 52% reported some degree of ED. 52% reported some degree of ED. 40 40 70 the probability of: 70 the probability of:

complete impotence tripled from 5.1% complete impotence tripled from 5.1% 15% 15% moderate impotence doubled from 17% moderate impotence doubled from 17% 34% 34% minimal impotence remained constant at 17%.minimal impotence remained constant at 17%.

By the age of 70 years 68 % have ED.By the age of 70 years 68 % have ED.

1709 noninstitutionalized men The Massachusetts Male Aging Study 1994

1709 noninstitutionalized men The Massachusetts Male Aging Study 1994

ED in SAED in SA

680 patients:680 patients:

AI El-sakka, 2004

International Journal of Impotence Research

ED = consistent or recurrent inability to ED = consistent or recurrent inability to attain and/or maintain penile erection attain and/or maintain penile erection sufficient for sexual performance. sufficient for sexual performance.

AnatomyAnatomy

Diagram of Penile ErectionDiagram of Penile Erection

PhysiologyPhysiology

Relaxation of the Relaxation of the cavernous smooth muscle cavernous smooth muscle is the key to penile is the key to penile erection.erection.

PENILE SMOOTH MUSCLE PENILE SMOOTH MUSCLE RELAXATION CAUSES ERECTIONRELAXATION CAUSES ERECTION

Sexual stimulation

Sympathetic + parasymp

Smooth muscle relaxation

Arterial dilation + venous occlusion

Sexual Ctre

Hypothalamus

Testosterone

visual

psych

tactile

olfactory

memory

imagination auditory

Sympathetic + parasympathetic

Estradiol

CNSCNS

Nitric oxideNitric oxide Synthesis of NO is catalyzed by NOS, Synthesis of NO is catalyzed by NOS,

converts l-arginine and oxygen converts l-arginine and oxygen l-citrulline and NO. l-citrulline and NO.

NOS exists as three isoforms in mammals: NOS exists as three isoforms in mammals: nNOS - in neurons cellsnNOS - in neurons cells eNOS - in endothelial cells, eNOS - in endothelial cells, iNOS in virtually all cell types. iNOS in virtually all cell types.

In the corpus cavernosum:In the corpus cavernosum: nNOS nNOS initiating erectioninitiating erection eNOS eNOS sustaining erection. sustaining erection.

Future:Future: Gene transfer of nNOS or eNOS to the penis has been shown to Gene transfer of nNOS or eNOS to the penis has been shown to

augment erectile responses in animal studies.augment erectile responses in animal studies.

Nitric oxide Nitric oxide • Upon entering the smooth muscle Upon entering the smooth muscle

cells, stimulates the production of cells, stimulates the production of cGMP.cGMP.

Cyclic GMP Cyclic GMP activates protein kinase G, activates protein kinase G,

• opens potassium channels and closes calcium opens potassium channels and closes calcium channels.channels.

Low cytosolic calcium favors smooth Low cytosolic calcium favors smooth muscle relaxation.muscle relaxation.

The smooth muscle regains its tone when The smooth muscle regains its tone when cGMP is degraded by phosphodiesterase.cGMP is degraded by phosphodiesterase.

PhosphodiesterasePhosphodiesterase

All PDEs have been identified in the corpus All PDEs have been identified in the corpus cavernosum cavernosum With the exception of PDE6, which is specifically With the exception of PDE6, which is specifically

expressed in photoreceptor cellsexpressed in photoreceptor cells. .

PDE5 is the principal PDE for the termination PDE5 is the principal PDE for the termination of cavernous cGMP signalingof cavernous cGMP signaling. .

Inhibition of the cGMP-catalytic activity of Inhibition of the cGMP-catalytic activity of PDE5 by specific inhibitors has been shown PDE5 by specific inhibitors has been shown to be highly effective in treating EDto be highly effective in treating ED . .

11

22

33

Nitric Oxide-Nitric Oxide-cGMPcGMP

Mechanism Mechanism of of

Corpus Corpus Cavernosal Cavernosal

Smooth Smooth Muscle Muscle

RelaxationRelaxationand and

Penile Penile ErectionErection

!!!!!! Other substrates relevant to vascular or Other substrates relevant to vascular or

cavernous smooth muscle functions are as cavernous smooth muscle functions are as follows: follows: Inositol 1,4,5-trisphosphate (IP3) receptor Inositol 1,4,5-trisphosphate (IP3) receptor IP3 receptor-associated PKG substrate (IRAG) IP3 receptor-associated PKG substrate (IRAG) Phospholamban (PLB) Phospholamban (PLB) Heat shock-related protein (HSP20) Heat shock-related protein (HSP20) Myosin phosphatase (MP) Myosin phosphatase (MP) Phosphatase inhibitor-1 (PPI-1) Phosphatase inhibitor-1 (PPI-1) GTPase RhoA GTPase RhoA

Etiology of Erectile Etiology of Erectile DysfunctionDysfunction

For simplicity, erectile dysfunction can be classified as

• Organic - due to vasculogenic, neurologic, hormonal, or cavernosal abnormalities or lesions

• Psychogenic - due to central inhibition of the erectile mechanism without a physical insult

However, in most patients with erectile dysfunction, a combination of organic and psychogenic components is involved.

EtiologyEtiology

Note that it is unlikely for an individual patient’s impotence to derive solely Note that it is unlikely for an individual patient’s impotence to derive solely from one sourcefrom one source

A functional classification of impotence. A functional classification of impotence.

Mixed80%

organic10%

psych10% Mixed

organic

psych

Causes of ED Causes of ED

Major organic causes of EDMajor organic causes of ED

DM30%

Vascular40%

Surgery13%

MS3%Trauma

8%

Endocrine6%

ED in SAED in SA

680 patients:680 patients:

AI El-sakka, 2004

International Journal of Impotence Research

Significant association to severity of ED: •diabetes, •hypertension, •dyslipidemia, •smoking, •increased BMI,

CharacteristicCharacteristic OrganicOrganic PsychogenicPsychogenic

OnsetOnset GradualGradual AcuteAcute

CircumstancesCircumstances GlobalGlobal SituationalSituational

CourseCourse ConstantConstant VaryingVarying

Noncoital erectionNoncoital erection PoorPoor RigidRigid

Psychosexual Psychosexual problemproblem

SecondarySecondary Long historyLong history

Partner problemPartner problem SecondarySecondary At onsetAt onset

Anxiety and fearAnxiety and fear SecondarySecondary PrimaryPrimary

Organic vs. psychogenic causes for EDOrganic vs. psychogenic causes for ED

Psychogenic dysfunctionPsychogenic dysfunction

Two possible mechanisms to explain Two possible mechanisms to explain the inhibition of erection: the inhibition of erection:

1.1. Direct inhibition of the spinal erection Direct inhibition of the spinal erection center by the brain center by the brain

• exaggeration of the normal suprasacral exaggeration of the normal suprasacral inhibition inhibition

2.2. Excessive sympathetic outflow or Excessive sympathetic outflow or elevated peripheral catecholamine levels, elevated peripheral catecholamine levels,

• increase penile smooth muscle tone to increase penile smooth muscle tone to prevent its necessary relaxation.prevent its necessary relaxation.

Diabetes MellitusDiabetes Mellitus

Diabetes mellitus is a common chronic diseaseDiabetes mellitus is a common chronic disease

Affecting 0.5% to 2% worldwide.Affecting 0.5% to 2% worldwide.

The overall prevalence of DM in KSA is 23.7%. The overall prevalence of DM in KSA is 23.7%.

males males 26.2% 26.2% females females 21.5%. 21.5%.

Saudi Med J. 2004 Al-Nozha et al

Organic dysfunctionOrganic dysfunction

Diabetes MellitusDiabetes Mellitus

The prevalence of ED is three times higher in The prevalence of ED is three times higher in

diabetic men (28% versus 9.6%) diabetic men (28% versus 9.6%) occurs at an earlier age, occurs at an earlier age, increases with disease duration, being increases with disease duration, being

approximately 15% at age 30 and rising to 55% approximately 15% at age 30 and rising to 55% at 60 years at 60 years

Organic dysfunctionOrganic dysfunction

Chronic Renal FailureChronic Renal Failure

Sexual dysfunction has been reported in Sexual dysfunction has been reported in 20% to 50% of men with chronic renal 20% to 50% of men with chronic renal failure failure

Cavernous (Venogenic)Cavernous (Venogenic) Failure of adequate venous occlusion is the most Failure of adequate venous occlusion is the most

common causes of vasculogenic impotence. common causes of vasculogenic impotence. It may result from: It may result from:

degenerative tunical changes: degenerative tunical changes: Peyronie's disease, old age, and diabetesPeyronie's disease, old age, and diabetes

fibroelastic structural alterations, fibroelastic structural alterations, traumatic injury to the tunica albuginea: traumatic injury to the tunica albuginea:

penile fracturepenile fracture insufficient trabecular smooth muscle relaxation:insufficient trabecular smooth muscle relaxation:

anxious individuals with excessive adrenergic toneanxious individuals with excessive adrenergic tonepatients with inadequate neurotransmitter release patients with inadequate neurotransmitter release

venous shunts venous shunts

Anti HTN and EDAnti HTN and ED

The underlying disorder may be more The underlying disorder may be more relevant for ED than the medication.relevant for ED than the medication.

Thiazide diureticThiazide diuretic Associated with higher rates of ED, Associated with higher rates of ED, This may be reduced by combination therapy and This may be reduced by combination therapy and

weight loss. weight loss. The The α1 blockersα1 blockers and and Angiotensin II receptor Angiotensin II receptor

blockerblocker Tend to improve sexual functioning Tend to improve sexual functioning

Calcium Channel BlockersCalcium Channel Blockers No adverse effect on erection No adverse effect on erection

Effect of AntihypertensiveEffect of Antihypertensive

AgentAgent EffectEffect MechanismMechanismDiureticsDiuretics ED (twice as placebo)ED (twice as placebo) UnknownUnknown

β blocker (nonselective)β blocker (nonselective) EDED Prejunctional αPrejunctional α22--

receptor inhibitionreceptor inhibition

ββ11 blocker (selective) blocker (selective) NoneNone

αα11 blocker blocker Decreases ED rate but Decreases ED rate but may cause retrograde may cause retrograde

ejaculationejaculation

Relaxation of internal Relaxation of internal urinary sphincterurinary sphincter

αα22 blocker blocker EDED Inhibition of central αInhibition of central α22

receptorreceptor

ACE inhibitorACE inhibitor NoneNone

Angiotensin II receptor Angiotensin II receptor blockerblocker

Decreases ED rateDecreases ED rate

Calcium channel blockerCalcium channel blocker NoneNone

AntipsychoticsAntipsychotics

The prevalence of sexual dysfunction The prevalence of sexual dysfunction ranged from 40% to 70%. ranged from 40% to 70%.

Newer agents such as Newer agents such as clozapineclozapine showed showed a lower reduction in sexual desire. a lower reduction in sexual desire.

The group taking The group taking risperidonerisperidone had the had the greatest decrease in erectile frequency. greatest decrease in erectile frequency.

TricyclicsTricyclics Antagonize 5-HT receptors. Antagonize 5-HT receptors. Controlled clinical studies suggest that Controlled clinical studies suggest that

orgasmic disorders in both sexes are orgasmic disorders in both sexes are frequent, explaining the use of these drugs as frequent, explaining the use of these drugs as inhibitors of ejaculation inhibitors of ejaculation

AntidepressantsAntidepressants

Monoamine oxidase inhibitorsMonoamine oxidase inhibitors associated with higher rates of orgasmic associated with higher rates of orgasmic

dysfunction in controlled trials dysfunction in controlled trials


Selective serotonin reuptake inhibitorsSelective serotonin reuptake inhibitors (SSRIs)(SSRIs) Commonly used to treat depression. Commonly used to treat depression. They inhibit the reuptake of 5-HT into CNS neurons They inhibit the reuptake of 5-HT into CNS neurons

produce stimulatory effects on 5-HT receptors. produce stimulatory effects on 5-HT receptors. 50% of patients experience a change in sexual 50% of patients experience a change in sexual

function function • mainly anorgasmia, mainly anorgasmia,

adverse effects can be modified by co-treatment with adverse effects can be modified by co-treatment with sildenafilsildenafil


SSRIs differ in their ability to cause ED. SSRIs differ in their ability to cause ED. A high incidence has been observed in A high incidence has been observed in

patients treated with patients treated with paroxetineparoxetine A lesser impact has been reported with A lesser impact has been reported with

citalopramcitalopram.. Thus, the ability to produce ED and the Thus, the ability to produce ED and the

mechanism by which SSRIs cause ED mechanism by which SSRIs cause ED may differ with the specific SSRI may differ with the specific SSRI compound. compound.



Recently developed antidepressants such Recently developed antidepressants such as as mirtazapine mirtazapine and and nefazodonenefazodone tend to tend to have beneficial effects on sexual function, have beneficial effects on sexual function,

Possibly by activating the 5-HT1 C Possibly by activating the 5-HT1 C receptor, receptor, augments sexual response, augments sexual response,

But still antagonize the 5-HT2 C receptor. But still antagonize the 5-HT2 C receptor.

TobaccoTobacco

Tobacco induce vasoconstriction and Tobacco induce vasoconstriction and penile venous leakage. penile venous leakage.

Smokers reported an inverse correlation Smokers reported an inverse correlation between nocturnal erection (both rigidity between nocturnal erection (both rigidity and duration) and the number of cigarettes and duration) and the number of cigarettes smoked per day: smoked per day: men who smoked more than 40 had the men who smoked more than 40 had the

weakest and shortest nocturnal erections. weakest and shortest nocturnal erections.

erectile dysfuntion epidemiology and pathophysiology

Documents