1. Erectile Dysfuntion EPIDEMIOLOGY AND PATHOPHYSIOLOGY Dr. Anmar Nassir, FRCS(C) Canadian board in General Urology Fellowship in Andrology (U of Ottawa) Fellowship in EndoUrology and Laparoscopy (McMaster Univ) Assisstent Prof Umm Al-Qura Consultant Urology King Faisal Specialist Hospital

2.  Before age 40  1- 9%  from 40 to 59  5-30%  from 60 to 69  20- 40%  men in their 70s and 80s  50-75% 24 international studies between 1993 and 2003

3.  Males : 40 and 70 years  52% reported some degree of ED.  40  70 the probability of: complete impotence tripled from 5.1%  15% complete impotence tripled from 5.1%  15% moderate impotence doubled from 17%  34% moderate impotence doubled from 17%  34% minimal impotence remained constant at 17%. minimal impotence remained constant at 17%.  By the age of 70 years 68 % have ED.  Males : 40 and 70 years  52% reported some degree of ED.  40  70 the probability of: complete impotence tripled from 5.1%  15% complete impotence tripled from 5.1%  15% moderate impotence doubled from 17%  34% moderate impotence doubled from 17%  34% minimal impotence remained constant at 17%. minimal impotence remained constant at 17%.  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

4. ED in SA  680 patients: AI El-sakka, 2004 International Journal of Impotence Research

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

6. Anatomy

8. Physiology

10.  Relaxation of the cavernous smooth muscle is the key to penile erection. PENILE SMOOTH MUSCLE RELAXATION CAUSES ERECTION Sexual stimulation Sympathetic + parasymp Smooth muscle relaxation Arterial dilation + venous occlusion

11. Sexual Ctre Hypothalamus Testosterone visual psych tactile olfactory memory imaginationauditory Sympathetic + parasympathetic Estradiol CNS

12. Nitric oxide  Synthesis of NO is catalyzed by NOS, converts l-arginine and oxygen  l-citrulline and NO. converts l-arginine and oxygen  l-citrulline and NO.  NOS exists as three isoforms in mammals: nNOS - in neurons cells nNOS - 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: nNOS  initiating erection nNOS  initiating erection eNOS  sustaining erection. eNOS  sustaining erection.  Future: Gene transfer of nNOS or eNOS to the penis has been shown to augment erectile responses in animal studies. Gene transfer of nNOS or eNOS to the penis has been shown to augment erectile responses in animal studies.

13.  Nitric oxide Upon entering the smooth muscle cells, stimulates the production of cGMP.Upon entering the smooth muscle cells, stimulates the production of cGMP.  Cyclic GMP activates protein kinase G, activates protein kinase G, opens potassium channels and closes calcium channels.opens potassium channels and closes calcium channels.  Low cytosolic calcium favors smooth muscle relaxation.  The smooth muscle regains its tone when cGMP is degraded by phosphodiesterase.

14. Phosphodiesterase  All PDEs have been identified in the corpus cavernosum With the exception of PDE6, which is specifically expressed in photoreceptor cells. With the exception of PDE6, which is specifically expressed in photoreceptor cells.  PDE5 is the principal PDE for the termination of cavernous cGMP signaling.  Inhibition of the cGMP-catalytic activity of PDE5 by specific inhibitors has been shown to be highly effective in treating ED.

16. 1 2 3 Nitric Oxide- cGMP Nitric Oxide- cGMP Mechanism of Mechanism of Corpus Cavernosal Smooth Muscle Relaxation and Penile Erection

17. !!!  Other substrates relevant to vascular or cavernous smooth muscle functions are as 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

18. Etiology of Erectile Dysfunction 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. Etiology

19.  Note that it is unlikely for an individual patient’s impotence to derive solely from one source A functional classification of impotence.

20. Causes of ED

22. Major organic causes of ED

23. ED in SA  680 patients: AI El-sakka, 2004 International Journal of Impotence Research Significant association to severity of ED: diabetes, hypertension, dyslipidemia, smoking, increased BMI,

24. CharacteristicOrganicPsychogenic OnsetGradualAcute CircumstancesGlobalSituational CourseConstantVarying Noncoital erection PoorRigid Psychosexual problem Secondary Long history Partner problem Secondary At onset Anxiety and fear SecondaryPrimary Organic vs. psychogenic causes for ED

25. Psychogenic dysfunction  Two possible mechanisms to explain the inhibition of erection: 1. Direct inhibition of the spinal erection center by the brain exaggeration of the normal suprasacral inhibitionexaggeration of the normal suprasacral inhibition 2. Excessive sympathetic outflow or elevated peripheral catecholamine levels, increase penile smooth muscle tone to prevent its necessary relaxation.increase penile smooth muscle tone to prevent its necessary relaxation.

26. Diabetes Mellitus  Diabetes mellitus is a common chronic disease  Affecting 0.5% to 2% worldwide.  The overall prevalence of DM in KSA is 23.7%. males  26.2% males  26.2% females  21.5%. females  21.5%. Saudi Med J. 2004 Al-Nozha et al Organic dysfunction

27. Diabetes Mellitus  The prevalence of ED is three times higher in diabetic men (28% versus 9.6%)  occurs at an earlier age,  increases with disease duration, being approximately 15% at age 30 and rising to 55% at 60 years Organic dysfunction

28. Chronic Renal Failure  Sexual dysfunction has been reported in 20% to 50% of men with chronic renal failure

29. Cavernous (Venogenic)  Failure of adequate venous occlusion is the most common causes of vasculogenic impotence.  It may result from: degenerative tunical changes: degenerative tunical changes: Peyronie'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 fracture insufficient trabecular smooth muscle relaxation: insufficient trabecular smooth muscle relaxation: anxious individuals with excessive adrenergic tone patients with inadequate neurotransmitter release venous shunts venous shunts

30. Anti HTN and ED  The underlying disorder may be more relevant for ED than the medication.  Thiazide diuretic Associated with higher rates of ED, Associated with higher rates of ED, This may be reduced by combination therapy and weight loss. This may be reduced by combination therapy and weight loss.  The α1 blockers and Angiotensin II receptor blocker Tend to improve sexual functioning Tend to improve sexual functioning  Calcium Channel Blockers No adverse effect on erection No adverse effect on erection

31. Effect of Antihypertensive Effect of Antihypertensive AgentEffectMechanism Diuretics ED (twice as placebo) Unknown β blocker (nonselective) ED Prejunctional α 2 - receptor inhibition β 1 blocker (selective) None α 1 blocker Decreases ED rate but may cause retrograde ejaculation Relaxation of internal urinary sphincter α 2 blocker ED Inhibition of central α 2 receptor ACE inhibitor None Angiotensin II receptor blocker Decreases ED rate Calcium channel blocker None

32. Antipsychotics  The prevalence of sexual dysfunction ranged from 40% to 70%.  Newer agents such as clozapine showed a lower reduction in sexual desire.  The group taking risperidone had the greatest decrease in erectile frequency.

33.  Tricyclics Antagonize 5-HT receptors. Antagonize 5-HT receptors. Controlled clinical studies suggest that orgasmic disorders in both sexes are frequent, explaining the use of these drugs as inhibitors of ejaculation Controlled clinical studies suggest that orgasmic disorders in both sexes are frequent, explaining the use of these drugs as inhibitors of ejaculation Antidepressants

34.  Monoamine oxidase inhibitors associated with higher rates of orgasmic dysfunction in controlled trials associated with higher rates of orgasmic dysfunction in controlled trials Antidepressants

35.  Selective serotonin reuptake inhibitors (SSRIs) Commonly used to treat depression. Commonly used to treat depression. They inhibit the reuptake of 5-HT into CNS neurons  produce stimulatory effects on 5-HT receptors. They inhibit the reuptake of 5-HT into CNS neurons  produce stimulatory effects on 5-HT receptors. 50% of patients experience a change in sexual function 50% of patients experience a change in sexual function mainly anorgasmia,mainly anorgasmia, adverse effects can be modified by co-treatment with sildenafil adverse effects can be modified by co-treatment with sildenafil Antidepressants

36.  SSRIs differ in their ability to cause ED. A high incidence has been observed in patients treated with paroxetine A high incidence has been observed in patients treated with paroxetine A lesser impact has been reported with citalopram. A lesser impact has been reported with citalopram.  Thus, the ability to produce ED and the mechanism by which SSRIs cause ED may differ with the specific SSRI compound. Antidepressants

37. Antidepressants  Recently developed antidepressants such as mirtazapine and nefazodone tend to have beneficial effects on sexual function,  Possibly by activating the 5-HT1 C receptor, augments sexual response, augments sexual response,  But still antagonize the 5-HT2 C receptor.

38. Tobacco  Tobacco induce vasoconstriction and penile venous leakage.  Smokers reported an inverse correlation between nocturnal erection (both rigidity and duration) and the number of cigarettes smoked per day: men who smoked more than 40 had the weakest and shortest nocturnal erections. men who smoked more than 40 had the weakest and shortest nocturnal erections.