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Wanwisa Tharnprisarn ,M.D. Assoc.Prof.SurasakThaneepanichskul,M.D.

Erectile dysfunction. Wanwisa Tharnprisarn ,M.D. Assoc.Prof.SurasakThaneepanichskul,M.D. DEFINITION. Inability of the male to attain and maintain erection of the penis sufficient to permit satisfactory sexual intercourse (NIH Consensus Conference 1993)

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Wanwisa Tharnprisarn ,M.D. Assoc.Prof.SurasakThaneepanichskul,M.D.

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  1. Erectile dysfunction Wanwisa Tharnprisarn ,M.D. Assoc.Prof.SurasakThaneepanichskul,M.D.

  2. DEFINITION • Inability of the male to attain and maintain erection of the penis sufficient to permit satisfactory sexual intercourse (NIH Consensus Conference 1993) • Preceding by loss of rigidity when intromission or premature ejaculation • Accompanied by reduced libido/orgasmic sensation, infertility

  3. Epidemiology • Prevalence and incidence increased with age : > 75% age 70 yrs • Differed from place to place • Social problems of 50% male 40-70 yrs ( Feldman et al. J Uro 1994 .)

  4. Risk factors * aging * organic diseases : hepatic failure , renal failure * systemic disease affected penile blood supply : DM, HT, IHD, hypercholesterolemia * Peyroney’s disease * Depression

  5. * Spinal cord injury or pelvic trauma * Substance abuse * Cigarette smoking * Endocrine abnormalities * Medication : -blocker,thaizide,verapamil, naproxen, amitryptyine, digoxin, phenytoin, hydralazine, clofibrate, indomethacin,cimetidine, omeprazole, lithium

  6. Anatomy • Anatomy • Blood supply : artery, venous • Nerve supply • Fig.

  7. Vascular processes of penile erection • Flaccidity • Filling phase • Tumescence • Full erection • Rigidity • Detumescence (Br J Nur 2000)

  8. Classification of erection • Reflextogenic : tactile-S2-4,T10-L2 • Psychogenic : audiovisual • Nocturnal : REM sleep : central impulse-unknown : 3-5 erection, 30 min

  9. Physiology & Biology • Penis is a tone and vascular organ • High tone : smooth muscle cells contract penis flaccid : extant partially contracted state – anxiety or cold environment elicited further contraction and cause penile shrivel

  10. Low tone : relaxed smooth muscle cells fully engorged penis : sexual excitement/ arousal REM sleep : release of relaxant neurotransmitter – NO, PGE1 : functionally antagonized release of constrictor neurotransmitter- ET1, NE

  11. Initiation * neural, chemical, central,mechanical stimulation (fig219) * release of local factor – NE, PGE1 * K-channel efflux/influx to change membrane potential in corporal smooth muscle * experiment on maxi-K gene transfected mice (fig 227)

  12. Maintainance and modulation *Ca-channel : voltage-dependent channel *ET1 induce alteration of intracellularCa *K-channel ablate transmembrane Ca-flux : critical role in maintainance and modulation of smooth muscle tone and erectile capacity

  13. Intercellular communication through Cx43 gap-junction to modulate K-channel of adjacent myocytes *syncytial cellular network *electrical or chemical alteration of any kind in small area are rapidly transmitted throuout the entire organ

  14. Pharmacology • Central pharmacological control * dopamine, serotonin, NE, ACTH,opiod, oxytocin,GABA,NO * tactile, olfactory, mental stimuli * PVN, SON of hypothalamus communicate with other areas

  15. Peripheral pharmacological control * contraction : NE, ET1 * relaxation : NO, VIP, prostanoids

  16. CENTRAL Dopamine and dopamine mechanism • dopaminergic neurones in hypothalamus (PVN,SON) regulate LS-spinal cord nuclei • injection of apomorphine facilitate sexual function - SON mainly D1-receptor - PVN mainly D2-receptor: oxytocin, NO

  17. Implication : apomorphine induced erection and potentiate visual erotic stimulation by dopamine receptor stimulation : 0.25-0.75 mg Sc(Segraves,et al.J Urol 1991) : side effect – high dose ( 5-6 mg) depress (no oral, sl-ok) respiration - low dose * emesis, yawning, drowsiness,nausea,flushing, lacrimation, dizziness

  18. (Central) Serotonin and serotonin mechanism • Serotonin containing-neurones : medullary raphe, ventral medullar innervate LS spinal cord • 5-HT fiber are densely in dorsal/ventral horn , sacral parasympathetic nucleus • 5-HT1C,2C facilitate erection,oxytocin,NO • 5-HT1A inhibit erection

  19. Implication : atypical antidepressant-trazodone selectively inhibit central 5-HT uptake and major metabolite mCCP has agonistic action at 5-HT2C , but antagonize -adrenoreceptor(NE) not as effective as papaverine/ phentolamine

  20. : injected intracarvernosally cause tumesence but not full erection : oral dose 50-150 mg/day : effectiveness remained to be established ( Costabil et al. J Urol 1999)

  21. (Central) NE mechanism • Sparse information • Ascending pathway to brain and descending pathway to spinal cord • 1-adrenoreceptor facilitate copulation • 2-adrenoreceptor inhibit copulation • Yohimbine 2-adrenoreceptor antagonist facilitate & increase sex behavior

  22. Implication : central action, not penile tissue (1) : controversial studies on beneficial effects – differences in dosage, patient selection, definition of positive response : not impressive result

  23. (Central) Opioid • -receptor stimulation prevent increase of NO production at PVN • Morphine prevents apomorphine , aspartate and oxytocin-induced erection • Opioid antagonist – naltrexone may be useful (lack of well controlled studies)

  24. (Central) ACTH and related peptide • ACTH/MSH mediate effects by specific melanocortin receptor • MC3-receptor in hypothalamus is important for erectile function • More studies for more selective MC-receptor for usefulness of erection

  25. (Central) Oxytocin • Oxytocinergic spinal projection from hypothalamus influence sacral autonomic outflow • In animal model : injected to PVN or hippocampus induce penile erection by increasing NO production • Elevated level following sex stimulation

  26. Implication : systemic administration does not penetrate blood-brain barrier to its central site of action; no erectile response

  27. (Central) NO • Physiologic mediator for erection at PVN and peripherally • Involve in action of apomorphine and oxytocin • Central effect implications to be evaluated

  28. Peripheral Contraction NE&adrenoreceptors • NE stimulates -adrenoreceptors in penile vasculature, contracting helicine vessels and trabecular muscle of corpus carvernosum : maintain detumescence • 1-adrenoreceptors predominate in corpus carvernosum than 2 or

  29. Implication : phentolamine , thymoxamine are the most widely used -adrenoreceptor antagonist , competitive inhibition with similar affinity for 1 / 2-receptors : phentolamine block receptor for 5-HT and cause release of histamine from mast cells and activate NO synthase, non-selectively block

  30. Phentolamine block prejunctional 2-receptors causing NE release from adrenergic nerves, counteracting its own postjunctional 1-receptors blocking • contributed to limited efficacy for erection • Moxysylate selective -adrenoreceptor antagonist,less potent than phentolamine when injected intracavernosally, but can be used alternatively

  31. (Contraction) Endothelins • ET1-mRNA expressed in endothelial cells of c. cavernosum with ET1-receptor in vasculature and cavernous tissue • ET1 maintain corporal smooth muscle tone by potently inducing slow,long-lasting contraction of various penile smooth muscles include vascular components

  32. ET1 induced contraction depended on transmembrane calcium flux and mobilization of IP3-intracellular Ca-store • ET1 modulate contractile effects of other agents : NE, cell proliferation, phenotypic expression • No clear evidence for roles of erection

  33. Peripheral Relaxation Ach & muscarinic receptors • Nerves of the penis contain Ach, VIP, NO-synthase and neuropeptide-Y • Ach-induced relaxation by inhibiting contractant factors e.g. NE or releasing relaxant factor e.g. NO via muscarinic receptors : M2 at c.carvernosum and M3 at endothelium

  34. Implication : cholinergic dysfunction may be cause of ED in DM : atropine or neostigmine given systemically or intracorporally had no effects on erection

  35. (Relaxation) NO & cGMP • 2-active synthesizing enzymes nNOS and eNOS* essential for erection • NO stimulates guanylate cyclase resulting in increase in intracellular cGMP which signals 3-receptors : ion channel, phosphodiesterase, protein kinase

  36. In mice, cGK1 inactivation abolish NO-cGMP- induced-relaxation of smooth muscle cell causing hypertension, intestinal dysmotility, inhibit platelet aggregation with abnormal homeostasis

  37. Low ability to reproduce and relax from NO • Not be compensated by cAMP signalling cascade • Activation of cGK1 is a key step in signal cascade leading to penile erection

  38. cGMP & cAMP are inactivated by PDE :hydrolytic cleavage at 3’-ribose phosphate bond • NO decreased in aging and DM • nNOS containing nerve fiber in penis declined in aging, central and peripheral stimulation of erectile response reduced • nNOS & eNOS impaired in DM due to advanced glycosylation products

  39. Atherosclerosis and hypercholesterolemia impaired eNOS , but not nNOS • L-arginine improve nNOS • Smoking caused age-dependent hypertension and decreased nNOS

  40. Implication : stimulation of NOS by L-arginine and stimulation of guanylate cyclase by NO - lacked proved clinical efficacy : inhibit PDE by sildenafil ( selective inhibitor of cGMP-specific PDE5) - a large number of RCT - improved erectile dysfunction regardless of causes

  41. Gene transfer of eNOS alone or in combination with PDE5 inhibitor may constitute a new therapeutic intervention for treatment of erectile dysfunction

  42. (Relaxation) VIP • Penis is supplied richly with nerves containing VIP • Most nerves also contain NOS • Most of these neurones are cholinergic

  43. VIP mediates action by G-protein linked to adenylyl cyclase leads to increase cAMP and activates protein kinase • VIP has an inhibitory and relaxation producing effect on corpus cavernosum : not established

  44. Implication : in potent men – no effect even in high dose (60g) : in impotent – combined with papaverine or phentolamine *similar effect, but no effect when used alone

  45. (Relaxation) Prostanoids • PG and TXA2 are locally acting hormones derived from arachidonic acid by cyclooxygenase • Corpus cavernosum synthesized various prostanoid, modurated by oxygen tension and suppressed by hypoxia

  46. Prostanoid receptors are G-protein-coupled receptor with differing transduction system • PGF2 and TXA2 involved in contraction of contraction of erectile tissues by phosphoinositide turnover and increased cAMP

  47. PGE1&PGE2 induced relaxation of corporal smooth muscles by hyperpolarization via Kca-channel • Prostanoids inhibit plate aggregation and white cell adhesion • Prostanoids and TGF modulate collagen synthesis and fibrosis of corpus carvernosum

  48. Implication - one of the most widely used treatments of ED is intracavernous or intraurethral injection of PGE1 - forskolin directly stimulates adenylate cyclase (potent stimulant of intracellular cAMP formation in smooth muscle cell) - threshold doses of forskolin synergist PGE1 to increase cAMP ,thus relax smooth muscle

  49. Clinical evaluation • Men are reluctant to discuss ED • 70% of ED remains undiagnosed • First step in assessing psychological issues is to gain trust and establish patient rapport • Questionaires • Partner interview

  50. No consensus on what constitutes an adequate evaluation for impotence • Comprehensive evaluation to ensure that no reversible etiologies or underlying diseases are missed • Full understanding the nature of ED helps the physicians to select the most appropriate

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