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

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