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Home , Erectile tissue, Erection, Fascia, Scrotum, Tunica albuginea (penis)

International Journal of Impotence Research (2003) 15, Suppl 7, S5–S8 & 2003 Nature Publishing Group All rights reserved 0955-9930/03 $25.00 www.nature.com/ijir

Chapter 2 and Physiology of : pathophysiology of

Reporters and participants of the 1st Latin American Dysfunction Consensus Meeting

International Journal of Impotence Research (2003) 15, Suppl 7, S5–S8. doi:10.1038/sj.ijir.3901127

Anatomy deep dorsal , the circumflex , the emissary veins, the cavernous veins and the crural veins). The lacunar spaces drain into small venules, which flow The , the male genital , has two func- together into a subalbugineal plexus, which in turn, tions: sexual and urinary. It is located above the emerges as emissary veins4,5 (Figure 1). , and it is linked to the pubic symphysis by two . It has a three-cylinder shape, integrated by two CROSS-SECTIONAL SECTION OF THE PENIS vascular tissue bodies (corpora cavernosa) (CC) and Superficial dorsal vein the corpus spongiosum (CS). The CCs have two Dorsal of penis Dorsal of portions: a fixed posterior one, or perineal, and one penis that is anterior or free. At its base, the ischiopubic Deep dorsal vein Colles’ rami are fixed, surrounded by the ischiocavernous muscles. The CS, in turn, stems from the , Buck’s fascia Circumflex Vein surrounded by the bulbocavernous muscle. The Corpus runs most of its length. At the distal end, cavernosum the CS dilates into a structure known as glans, Cavernous artery where the urethra opens to the outside of the Corpus spongiosum Urethral artery body through the meatus.1,2 Urethra Adapted and Modified from the 2ndBrazilian Consensus on Erectile Dysfunction2 The penis has an epidermal layer, underneath which is located the superficial fascia (Colles’), Figure 1 Cross-sectional section of the penis. whereas under the latter is found the Buck’s fascia, more resistant, surrounding the CCs and the CS. The Penis innervation stems from the autonomous CCs are linked at their free portion by the intraca- , with sympathetic (thoracolumbar vernous septum, with functional communications segment T11–L2) and parasympathetic (sacrum S2– between both, which means their turning into a 4) fibers. There is also a somatic innervation, which functional unit. The CCs account for the rigidity of is sensitive, whereas the motor innervation supplies the penis, since they are surrounded by the tunica to the ischiocavernous and bulbocavernous albuginea, an elastic fibrous structure.1 muscles.6 Penile stem from the internal pudenda, a branch of the hypogastric artery that, inside the organ, subdivides into three branches: Physiology  dorsal artery,  cavernous artery and  bulbourethral artery, which then divides itself Three types of erection are recognized: nocturnal, into its bulbar and urethral branches. that follows the periods; reflexogenic, from genital stimulations; and the The cavernous arteries run inside the CCs and end central or psychogenic one, with a single or multiple at the helicine arteries that open themselves inside starting point (smell, visual stimulations, recalls the lacunar spaces. The is comprised etc). Psychological and organic factors play different by the sinusoids, which are functional erectile roles in the phenomenon.4–6 structures. The sinusoids are made up of endothe- Erection is an active neural-hemodynamic process lium and a on a fibroelastic that takes place in a suitable endocrine environ- support.1,3 ment, due to several stimulations. Venous drainage is complex and it is integrated by Following arterial , an increased flow two systems: a superficial one and a deep one (the to the lacunar spaces occurs, while relaxation of the Chapter 2 Anatomy and Physiology of erection S6 sinusoidal smooth muscle allows for their disten- NEUROGENIC-ORIGIN NEUROTRANSMITTERS NEURO- ORIGIN RECEPTOR SECOND INTRA- SMOOTH tion (). The increased pressure generated TRANSMITTER MESSENGER CELLULAR MUSCLE leads to compression of the emissary veins against CALCIUM FIBER the tunica albuginea (veno-oclusion and rigidity). RESPONSE As the CS has no tunica albuginea, it shows nothing Norepinephrine Adrenergic Alpha- IP3/diaglycerol/ Increased Contraction 4–7 neuron adrenergic Ca2/PKC but tumescence (Figure 2). Cholinergic Muscarinic / Reduced Relaxation neuron guanylate cyclase/ cGMP/PKG CORPUS CAVERNOSUM WITH PENIS IN FLACCID STATE Nitric oxide Non-adrenergic Guanilato ciclase Guanylate Reduced Relaxation Deep dorsal vein (neuronal) Non-cholinergic Calcium and cyclase/cGMP/ Circumflex vein potassium channels PKG Sinusoidal space Vasoactive Non-adrenergic Vasoactive Adenyl cyclase/ Reduced Relaxation intestinal Non-cholinergic intestinal cAMP/PKA peptide peptide Resistance artery

Helicine artery ENDOTHELIAL-ORIGIN NEUROTRANSMITTERS Cavernous artery NEURO- ORIGIN RECEPTOR SECOND INTRA- SMOOTH TRANSMITTER MESSENGER CELLULAR MUSCLE Emissary vein Tunica albuginea CALCIUM FIBER RESPONSE

Endothelin 1 Endothelial Endothelin A IP3/diaglycerol/ Increased Contraction Figure 2 Corpus cavernosum with penis in flaccid state cells Endothelin B CA2/PKC Nitric oxide Guanylate cyclase Guanylate cyclase/ Reduced Relaxation (endothelial) Calcium and cGMP/PKG potassium channels Several areas associated with sexual response are Prostaglandin Endothelial Prostaglandin Adenyl cyclase/ Reduced Relaxation located in the (CNS). In E1 cells receptor cAMP/PKA K = potassium; IP3 = inositol triphosphate; Ca2= calcium; PKC = protein kinase-c; cGMP = cyclic guanosine- regard to erection proper, the paraventricular nuclei, monophosphate; PKG = protein kinase G; cAMP = cyclic adenosine-monophosphate; PKA = protein kinase A the medial preoptic area and the hippocampus are Adjusted and modified by Lue TF5 the areas most commonly studied. Yet, several neurotransmitters play a role in the sexual reply modulation, some being facilitative and others inhibitors. The major facilitative ones (or excitatory) are: dopamine, acetylcholine, and seroto- Peripheral mechanism of erection nine (Figure 3).4,6

CORPUS CAVERNOSUM WITH PENIS IN ERECTILE STATE Relaxation of the cavernous smooth muscle depends on the known neurotransmitters: Circumflex vein Sinusoidal space Tunica albuginea  prostaglandin E1 (PGE1) and  nitric oxide (NO). Resistance artery Emissary vein Apparently, the most important route in the peripheral mechanism of erection is that of NO- Helicine artery GTP (guanosine triphosphate). With sexual stimula- Cavernous artery tion, NO is released into the nervous terminations

Adjusted and modified from Valdivia P. Fisiologia da ereção – www.med.net8 (NANC—nonadrenergic, noncholinergic) and into the endothelial cells, turning the GTP into cyclic Figure 3 Corpus cavernosum with penis in erectile state. GMP (cGMP-second messenger) by means of an enzyme (guanylate cyclase). This process facilitates Dopamine is a catecholamine synthetized from the reduction of intracellular calcium, enabling the the phenylalanine amino acid. At the CNS level, it smooth muscle of the CC to relax, resulting in has several effects, and at the paraventricular erection. The cGMP is hydrolyzed into GMP nucleus level it facilitates erection through D2 (guanosine-monophosphate) by means of phospho- receptors.4,6,9 diesterase 5 (PDE 5) (Figure 4). Serotonine is a modulator that operates according In all, 11 types of phosphodiesterases have been to the active receptor. There are seven known types described in humans. cGMP is the only substrate in of receptors: HT1A inhibits erection and facilitates types 5, 6 and 9. That of type 5, in relation to the , whereas its action on HT2C stimulates penis, accounts for the cGMP hydrolysis. Other PDE erection. Inhibition is the prevailing action of 5 locations are: platelets, the aorta, , cerebel- serotonine on erection. lum, heart, bowel and suprarenal gland. The major inhibitors are: epinephrine, norepi- Other phosphodiesterases, as far as the penis is nephrine, serotonine, enkephalins, gamma amino- concerned,2–4 are not so important from the physio- butyric acid and prolactin (Pictures 1 and 2).4,6,10 logical point of view.4,6,9,11

International Journal of Impotence Research Chapter 2 Anatomy and Physiology of erection S7 Detumescence would result from several factors arising from reduced NO release, inactivation of the second messenger (cGMP) or from the action of the sympathetic system in ejaculation.4,6

Pathophysiology of ED

In terms of clinical approach, three types of ED are acknowledged: psychogenic, organic and mixed. Picture 1 Neurogenic-origin neurotransmitters. On the other , also acknowledged are the primary and secondary EDs or the ones acquired after a period of life of preserved sexual function.2,15,16 On the other hand, the vasoactive intestinal peptide and the PGE1 induce the transformation of adenosine triphosphate into cyclic AMP (via AMP). Organic ED cAMP also promotes muscle relaxation through intracellular reduction of calcium concentration. Organic-cause ED can be classified according to the Calcium (Ca2 þ ) plays a key role in the main- pathophysiological mechanism prevailing in: tenance of the muscle tonus, owing to its ions diffusion within the cell cytoplasm, through the ion-  Arterial: Hemodynamic alterations that affect selective membranes channels, which in turn, are erection may stem from chronic or trauma modulated by voltage changes. obstructions that might affect the penile On the other hand, intracellular calcium, whose supply and compromise both macro- and micro- concentration has been increased, combines with arterial circulation. Although arterial deficiency calmodulin to activate the kinase of the ‘light’ may result from either traumas or birth anomalies, chains of myosin, the enzyme that phosphorylyzes in most cases, arteriogenic ED is part of a them and stimulates the actinamyosin interactions, generalized arteriosclerosis process.2,4,6,14 generating contraction. Thus, the calcium flow  Neurogenic: Conditions involving the CNS, the through the membrane plays a key role, by main- and/or the peripheral nerves can alter taining and modulating the tonus of the smooth the quality of erection. Diabetes can alter the muscle fiber of the CC. The cell membrane potential erectile response through an autonomic neuro- depends on the outflow of potassium and it pathy, a gonadal dysfunction and by compromis- regulates muscle contractility. To date, four classes ing relaxation of the penile smooth muscles of potassium channels in those cells have been (endothelial or neurogenic route).17,18 described.  Endocrine: Androgens exercise a primary action The smooth muscle cells are joined to one another on desire, but their reduction (hypogonadism) (‘gap junctions’), at the cytoplasm level, through plays a role on the erective phenomenon. Hyper- protein bindings that stem from connexin 43, there- prolactinemia and thyroid disorders can also fore constituting a functional unit. This enables the affect the quality of erection.19 artery and corpora cavernosa myocytes to respond in  Penile: Local and/or diffuse penile structural a uniform and orderly manner to the different alterations, arising from the percentage modifica- stimulations, and any change, whether chemical or tion of , elastic and/or smooth muscle electric that should alter the operation of those fibers, can change the erectile response (venno- potassium channels, to reflect on the functional oclusive ED).2–4,6 unity.7,12–14  Toxic and drug: One in every four patients with Adrenalin, opioid peptides and endothelins ED is estimated to present with a drug-related should be mentioned among the erection peripheral problem. Drugs secondary effects can affect both inhibitor neurotransmitters deemed most important. erection and desire and/or ejaculation. More than In flaccidity, blood flow in the lacunar spaces is 100 usually and frequently used drugs can alter minimal, with passage facilitated up to the venous men’s sexuality. Among those one should mention drainage system. psychopharmacological drugs (antianxiety agents, Most of the time, the penis is maintained flaccid, antidepressants, antipsychotics), antihyper- which depends on the intrinsic myogenous activity, tensive agents, diuretics and antiandrogenics. In on the adrenergic activity and on the endothelium- all cases, therefore, the condition that originated derived contraction, such as the PGF2-alpha and the therapeutic indication should be considered. endothelins.4,6 Smoking can affect erection through different

International Journal of Impotence Research Chapter 2 Anatomy and Physiology of erection S8 mechanisms, among which hyperclotting, in- 5 Lue TF. Erectile dysfunction. N Engl J Med 2000; 342: 1802– creased platelet aggregation, unbalance between 1813. the thromboxane and prostacyclins concentra- 6 Mazza O, Zeller F. Tratamiento farmacolo´gico de la disfuncio´n ere´ctil. Editorial Panamericana: Buenos Aires, 1997. tions and its direct toxic effects on the vascular 7 Gerthoffer WT, Larsen JK. Regulation of smooth muscle endothelium. contractacion. In: Barr L, Christ JG (eds). A Functional View of Smooth Muscle. Jai Press: Stanford, 2000, pp 49–80. Long-term alcohol consumption can affect the 8 Giuliano F, Allard J. Dopamine and male sexual function. Eur erectile response upon an endocrine alteration Urol 2001; 40: 601–608. through increased estrogens arising from androgen 9 Andersson KE. Neurophysiology/pharmacology of erection. aromatization, through polyneuropathy and through Int J Impot Res 2001; 13 (Suppl 3): S8–S17. 2,4,6 10 Burnett AL. Nitric oxide in the penis: physiology and changes in . pathology. J Urol 1997; 157: 320–324. Cocaine consumption can affect sexual response 11 Christ GJ. K þ chanels and gap junctions in the modulation of through behavior disorders (anxiety), increased corporal smooth muscle tone. Drug News Perspect 2000; 13: alpha-adrenergic activity and through changes in 28. the arterial endothelium.5 12 Melman A, Christ G. Biologia integrada de la ereccio´n. Urol Clin N Am 2001; 28: 217. 13 Clement-Chomienne O. Properties, regulation, and role of potassium chanel. In: Barr L, Christ GJ (eds). A Functional Psychogenic ED View of Smooth Muscle. Jai Press: Stanford, 2000, pp 247–317. 14 1er Consenso Argentino Sobre Disfunciones Erectil. Subco- mite´ de Disfunciones Sexuales de la Sociedad Argentina de To be discussed in Chapter 5. Urologı´a, November 1998. 15 Wagner G, Mulhall J. Pathophysiology and diagnosis of male erectile dysfunction. BJU Int 2001; 88 (Suppl 3): 3–10. References 16 Nehra A, Moreland RB. Neurologic erectile dysfunction. Urol Clin N Am 2001; 28: 289–308. 17 De Groat WC, Steers W. Neuroanatomy and neurophysiology 1 Testut L, Latarjet A. Tratado de anatomı´a descriptiva, 8th edn. of penile erection. In: Tanagho E, Leu TF, McClure D (eds). Ed. Salvat. Contemporary Management of Impotence and Infertility. 2 II Consenso Brasileiro de Disfunc¸a˜o Ere´til. Sociedade Brasi- Williams and Wilkins: Baltimore, 1998. leira de Urologia, Abril 2002. 18 Zonszein J. Diagnosis and management of endocrine disorders 3 Lue T. Erectile dysfunction, and Peyronie’s disease. of erectile dysfunction. Urol Clin N Am 1995; 22: 789–802. Post-graduate Course (H0002PG)—96th Annual Meeting of the 19 Valdivia P. Fisiologı´a de la ereccio´n, Ref. eletro´nica: http:// American Urological Association 2001. www.mundomed.net. 4 Saenz de T. Ereccio´n, eyaculacio´n y sus trastornos. Madrid, Fomento Salud, 1997.

International Journal of Impotence Research