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 Anatomy and Physiology of erection: pathophysiology of erectile dysfunction 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 vein, the circumflex veins, the emissary veins, the cavernous veins and the crural veins). The lacunar spaces drain into small venules, which flow The penis, the male genital organ, 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). scrotum, and it is linked to the pubic symphysis by two ligaments. 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 artery of penis Dorsal nerve 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’ fascia rami are fixed, surrounded by the ischiocavernous muscles. The CS, in turn, stems from the perineum, Buck’s fascia Circumflex Vein surrounded by the bulbocavernous muscle. The Corpus urethra runs most of its length. At the distal end, cavernosum Tunica albuginea 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- nervous system, 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 nerves to the ischiocavernous and bulbocavernous albuginea, an elastic fibrous structure.1 muscles.6 Penile arteries 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 rapid eye movement sleep 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 erectile tissue 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 smooth muscle 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 vasodilation, 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 (tumescence). 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). Acetylcholine Cholinergic Muscarinic Nitric oxide/ 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 Endothelium 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 central nervous system (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, oxytocin 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 ejaculation, 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, lungs, 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 hand, 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,