Erectile Dysfunction

Transcription

1 Erectile Dysfunction

2 ii Colloquium Digital Library of Life Sciences This e-book is an original work commissioned for the Colloquium Digital Library of Life Sciences, a curated collection of time-saving pedagogical resources for researchers and students who want to quickly get up to speed in a new area of life science/biomedical research. Each e-book available in Colloquium is an in-depth overview of a fast-moving or fundamental area of research, authored by a prominent contributor to the field. We call these resources Lectures because authors are asked to provide an authoritative, state-of-the-art overview of their area of expertise, in a manner that is accessible to a broad, diverse audience of scientists (similar to a plenary or keynote lecture at a symposium/meeting/colloquium). Readers are invited to keep current with advances in various disciplines, gain insight into fields other than their own, and refresh their understanding of core concepts in cell & molecular biology. For the full list of available Lectures, please visit; All Lectures available as PDFs on our website. Access is free for readers at institutions that license Colloquium. Please info@morganclaypool.com for more information.

3 iii Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease Editors D. Neil Granger, Louisiana State University Health Sciences Center Joey P. Granger, University of Mississippi Medical Center Physiology is a scientific discipline devoted to understanding the functions of the body. It addresses function at multiple levels, including molecular, cellular, organ, and system. An appreciation of the processes that occur at each level is necessary to understand function in health and the dysfunction associated with disease. Homeostasis and integration are fundamental principles of physiology that account for the relative constancy of organ processes and bodily function even in the face of substantial environmental changes. This constancy results from integrative, cooperative interactions of chemical and electrical signaling processes within and between cells, organs and systems. This ebook series on the broad field of physiology covers the major organ systems from an integrative perspective that addresses the molecular and cellular processes that contribute to homeostasis. Material on pathophysiology is also included throughout the ebooks. The state-of the-art treatises were produced by leading experts in the field of physiology. Each ebook includes stand-alone information and is intended to be of value to students, scientists, and clinicians in the biomedical sciences. Since physiological concepts are an ever-changing work-in-progress, each contributor will have the opportunity to make periodic updates of the covered material. Published titles (for future titles please see the website,

4 Copyright 2014 by Morgan & Claypool Life Sciences All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means electronic, mechanical, photocopy, recording, or any other except for brief quotations in printed reviews, without the prior permission of the publisher. Erectile Dysfunction Rany Shamloul, Anthony J. Bella ISBN: paperback ISBN: ebook DOI: /C00105ED1V01Y201403ISP051 A Publication in the Colloquium Series on INTEGRATED SYSTEMS PHYSIOLOGY: FROM MOLECULE TO FUNCTION TO DISEASE Lecture #51 Series Editor: D. Neil Granger, LSU Health Sciences Center, and Joey P. Granger, University of Mississippi Medical Center Series ISSN ISSN X ISSN print electronic

5 Erectile Dysfunction Rany Shamloul, MD, PhD Ottawa Hospital Research Institute, Ottawa, Canada; Department of Andrology, Cairo University, Cairo, Egypt Anthony J Bella, MD, FRCSC Greta and John Hansen Chair in Men s Health Research, Assistant Professor of Urology, Department of Surgery, Associate Scientist, Neuroscience, University of Ottawa COLLOQUIUM SERIES ON Integrated Systems Physiology: From Molecule to Function to Disease #51

6 vi Abstract The understanding of the pathophysiology of erectile dysfunction (ED) has advanced significantly over the past 2 decades. In this ebook, we provide an in-depth analysis of the current knowledge of the pathophysiology of ED in order to provide the reader with an up-to-date and comprehensive understanding of the pathophysiology of ED, which is complex but fascinating. Intensive and intricate mechanisms govern the development of ED. These mechanisms involve complex interaction between vascular, hormonal and neural regulation. Current research on the central regulation of ED is key for the advancement of our understanding of this complex disease. Recent advances in our knowledge of the vascular mechanisms regulating penile erection led to appreciation of ED as an early symptom of cardiovascular disease. Major health concerns such as atherosclerosis, hyperlipidemia, hypertension and diabetes have become well integrated into the investigation of ED. Extensive research on the mechanisms involved in the regulation of penile erection have led to unparalleled advances in the understanding of general vascular regulation. However, many unknowns remain, which provides vast opportunities for future basic and clinical investigations. Key Words erectile dysfunction, erection, penis, sexual dysfunction, pathophysiology, physiology, nitric oxide, corpora cavernosa, corpus spongiosum, coronary artery disease

7 vii Contents 1. Anatomy of the Penis Introduction Skin and Fascia Tunica Albigunea Corpora Cavernosa Associated Musculature Penile Vascular Anatomy Lymphatics Innervation The Male Urethra Microscopic Anatomy of the Penis Tunica Albuginea Corpora Cavernosa Ultrastructure, Corpus Spongiosum, and Glans Penis Cavernous Smooth Muscle General Pathophysiology Dopamine Oxytocin Adrenocorticotropic Hormones (ACTH) and Related Peptides Nitric Oxide (NO) Serotonin Opioid Peptides Prolactin Sexual Hormones Control of Cavernous Smooth Muscle Function Mechanism of Smooth Muscle Contraction Regulation of VSMC Tone Peripheral Neurotransmitters... 23

8 viii erectile dysfunction 3. Diabetes and ED Epidemiologic Data Pathophysiology ED and Cardiovascular Disease Drugs Causing ED Cardiovascular Drugs and Erectile Function Antihypertensive Treatment and ED Diuretics α-adrenoceptor Antagonists ACE Inhibitor Calcium Channel Blockers Lipid-Lowering Drugs (Fibrates, Statins) Psychotropic Medication Antidepressants Antipsychotics Other Psychotropic Medications Anti-Androgens References Author Biographies... 71

9 1 c h a p t e r 1 Anatomy of the Penis 1.1 INTRODUCTION The male genital system includes the external and internal genital organs. The penis or the phallus is the male external genital organ, while the testis, epididymis, vas deferens, seminal vesicles and the prostate are considered the male internal genital organs. In this chapter, we will provide an overview of the gross and microscopic anatomies of the male genitalia. The penis is a tripartite structure, with bilateral corpora cavernosa and the midline ventral corpus spongiosum/glans, all three of which are surrounded by loose subcutaneous tissue and skin which can be moved freely over the erect organ (Figure 1). The corpora cavernosa s main function is to provide an adequate erection by complete relaxation of its massive amounts of smooth muscles allowing arterial blood to flow inside the penis. The corpus spongiosum contains a considerable amount of erectile tissue, and its main function is to provide adequate covering of the male penile urethra. It is noticeable that the length of the penis varies widely, especially in the flaccid state, FIGURE 1: Transverse section of the penis (Gray s Anatomy).

10 2 erectile dysfunction most probably due to geographic distribution, man s own height is highly dependent on the degree of contraction of the cavernosal smooth muscle tissue. However, there is considerably less variation in length of the fully erect penis, with one study demonstrating a good correspondence between erect length and stretched penile length, as measured from the pubopenile junction to the meatus [1]. This length was found to be an average of 12.4 cm Skin and Fascia Penile skin is continuous with that of the lower abdominal wall and continues over the glans penis; there it folds back on itself and attaches at the coronal sulcus. The folded portion is known as the prepuce. There are two fascial layers. The more superficial is the dartos fascia, continuous with Scarpa s fascia of the abdomen. It continues caudally as the dartos fascial layer of the scrotum and Colles fascia in the perineum. The deeper fascial layer is Buck s fascia, which covers the corpora cavernosa and the corpus spongiosum in separate compartments, including coverage of the deep dorsal vein as well as the dorsal neurovascular bundles. The fundiform and suspensory ligaments attach to the pubic symphysis and Buck s fascia and allow the erect penis to achieve a horizontal or greater angle (Figure 2). FIGURE 2: Section of corpus cavernosum penis in a non-distended condition (Gray s Anatomy).

11 anatomy of the penis Tunica Albigunea The tunica albigunea (TA) is a very strong structure of heterogeneous thickness and anatomy that surrounds the corpora cavernosa. The main purpose of this thick covering is to both provide rigidity of the erectile bodies as well as to function in the venoocclusive mechanism. It is mainly composed of two layers, the outer layer of which is oriented longitudinally and the inner layer consisting circular fibers. The inner layer contains strong supports that traverse the cavernosal space and serve to expand the support provided by the intracavernosal septum. The corpus spongiosum lacks both the outer layer as well as the strong supports or struts. The TA s thickness and strength are highly variable, depending mainly on the location of the thick fibres. Thickness ranges from approximately 0.8 mm at the 5:00 and 7:00 position (just lateral to the corpus spongiosum) to 2.2 mm at the 1:00 and 11:00 positions [2] Corpora Cavernosa The two corpora cavernosa originate underneath the ischiopubic rami, then merge as they pass under the pubic arch. The septum between them is incomplete in humans, although complete in some other species [3]. They are supported by several fibrous structures, including the surrounding TA, the intracavernous struts radiating from the inner layer of TA, and perineural/periarterial fibrous sheaths. The spongy inner portion of the corpora consists mainly of interconnected sinusoids separated by smooth muscle trabeculae, which are surrounded by collagen and elastic fibers. These sinusoids are larger centrally and smaller towards the periphery [3]. The corpus spongiosum and its distal termination in the glans penis are similar in internal structure to the corpora cavernosa except that the sinusoids are larger, there is a lack of outer layer of TA, and the TA is absent in the glans Associated Musculature The two ischiocavernosus muscles originate from the ischial tuberosity, cover the proximal corpora, and insert into the inferiomedial surface of the corpora. Nerve supply of these muscles is from the perineal branch of the pudendal nerve. The ischiocavernosus muscles function mainly by allowing the corpora cavernosa to obtain very high intracorporal pressures than would be possible with arterial pressure alone. The bulbospongiosal muscle originates at the central perineal tendon, covers the urethral bulb and corpus spongiosum, and inserts into the midline. Nerve supply of this muscle is through a branch of the perineal nerve. The bulbospongiosal muscle has an important role in the ejaculation of semen [3].

12 4 erectile dysfunction Penile Vascular Anatomy The internal pudendal artery, a branch of the internal iliac artery is the main source of arterial blood supply to the penis. In many instances, however, accessory arteries arise from the external iliac, obturator, vesical, and/or femoral arteries, and may occasionally become the dominant or only arterial supply to the corpus cavernosum [3]. Damage to these accessory arteries during radical prostatectomy or cystectomy may result in vasculogenic erectile dysfunction (ED) after surgery [4, 5]. The internal pudendal artery becomes the common penile artery after giving off a branch to the perineum. The three branches of the penile artery are the dorsal, bulbourethral, and cavernous arteries. The cavernous artery is responsible for tumescence of the corpus cavernosum and the dorsal artery for engorgement of the glans penis during erection. The bulbourethral artery supplies the bulb and corpus spongiosum. The cavernous artery enters the corpus cavernosum at the hilum of the penis, where the two crura merge. Distally, the three branches join to form a vascular ring near the glans. Along its course, the cavernous artery gives off many helicine arteries, which supply the trabecular erectile tissue and the sinusoids. These helicine arteries are contracted and tortuous in the flaccid state and become dilated and straight during erection. The helicine arteries enter into the blood sinusoids directly without traversing a capillary bed. The blood supply to the penile skin is dependent upon the right and left external pudendal arteries that arise from the femoral artery (Figures 3 and 4). FIGURE 3: Diagram of the arteries of the penis (Gray s Anatomy).

13 anatomy of the penis 5 FIGURE 4: Veins of the penis (Gray s Anatomy). The venous drainage from the three corpora originates in tiny venules leading from the peripheral sinusoids immediately beneath the tunica albuginea. These venules travel in the trabeculae between the tunica and the peripheral sinusoids to form the subtunical venular plexus before exiting as the emissary veins. Outside the tunica albuginea, the venous drainage is as follows [3]: The skin and subcutaneous tissue drain through multiple superficial veins that run subcutaneously and unite near the root of the penis to form a single (or paired) superficial dorsal vein, which in turn drains into the saphenous veins. Occasionally, the superficial dorsal vein may also drain a portion of the corpora cavernosa. In the pendulous penis, emissary veins from the corpus cavernosum and spongiosum drain dorsally to the deep dorsal, laterally to the circumflex, and ventrally to the periurethral veins. Beginning at the coronal sulcus, the prominent deep dorsal vein is the main venous drainage of the glans penis, corpus spongiosum, and distal two thirds of the corpora cavernosa. Usually, a single vein, but sometimes more than one deep dorsal vein, runs upward behind the symphysis pubis to join the periprostatic venous plexus. Emissary veins from the infrapubic penis drain the proximal corpora cavernosa and join to form cavernous and crural veins. These veins join the periurethral veins from the urethral bulb to form the internal pudendal veins [3].

14 erectile dysfunction Lymphatics Lymphatics of the prepuce and penile shaft converge dorsally, and then drain into both right- and left-sided superficial inguinal lymph nodes via channels alongside superficial external pudendal vessels. Lymphatics of the glans and penile urethra pass deep to Buck s fascia and drain into both superficial and deep inguinal nodes [3] Innervation The penis is supplied by both somatic and autonomic nerves. The somatic dorsal nerves provide sensory innervation (as well as provide some degree of autonomic function) for the penile skin and glans, and approximately follow the course of the dorsal penile arteries, eventually becoming the pudendal nerve (after joining with other nerves) and entering the spinal cord via S2 4 nerve roots. The pudendal nerve gives off a motor branch to the ischiocavernosus and bulbocavernosus muscles whose contraction help to increase the rigidity of erection. It also gives a sensory branch that supplies the penis, perineum, and the rectum. Sympathetic autonomic fibers derive from the hypogastric plexus and join parasympathetic autonomic fibers from S2 4 in the pelvic plexus. Cavernous nerves represent the penile branches of the pelvic plexus that ramify once piercing the corporal bodies, and thus contain both sympathetic and parasympathetic fibers [3]. 1.2 THE MALE URETHRA The male urethra is a canal that extends from the bladder neck to the external urethral meatus passing through the substance of the corpus spongiosum. It is about cm in length (Figure 5). The urethra is essentially a potential canal that opens only during micturition and has a characteristic S-shaped course. These two factors render its drainage difficult and predispose to the chronicity and the wide spread of infection frequently observed with urethritis. The male urethra is further divided into the following parts [3]: 1. Posterior urethra: This is composed of the prostatic urethra and the membranous urethra. The prostatic urethra is 3 cm in length and considered to be the widest and most distensible part of the whole canal. It extends from the neck of the bladder passing through the substance of the prostate to end at the neck of the prostate by becoming the membranous urethra. Its posterior wall shows an elevation termed the veromontanum which is related to three important structures, the prostatic utricle, the two ejaculatory ducts, and the prostatic

15 anatomy of the penis 7 FIGURE 5: Vertical section of bladder, penis, and urethra (Gray s Anatomy). 2. ducts. The membranous urethra is the thickest part of the urethra as it passes through the urogenital diaphragm and it is a muscular organ with both smooth and skeletal muscles. The skeletal muscle part of the membranous urethra forms the external (voluntary) sphincter. Anterior urethra: It is about 15 cm long extending from the membranous urethra until the external urethral meatus at the tip of the glans penis. The anterior urethra is formed of two main parts, the bulbous urethra and the penile or pendulous urethra. The bulbous urethra is the proximal part of the anterior urethra and is surrounded by the bulb of the penis and the bulbospongiosus muscle, while the penile urethra is the distal-free part of the anterior

16 erectile dysfunction 3. urethra and is the continuation of the proximal bulbar urethra at the lowest level of symphysis pubis. The penile urethra ends by passing through the glans penis where it forms a small dilatation named the fossa navicularis to end finally at the external meatus, the narrowest point of the entire canal. Urethral sphincters a) The internal sphincter: It controls the bladder neck and the prostatic urethra above the opening of the ejaculatory ducts. It is formed of involuntary non-striated muscles and supplied by autonomic nerve supply. b) The external sphincter: It controls the membranous urethra. It is formed of voluntary striated muscles and supplied by somatic nerve supply [6]. 1.3 MICROSCOPIC ANATOMY OF THE PENIS Tunica Albuginea The primary function of the tunica albuginea is to afford rigidity, flexibility, and tissue strength to the penis [1]. It is a bilayered covering of the corpora cavernosa with multiple sublayers. The inner layer bundles of the corpora cavernosa are circular, and serve to support and contain the cavernous tissue. Also, intracavernosal pillars branch from the inner layer into the corpora, acting as strong supports to augment the penile septum and provide support to the erectile tissues. The outer longitudinally oriented layer is composed of connective tissue bundles that extend from the glans penis to the proximal crura, inserting upon the inferior pubic rami [7]. The tunica itself may be considered as a mesh that is composed of elastic fibers that form an irregular, latticed network on which the collagen fibers rest. This intriguing ultrastructural arrangement provides strength and allows the tissue to return to its baseline configuration after the corporal expansion during erection. The composition and distribution of component fibers is a fundamental factor in rendering the function of the tunica; it is primarily composed of type I, but also type III, fibrillar collagen in organized arrays throughout which are interspersed elastin fibers [8]. Both fiber types are essential for normal function: the steel-like tensile strength of collagen is unyielding and resists uncontrolled deformity at high pressure, while elastin content allows for tunical expansion as these fibers are able to stretch to approximately 150% of resting length [9]. Elastin content is also an important determinant of stretched penile length. The presence or absence of both tunical layers, thickness of the tunica itself, and intracavernous pillars varies throughout the course of the penis, as does histological composition, reflecting the relationship between the anatomical design and function. The strength and thickness of this

17 anatomy of the penis 9 layer correlates with location, with the thinnest portion noted to be between the 5 and 7 o clock positions [10]. This coincides with the absence of the outer longitudinal layer at the ventral groove over the urethra; extrusion of penile prosthesis is most common at this location [11]. As the crura diverge proximally, circular fibers provide sole support. A higher elastin to collagen ratio, as well as the absence of the outer layer and struts, for the tunica overlying the corpus spongiosum ensures a low-pressure structure during erection [12]. In addition to providing a supportive framework to the paired corpora, the tunica albuginea is essential to venous trapping and pathophysiological changes such as those seen with Peyronie s disease may compromise this function and lead to venous leak. The emissary veins, travel between the inner and outer layers of the tunica for short distances, and often pierce the outer bundles in an oblique manner [13]. The outer longitudinal layer serves as a backboard, resulting in compression of the emissary veins during penile engorgement and limiting the amount of penile blood which is able to drain away from the corpora. The end-result is maintenance of an erect penis. Inadequate venous occlusion may result in erectile dysfunction via the following mechanisms: 1. degenerative tunical changes secondary to Peyronie s disease, aging, or diabetes, or traumatic injury impairing subtunical and emissary vein compression; 2. alteration in the fibroelastic components of the cavernous smooth muscle, trabeculae, or endothelium; 3. inadequate cavernous smooth muscle relaxation; 4. acquired venous shunts; or 5. congenital anomalous large venous channels [7]. Inherent differences for the arterial system ensures that occlusion by the tunica albuginea does not occur during tumescence; the cavernous artery and branches of the dorsal artery traverse the outer layer in a more direct manner (perpendicular) and are instead surrounded by a periarterial fibrous sheath, limiting occlusive ability [8] Corpora Cavernosa Ultrastructure, Corpus Spongiosum, and Glans Penis The spongy, paired corpora cavernosa are paired cylinders contained within the supportive envelope of the tunica albuginea; located on the dorsal aspect of the penis, the proximal ends (crura) originate at the undersurface of the puboischial rami as two separate structures and merge under the pubic arch, continuing as a unit to the glans. Corpora support is provided by a fibrous skeleton that includes the tunica albuginea, intracavernous pillars, intracavernous fibrous network, and the periarterial and perineural fibrous sheath. The midline corporal septum is incomplete, allowing blood to flow from one side to the other [3]. Similar to the tunica, cavernosal design reflects a functional need for rigidity, strength, and flexibility. It has been suggested that the intracavernous fibrous framework adds strength to the tunica albuginea. Within the tunica are the interconnected sinusoids separated by smooth muscle

18 10 erectile dysfunction trabeculae and surrounded by collagen (predominant types I and IV), elastin, fibroblasts, and loose areolar tissue [14, 15]. Smooth muscle predominates, accounting for 45% of corporal volume [16]. Alterations of the cytoskeleton for either tissue-type components and/or relative quantities may be responsible for changes in penile morphology in flaccid and erect states. For example, loss of compliance of the penile sinusoids has been observed as a by-product of aging, and is associated with increased deposition of collagen; hypercholesterolemia induced dysregulation of collagen may also cause loss of compliance [17]. Terminal branches of the cavernous nerves and helicine arteries are intimately associated with corporal smooth muscle; sinusoids are larger in the center and grow progressively smaller in the periphery [7]. Blood slowly diffuses from the central to the peripheral sinusoids in the flaccid state, and the blood gas levels are similar to those of venous blood. During erection, the oxygen tension approximates that of arterial blood due to the rapid entry of arterial blood to the central and peripheral sinusoids [18]. The structure of the corpus spongiosum is similar to that of the corpora except that sinusoids are larger and the outer layer of the tunica is absent. Intraspongiosal pressures reach only one half to one third that of the cavernosa due to the less constraining tunical layer, resulting in lesser venous occlusion [17]. The glans itself has no tunical covering; however, it is still able to engorge due to the presence of continued arterial inflow and venous outflow during erection [6]. Partial compression of the deep dorsal and circumflex veins between Buck s fascia and the engorged corpora cavernosa also contribute to glanular tumescence. The spongiosal and penile veins are externally compressed by the ischiocavernosus and bulbocavernosus muscles during the rigid erection phase, further increasing engorgement and pressure in the glans and spongiosum Cavernous Smooth Muscle In the flaccid state, cavernous (or corporal) smooth muscle is tonically contracted with a partial pressure of oxygen measuring approximately 35 mm Hg [18]. Blood flow to the penis is approximately 5 ml per minute. With sexual stimulation and the release of neurotransmitters from the cavernous nerve terminals, smooth muscle relaxation occurs and the end-result is an erect penis. Modulation of the cavernous smooth muscle tone is a complex process regulated by a myriad of intracellular events and extracellular signals; therefore, it is not surprising that ultrastructure reflects these physiologic functions. Cavernous smooth muscle cells are composed of thin, intermediate and thick filaments which are primarily composed of actin, desmin or vimentin, and myosin, respectively. In humans, two types of electrical activity have been reported for the corpus cavernosum: spontaneous and activity-

19 anatomy of the penis 11 induced [19]. Further, DiSanto and associates have reported overall composition to be in-between aortic (tonic) and bladder smooth muscle (phasic) [20]. Smooth muscle contraction and relaxation is primarily regulated by sarcoplasmic-free calcium. Each of the filament types has a specific role, but the primary mechanism is the interaction between actin and myosin. Contractile tone is conferred by cross-bridges linking regulatory myosin light chain globular heads and actin; tone is maintained with minimal expenditure of energy [21]. Relaxation occurs with a decrease in cytosolic calcium. Smooth muscle fibers damaged by vasculogenic or neurogenic causes of erectile dysfunction demonstrate similar ultrastructural changes, suggesting a variety of pathological mechanisms with common endpoints [22]. Patients undergoing implantation of a penile prosthesis placement for ED of varying etiologies have been shown to have a decreased number of smooth muscle cells and sinusoidal endothelial changes [12]. The decreased oxygen tension of arteriogenic ED may diminish trabecular smooth muscle content, leading to venous leakage. Hypercholesterolemic rabbits demonstrate early atherosclerotic changes and significant smooth muscle degeneration with loss of cell-tocell contact [23]. Diabetes may compromise contractility, reduce cavernous smooth muscle content, thicken the basal lamina, increase collagen, and cause the loss of endothelial cells [12]. Cavernous nerve injury at time of radical prostatectomy may also decrease levels of cavernous smooth muscle while increasing collagen content, compromising the erectile process [24].