Biology of Erectile Dysfunction (ED)
CENTRAL MECHANISMS OF MALE SEXUAL AROUSAL
The regulation of sexual function by the central nervous system (CNS) remains poorly understood. Control of penile erection is organized in a diffuse network of multiple and interconnected sites within the CNS and specific neuronal pathways remain largely undefined. However, progress has been made in identifying key central structures that regulate the sexual arousal response in males. Studies using positron emission tomography (PET) in healthy male subjects have identified specific regions of the brain that are activated in response to visually evoked sexual arousal. These include the inferior temporal cortex (bilaterally), right insula, right inferior frontal cortex and left anterior cingulate cortex; areas linked to visual association, processing of sensory information and motivational states, and regulation of autonomic and neuroendocrine functions.
Experimental studies in animal models have proven invaluable in further elucidating mechanisms of central control. In particular, stimulation of the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) within the hypothalamus is known to stimulate pro-erectile nerve pathways in rats. Both regions process and integrate information from multiple parts of the CNS, receiving sensory input from visual (occipital), tactile (thalamus), and olfactory (rhinencephalon) stimulation as well as imaginative input (limbic system). Increased levels of dopamine and oxytocin have been associated with sexual activity and these neurotransmitters are thought to play important roles in mediating the pro-erectile response in the MPOA and PVN, respectively.
In contrast, the nucleus paragigantocellularis (nPGi) in the brain stem exerts an inhibitory effect on sexual arousal. Nerves from the nPGi project to sacral segments of the spinal cord and release serotonin. This has been postulated as the reason why SSRI’s (specific serotonin reuptake inhibitors) depress sexual function. Interestingly, since men treated with SSRI drugs most commonly exhibit delayed or blocked ejaculation, cases of premature ejaculation have also been successfully managed with SSRI treatment. The locus coeruleus also exerts inhibitory input via sympathetic nerves that interface with hypothalamic nuclei as well as the spinal cord. Withdrawal of sympathetic input due to suppressed activity of the locus coeruleus during REM (rapid eye movement) sleep is thought to lead to episodes of nocturnal penile tumescence.
Further anatomical and functional studies should increase our understanding of the neural circuitry within the CNS that regulates penile erection. Defining the roles of neurotransmitters continues to be a complex task, since they potentially may exert different effects depending upon the site of action and receptor subtype distribution in specific neuronal subpopulations.
PERIPHERAL MECHANISMS OF MALE SEXUAL AROUSAL
Neurogenic Regulation of Penile Erection
Erectile function in the penis is regulated by autonomic (parasympathetic and sympathetic) and somatic (sensory and motor) pathways to the erectile tissues and perineal striated muscles. Three sets of peripheral nerves innervate the penis.
The sympathetic nerves (T10 - L2), responsible for detumescence and maintaining flaccidity, project to the corpora, as well as the prostate and bladder neck via the hypogastric nerves. Postganglionic noradrenergic fibers pass posterolateral to the prostate in the so-called nerves of Walsh to enter the corpora cavernosa medially. Adrenergic tone is crucial in initiating detumescence and maintaining the flaccid state of the penis since the smooth muscle of the arteries and cavernosal trabeculae must remain actively contracted. Contraction of cavernosal trabecular smooth muscle to norepinephrine is mediated by alpha-1 adrenergic receptors. Pre-junctional alpha-2 adrenergic receptors on adrenergic nerves inhibit neurotransmission and provide a self-regulating negative feedback loop for secreted norepinephrine. Cholinergic nerves act on pre-junctional muscarinic receptors to also inhibit adrenergic nerve activity.
It is possible that adrenergic imbalance towards vasoconstriction impairs erection. While specific factors that contribute to this imbalance remain unknown, aging and/or associated disease states may cause selective up-regulation of specific adrenergic receptor subtypes, resulting in higher efficacy for norepinephrine action. Since norepinephrine is a key modulator of erectile function, it is plausible that alpha-adrenergic receptor antagonists may prove useful in the treatment of ED. Clinical experience with drugs such as yohimbine and phentolamine has demonstrated varying efficacy in men with ED. The role of alpha-adrenergic receptors in the physiology of penile erection is more completely reviewed elsewhere.
The parasympathetic nerves, originating in the intermediolateral nuclei of S2 - S4 spinal cord segments, provide the major excitatory input to the penis and are responsible for vasodilation of the penile vasculature and subsequent erection. Exiting through the sacral foramina, these nerves pass forward lateral to the rectum as the pelvic nerve and synapse in the pelvic plexus with post-ganglionic nonadrenergic, noncholinergic (NANC) nerve fibers, which travel within the cavernous nerves to the corpora cavernosa. Vasoactive intestinal peptide (VIP) and nitric oxide (NO) are two NANC neurotransmitters that are often co-localized in the same nerves in penile tissue. However, the role of VIP as a modulator of penile erection remains unclear since the experimental results with this peptide on erectile function are inconsistent. Intracavernosal administration of VIP in animals and humans has yielded varying results, ranging from no effect to partial tumescence to full erection. Further, the lack of specific and effective antagonists for VIP hinders experimental investigation concerning its role in erectile function.
The primary mediator of NANC parasympathetic input is NO. The ability of NO, a highly reactive and unstable gas, to regulate a wide array of physiological functions in mammals has only become evident within the last 2 decades. Along with carbon monoxide, NO is a unique primary effector molecule with the characteristics of an intracellular second messenger that defies previous classification schemes. It is apparently synthesized on demand with little or no storage and it directly activates a soluble enzyme (guanylate cyclase) rather than a "traditional" receptor molecule. NO is produced by nitric oxide synthase (NOS) which utilizes the amino acid L-arginine and molecular oxygen as substrates to produce NO and L-citrulline. NO can readily cross plasma membranes to enter target cells where it binds the heme component of soluble guanylate cyclase. This activation of guanylate cyclase stimulates the production of cGMP with the resultant activation of the cGMP-dependent protein kinase that regulates the intracellular events that lead to trabecular smooth muscle relaxation. The levels of cGMP are also regulated by phosphodiesterases, which break down cGMP and terminate signalling. Sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra) are potent, selective and reversible inhibitors of phosphodiesterase type 5, the major enzyme responsible for cGMP hydrolysis in penile erectile tissue. Inhibition of this enzyme leads to the increase of intracellular cGMP levels and enhancement of smooth muscle relaxation in response to stimuli that activate the NO/cGMP pathway. Such activity may explain the successful utility of these agents in the treatment of male ED.
Recently, it has become evident that NO interacts directly with other cellular targets including receptors, ion channels and pumps, which may modulate smooth muscle cell contractility, independent of the cGMP pathway. Thus, in addition to guanylate cyclase, NO has other intracellular targets, which may play a role in the regulation of vascular and trabecular smooth muscle contractility.
The activity of NANC nerves may be modulated by cholinergic nerves, which facilitate nonadrenergic, noncholinergic relaxation by stimulating the synthesis and release of NO and other vasodilatory neurotransmitters such as VIP. Thus, the release of acetylcholine may coordinate withdrawal of adrenergic input and increase of NANC input by binding to pre-junctional muscarinic receptors on adrenergic and NANC nerves. In certain disease states such as diabetes, the ability of the corpus cavernosum to synthesize and release acetylcholine is diminished. Such processes may be partially responsible for the compromised erectile function associated with diabetes. Parasympathetic nerves are also vulnerable during surgical procedures, such as abdominoperineal resection of the rectum and radical prostatectomy.
The pudendal nerves comprise motor efferent and sensory afferent fibers innervating the ischiocavernous and bulbocavernous muscles as well as the penile and perineal skin. Pudendal motor neuron cell bodies are located in Onuf’s nucleus of the S2-S4 segments. The pudendal nerve enters the perineum through the lesser sciatic notch at the posterior border of the ischiorectal fossa and runs in Alcock’s canal (pudendal canal) towards the posterior aspect of the perineal membrane. At this point, it gives rise to the perineal nerve with branches to the scrotum and the rectal nerve supplying the inferior rectal region. The dorsal nerve of the penis emerges as the last branch of the pudendal nerve. It then turns distally along the dorsal penile shaft, lateral to the dorsal artery. Multiple fascicles fan out distally, supplying proprioceptive and sensory nerve terminals to the dorsum of the tunica albuginea and skin of the penile shaft and glans penis.
Non-neuronal Modulators of Penile Erection
In addition to neurogenic mechanisms, it has become evident that local paracrine/autocrine factors, with vasoactive and/or trophic effects, can profoundly influence the function of the smooth muscle in the penis. These include endothelins, prostanoids, nitric oxide and oxygen.
Endothelin-1 (ET-1), a member of the endothelin family of peptides, is one of the most potent vasoconstrictors yet described. Similar to nitric oxide, endothelin release from the intimal lining of vascular compartments can be induced by shear stress. However, little is known about the physiological or cellular mechanisms, which regulate its production. In human corpus cavernosum, ET-1 is synthesized by the endothelium and elicits strong, sustained contractions of corpus cavernosum smooth muscle. Both major subtypes of endothelin receptors (ETA and ETB) have been identified in penile corpus cavernosum and are distributed on both the endothelium and the smooth muscle. It has also been suggested that endothelin may exert vasodilatory effects at low concentrations through a "super-high" affinity form of the ETB receptor, potentially by stimulating NO production. However, the significance of this mechanism in penile erection remains unclear. In rabbit models of disease, ETB receptors in penile corpus cavernosum were up-regulated in alloxan-induced diabetic rabbits and down-regulated in hypercholesterolemic Watanabe rabbits. Additionally, elevated plasma endothelin levels have been reported in both diabetic and non-diabetic men with erectile dysfunction. Thus, endothelin may contribute to the maintenance of penile flaccidity by providing sustained tone to the trabecular smooth muscle and alterations in endothelin production may result in impaired erectile function. Several endothelin receptor subtype selective antagonists have been developed, but their efficacy and safety in treatment of ED has not been fully evaluated.
In addition to the NANC nerves, the vascular endothelium synthesizes and releases nitric oxide . Vasodilators such as acetylcholine and bradykinin act by binding their respective membrane receptors and increasing intracellular Ca2+ within endothelial cells. Physical stimuli, such as shear stress, are also known to enhance NO production in endothelium. In the penis, shear-induced NO production by endothelium is most likely to occur during the onset of erection when blood flow into the cavernosal bodies is rapidly increased. The mode of action of endothelium-derived NO is identical to nerve-derived NO, as described in the previous section.
Prostanoids (eicosanoids, prostaglandins) are twenty-carbon derivatives produced by the action of cyclooxygenases on the common precursor arachidonic acid in both endothelial and smooth muscle cells of the corpora cavernosa. Prostanoids act locally and exert both trophic and tonic effects in an autocrine and paracrine manner. Although the precise physiologic role of prostaglandins in penile erection remains poorly defined, experimental evidence indicates that they may play an important role in the regulation of extracellular matrix production. Further, the anti-platelet aggregating effects of PGI2 (prostacyclin), similar to NO, may be important in preventing coagulation of blood, since blood flow within the cavernosal bodies is negligible during full penile tumescence. The five primary active prostanoid compounds in the penis are the prostaglandins PGD2, PGE2, PGF2?, PGI2 and thromboxane A2 (TXA2). Prostanoids can induce both relaxation and contraction in penile corpus cavernosum. PGE is the only endogenous prostaglandin that appears to elicit relaxation of human trabecular smooth muscle; the others causing constriction or having no effect on smooth muscle tone. There are five major groups of prostanoid receptors termed DP, EP, FP, IP and TP, which mediate the effects of PGD, PGE, PGF, PGI and thromboxane, respectively. The multi-functional, dose-dependent effects of prostanoids may be explained by the coupling of receptor subtypes and isoforms to different second messenger systems. Clinically, prostaglandin E1 (alprostadil) has been developed as the first FDA approved intracavernosal injectable drug for the treatment of male ED.
Oxygen tension plays an active role in regulating penile erection. Measurements of cavernosal blood PO2 in human volunteer subjects indicate that oxygen tensions change rapidly from venous (~35 mm Hg) to arterial (~100 mm Hg) levels during the transition from the flaccid to the erect state. Maintenance of constant oxygen tension is a critical imperative in most tissues of the body but the penis is the only organ, which changes from venous to arterial oxygen tensions during the course of its normal function. This transition is the basis of a unique regulatory mechanism that takes advantage of key synthetic enzymes, which utilize molecular oxygen as a co-substrate. NO synthase and prostaglandin synthase are two well-studied examples of a class of enzymes known as dioxygenases. At low oxygen tension, measured in the flaccid state of the penis, the synthesis of NO is inhibited, preventing trabecular smooth muscle relaxation. This inhibition of NO production is probably necessary for the maintenance of penile flaccidity. Following vasodilation of the resistance arteries, the increase in arterial flow raises oxygen tension. In the oxygen enhanced environment, autonomic dilator nerves and the endothelium are able to synthesize NO, mediating trabecular smooth muscle relaxation. The synthesis of prostanoids is similarly regulated in the flaccid versus the erect state. Therefore, oxygen tension may regulate the types of vasoactive substances present in this vascular bed. At low oxygen tension, norepinephrine and endothelin-induced contraction may predominate, while at high oxygen tension, NO and prostaglandins are produced due to the availability of molecular oxygen that is required for their synthesis.
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