Penile erection is a neurovascular event that occurs when blood flow to the penis exceeds flow out of the penis. Successful erections depend on precise modulation of neural pathways as well as penile vascular integrity. The relaxation of trabecular smooth muscle results in increased blood flow to the corpora cavernosa, leading to sinusoidal expansion. This, in turn, leads to mechanical compression of the emissary veins, thus inhibiting the drainage of blood, which results in an erection. Conversely, penile flaccidity results from the release of norepinephrine (NE) from sympathetic nerve terminals and contraction of smooth muscle tissue within the corpora. Blood flow to the penis is controlled by the autonomic erection center, the source of parasympathetic (S2–S4) and sympathetic (T12–L2) input to the pelvic plexus, as well as the cavernous nerves innervating the trabecular smooth muscle. Neural stimulation is transmitted through the Nervi erigentes (i.e., the pelvic autonomic fibers), which release three important neurotransmitters: (a) norepinephrine (sympathetic fibers); (b) acetylcholine (ACh; parasympathetic); and (c) nitric oxide (NO; nonadrenergic–noncholinergic). High levels of NO within the trabecular smooth muscle results in relaxation. Diffusion of NO through the smooth muscle membrane leads to the activation of guanylate cyclase, which produces cyclic guanosine monophosphate (cGMP). A biochemical cascade results in altered calcium and potassium ion channel permeability; a reduction in cytosolic calcium leads to smooth muscle relaxation and increased blood flow.What is ‘‘normal?’’ A recent Italian study showed that the typical flaccid penis is 9 centimeters (3.54 inches) long while the stretched penis is 12.5 centimeters (4.92 inches). The typical circumference at the middle of the shaft is 10 centimeters (3.94 inches). Other research has shown that 70 percent of men’s erect penises range from 5 inches to 7 inches, and a penis is considered ‘‘abnormally’’ small only when it measures smaller than 3 inches when erect. It is important to remember that the female has very little sensation in the upper two-thirds of her vagina, meaning that stimulation in this area is unlikely to enhance sexual arousal. In short, bigger is not necessarily better. Erection-initiating neurotransmitters include, among others, dopamine (via D2-receptors) and melanocortins. Five melanocortin receptors (MCR) have been identified. MC-4-R seems to have special importance for erection. Therefore, the brain must exert an important modulator influence over the spinal reflex pathways mediating penile erection. Although the precise anatomic regions are not completely known, it appears that the thalamic nuclei, the rhinencephalon, and the limbic structures play a role in modulating psychogenic penile erections.CENTRAL NEUROPHYSIOLOGYDopamineFive dopamine receptor families have been identified (D1–D5). The family of D1 and D2 receptors and their role in the central regulation of penile erection, copulatory behavior, and genital reflexes (with the D2 receptors playing a major role) are particularly interesting. Selective D2 agonists cause penile erections that are accompanied by stretch yawning and sedation, which are typical of central dopaminergic stimuli.SerotoninSeven families of 5-HT receptors as well as several receptor subtypes (denoted by subscripts A–D) have been identified. 5-HT3 receptors are unusual because they are coupled to a cation channel, whereas the remaining 5-HT receptor families act via G proteins.There are two serotoninergic paths within the CNS. One pathway originates in the raphenuclei and has interconnections throughout the brain, whereas the other pathway originates in the brain stem and continues caudally toward the spinal cord. Generally, serotonin acts to depress male sexual behavior.Noradrenaline
Noradrenergic pathways in the brain may exert an inhibitory influence on penile erection. Within the CNS, the most distinct group of noradrenergic neurons is located within the locus ceruleus. These neurons project through the dorsal noradrenergic bundles to innervate the cortex, cerebellum, and hippocampus. Additional projections travel through the ventral noradrenergic bundles to the hypothalamus, hippocampus, cerebellum, and spinal cord.Connections between the locus ceruleus and hippocampal formation play an inhibitory role on erection, as demonstrated by electrical stimulation of the locus ceruleus and micro-injection of adrenoreceptor agonists (e.g., NE) within the hippocampus in male rats.
Endogenous Opioid Peptides and GABA
Administration of opioid receptor agonists to the CNS inhibits—whereas opioid receptor antagonists facilitate—copulatory behavior in male rats.Impotence, decreased libido, anorgasmia and the ability to achieve or maintain erection are not uncommon with patients addicted to heroin or methadone.Spontaneous erections, priapism, and ejaculation occur during withdrawal from narcotics or with the administration of opiate antagonists such as naloxone.Endogenous opioid production may contribute to impotence.GABA is present at high concentrations within the MPOA in male rats.This neurotransmitter likely plays an inhibitory role in the control of penile erection. Both GABAᴀ fibers and GABAв receptors have been demonstrated in the spinal cord dorsal horn as well as in the vicinity of sacral parasympathetic and bulbocavernosi motor nuclei.
Oxytocin
Micro-injection of oxytocin into the lateral cerebral ventricles, the PVN of the hypothalamus, or the hippocampal formation induces erection. Oxytocinergic neurons are found within the descending pathways from the midbrain, brain stem, and spinal autonomic centers. Following sexual activity, serum and cerebrospinal fluid levels of oxytocin are elevated suggesting that oxytocin functions as excitatory transmitter in the control of penile erection within the hypothalamus.
Prolactin
Long-term exposure to elevated prolactin levels suppresses sexual behavior and reducedpotency in men. Moreover, prolactin disrupts genital reflexes, leading to decreased frequency of erections in rats.
Melanocortin System
Melanocortins (MCs) are bio-active peptides that have been shown to play a role in the neural control of penile erection. Derived from the precursor molecule pro-opiomelanocortin, cleavage at several sites within the prohormone results in at least eight distinct peptides. Experiments have demonstrated that intracerebroventricular administration of adrenocorticotropic and α-melanocyte hormones induces penile erection, yawning, and stretching.
Centrally Acting Drugs under Clinical Investigation
Melanocortin receptor (MCR) agonists
Presently there are five MCRs identified and all five are activated by adrenocorticotropin hormone (ACTH) and four out of five, except MC2R, by alphamelanocyte stimulating hormone (a -MSH) the five MCRs only two (MC3R and MC4R) are expressed in cerebral regions known to be involved in the modulation of Erectile function. The origin of both α -MSH and ACTH is the pro-opiomelanocortin (POMC) gene, and the biologic effects of these two hormones are mediated via activation of one or more of the five MCRs. All five MCRs use cAMP as the second neurotransmitter mediating the final biologic (physiologic) effects upon their activation.
Various Causes for Erectile Dysfunction
Cardiovascular risk factors (diabetes mellitus, smoking hypertension, hypercholesterolemia, sedentary lifestyle, obesity, atherosclerosis, vascular surgery, known heart disease), drug abuse, alcohol, medical disorders (renal failure, abnormal liver function), endocrine disorders (hypogonadism, hyperprolactinemia, hypo- and hyperthyroidism), sickle cell anemia, neurogenic factors, neuropathies (diabetes, etc.), other neurological disorders (spinal cord injury, cerebrovacular insult, multiple sclerosis, nerve damage resulting from prostate surgery, etc.), drug treatment selection (thiazide diuretics, spironolactone, digoxin, antidepressants, b-blockers, phenothiazines, carbamazepin, phenytoin, fibrates, statins, histamine-2-receptor antagonists, allopurinol, indomethacin, tranquilizer, levodopa, chemotherapeutics, and so on); Anatomical–structural Priapism, trauma, and so on; Psychic Anxiety disorder, depression, problems, or changes in relationship.