Some background on erectile dysfunction
Sexual health and function are important determinants of quality of life. Disorders such as erectile dysfunction (ED) and female sexual dysfunction are becoming increasingly more important as a result of the aging US population and newer therapies. Because this subject is discussed widely in the media, men and women of all ages are seeking guidance in an effort to improve their relationships and experience satisfying sexual lives.
This review article discusses the physiology of the normal erection and the pathophysiology, etiology, and treatment of ED. For additional resources, visit Erectile Dysfunction.
Successful treatment of sexual dysfunction has been demonstrated to improve sexual intimacy and satisfaction, improve sexual aspects of quality of life, improve overall quality of life, and relieve symptoms of depression.
Although this article focuses primarily on ED in males, one must remember that the sexual partner plays an integral role. If successful and effective management is to be achieved, the evaluation and discussion of any intervention should include both partners.
The Process of Care Model for the Evaluation and Treatment of Erectile Dysfunction has been developed to advance new guidelines for the diagnosis and management of ED in the primary care and multidisciplinary setting. The model was developed under the auspices of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School. The chairman of the group of experts who prepared the guidelines was Raymond Rosen, MD.
The key components of this model are (1) a rational approach to diagnosis and treatment, (2) emphasis on clinical history taking and a focused examination, (3) specialized testing and referral in predefined situations, (4) a step-wise management approach with ranking of treatment options, and (5) incorporation of patient and partner needs and preferences in the decision-making process.
An alternative model is the patient goal-oriented approach as suggested by Tom Lue, MD, in which a minimum of testing is performed. The patient and his partner express a preference for reasonable and appropriate treatment options and work with the physician to implement this plan.
The availability of three phosphodiesterase-5 (PDE-5) inhibitors, ie, sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), has permanently altered the medical management of ED. Many patients no longer expect or are willing to undergo a long evaluation and testing process to obtain a better understanding of their sexual problem, and they are less likely to involve their partner in a discussion of their sexual relationship with the physician.
Because of intense mass-media marketing efforts, the sexual expectations of men have risen to new highs and the attitude that something is wrong with a man if he does not achieve a perfect erection is prevalent. Men who have no difficulty obtaining erections are taking these PDE-5 inhibitor medications in the belief that their sexual performance will be enhanced and the opportunity for multiple orgasms will increase. Their medications are often obtained by a phone call to their doctor or even over the Internet with minimal or no physician contact at all. The misuse and overuse of these remarkable medications are likely to have a major impact on how sexual performance and sexual relationships are viewed.
Physiology of normal erections
Penile erections involve an integration of complex physiologic processes involving the CNS, peripheral nervous system, and hormonal and vascular systems. Any abnormality involving these systems, whether from medication or disease, has a significant impact on the ability to develop and sustain an erection, ejaculate, and experience orgasm. Tumescence, the vascular filling of the cavernous bodies, relies on neural and hormonal mechanisms operating at various levels of the neural axis. This is unique among visceral functions because it requires central neurological input.
Andersson summarized some of the information related to the pathways involved in erectile function.1 The degree of contraction of corpus cavernosal smooth muscle determines the functional state of the penis. The balance between contraction and relaxation is controlled by central and peripheral factors that involve many transmitters and transmitter systems. At the cellular level, smooth muscle relaxation occurs following the release of acetylcholine from the parasympathetic nerves.
The nerves and endothelium of sinusoids and vessels in the penis produce and release transmitters and modulators that control the contractile state of corporal smooth muscles. Although the membrane receptors play an important role, downstream signaling pathways are also important. The RhoA–Rho kinase pathway is involved in the regulation of cavernosal smooth muscle contraction.
The nitric oxide (NO) pathway is of critical importance in the physiologic induction of erections. The drugs currently used to treat erectile dysfunction were developed as a result of experimental and clinical work that demonstrated that NO released from nerve endings relaxes the vascular and corporal smooth muscle cells of the penile arteries and trabeculae, resulting in an erection.
NO is produced by the enzyme nitric oxide synthase (NOS). Three forms have been identified: nNOS, eNOS, and iNOS, which are produced by the genes NOS1 (nNOS), NOS2 (iNOS), and NOS3 (eNOS). This nomenclature is derived from the source of the original isolates. nNOS was found in neuronal tissue, iNOS was found in immunoactivated macrophage cell lines, and eNOS was found in vascular endothelium. All forms of NOS produce NO, but various factors trigger and regulate this process. NOS plays many roles, ranging from homeostasis to immune system regulation. These subtypes are not limited to the tissues from which they were first isolated. Each NOS subtype may play a different biological role in various tissues.
nNOS and eNOS are considered constitutive forms because they share biochemical features. They are calcium-dependent, they require calmodulin and reduced nicotinamide adenine dinucleotide phosphate for catalytic activity, and they are competitively inhibited by arginine derivatives. These 2 subtypes use the biochemical pathway that targets cyclic guanosine monophosphate (cGMP). They are involved in the regulation of neurotransmission and blood flow, respectively.
iNOS is considered inducible because it is calcium-independent. iNOS is induced by the inflammatory process, in which it is involved in the production nitrogenous amines. This subtype has been shown to be involved in the carcinogenic process, leading to transitional cell carcinoma.
All 3 NOS subtypes produce NO by oxidation of L-arginine, which is one of the basic amino acids. It circulates in the blood and is found in cells synthesized from the urea cycle or from oral ingestion. The concentration of L-arginine within the cell far exceeds that in the circulation. Inside the cell, NOS catalyzes the oxidation of L-arginine to NO and L-citrulline. Endogenous blockers of this pathway have been identified.
The gaseous NO that is produced acts as a neurotransmitter or paracrine messenger. Its biologic half-life is only 5 seconds. NO may act within the cell or diffuse and interact with nearby target cells.
Potential ways to alter NO levels include the following:
* Directly administering NO as a gas
* Administering NO donors such as nitrates, nitrites, and inorganic nitroso compounds
* Administering of NO agonists such as ACE, which enhances the production of NO within endothelial cells
* Preserving cGMP: Inhibitors of phosphodiesterase, which primarily hydrolyze cGMP type 5, provided the basis for the development of sildenafil, vardenafil, and tadalafil.
* Lowering endogenous inhibitors: Some analogs of L-arginine act as competitive and sometimes irreversible inhibitors of NOS. Some of these are present in the plasma and urine.
* Administering exogenous NOS activators: One example is methylene blue.
* Increasing the substrate for NO synthesis: Oral supplementation of NO has generated interest. Chen et al administered oral L-arginine and reported subjective improvement in 50 men with ED.2 These supplements are readily available commercially. Reported adverse effects include nausea, diarrhea, headache, flushing, numbness, and hypotension.
Increasing evidence indicates that NO acts centrally to modulate sexual behavior and to exert its effects on the penis. NO is thought to act in the medial preoptic area and the paraventricular nucleus. Injection of nitric acid synthase inhibitors prevents the erectile response in rats that have been given erectogenic agents.
Factors that mediate contraction in the penis include noradrenaline, endothelin-1, neuropeptide Y, prostanoids, angiotensin II, and other factors not yet identified. Factors that mediate relaxation include acetylcholine, NO, vasoactive intestinal polypeptide, pituitary adenylyl cyclase–activating peptide, calcitonin gene–related peptide, adrenomedullin, adenosine triphosphate, and adenosine prostanoids.
Sexual behavior involves the participation of autonomic and somatic nerves and the integration of numerous spinal and supraspinal sites in the CNS. The penile portion of the process that leads to erections represents only a single component. The ability to achieve and maintain a full erection also depends on the status of the peripheral nerves, integrity of the vascular supply, and biochemical events within the corpora.
Erections occur in response to tactile, olfactory, and visual stimuli. The hypothalamic and limbic pathways play an important role in the integration and control of reproductive and sexual functions. The medial preoptic center, paraventricular nucleus, and anterior hypothalamic regions modulate erections and coordinate autonomic events associated with sexual responses. Afferent information is assessed in the forebrain and relayed to the hypothalamus. The efferent pathways from the hypothalamus enter the medial forebrain bundle and project caudally near the lateral part of the substantia nigra into the midbrain tegmental region.
Several pathways have been described to explain how information travels from the hypothalamus to the sacral autonomic centers. One pathway travels from the dorsomedial hypothalamus through the dorsal and central gray matter, descends to the locus ceruleus, and projects ventrally in the mesencephalic reticular formation. Input from the brain is conveyed through the dorsal spinal columns to the thoracolumbar and sacral autonomic nuclei.
The primary nerve fibers to the penis are from the dorsal nerve of the penis, a branch of the pudendal nerve. The cavernosal nerves are a part of the autonomic nervous system and incorporate both sympathetic and parasympathetic fibers. They travel posterolaterally along the prostate and enter the corpora cavernosa and corpus spongiosum to regulate blood flow during erection and detumescence. The dorsal somatic nerves are also branches of the pudendal nerves. They are primarily responsible for penile sensation.
Sexual stimulation causes the release of neurotransmitters from the cavernosal nerve endings and relaxation factors from the endothelial cells that line the sinusoids. NOS produces NO from arginine. This, in turn, produces other muscle-relaxing chemicals such as cGMP and cyclic adenosine monophosphate, which work via calcium channel and protein kinase mechanisms. This results in the relaxation of smooth muscle in the arteries and arterioles that supply the erectile tissue, producing a dramatic increase in penile blood flow. Relaxation of the sinusoidal smooth muscle increases its compliance, facilitating rapid filling and expansion (40-52% of the corpora cavernosa tissue is composed of smooth muscle cells). The venules beneath the rigid tunica albuginea are compressed, resulting in near-total occlusion of venous outflow. These events produce an erection with an intracavernosal pressure of 100 mm Hg.
Additional sexual stimulation initiates the bulbocavernous reflex. The ischiocavernous muscles forcefully compress the base of the blood-filled corpora cavernosa, and the penis reaches full erection and hardness when intracavernous pressure reaches 200 mm Hg or more. At this pressure, both the inflow and outflow of blood temporarily cease.
Detumescence results from the cessation of neurotransmitter release, the breakdown of second messengers by phosphodiesterases, and sympathetic nerve excitation during ejaculation. Contraction of the trabecular smooth muscle reopens the venous channels, allowing the blood to be expelled, which results in flaccidity.
Pathophysiology of erectile dysfunction
ED is essentially a vascular disease. It is often associated with other vascular diseases and conditions such as diabetes, hypertension, and coronary artery disease. Other conditions associated with ED include neurologic disorders, endocrinopathies, benign prostatic hyperplasia, and depression. Conditions associated with reduced nerve and endothelium function, such as aging, hypertension, smoking, hypercholesterolemia, and diabetes, alter the balance between contraction and relaxation factors. These conditions cause circulatory and structural changes in penile tissues, resulting in arterial insufficiency and defective smooth muscle relaxation. In some patients, sexual dysfunction may be the presenting symptom of these disorders.
Additionally, ED is often an adverse effect of many commonly prescribed medications. Some psychotropic drugs and antihypertensive agents are associated with ED.
Trauma that affects the neurologic or vascular components can also lead to ED. Men with severe Peyronie disease, an inflammatory vasculitis, may have enough scar tissue in the corpora to impede blood flow. Men with sleep disorders commonly experience ED.
Another important consideration is the hormonal status of the patient. Hypogonadism that results in low testosterone levels adversely affects libido and erectile function. Hypothyroidism is a very rare cause of ED.
Most patients with ED have multiple etiological factors; thus, assessing how much each is contributing to the problem is difficult. Because most men with ED have an organic cause, a thorough evaluation is necessary to correctly identify the specific etiology in any given individual.
to be continued..
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