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HPV na Prática Clínica

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Doenças e Disfunções
.Infertilidade
.Disfunção erétil
.Infecção urinária
.DST
.Próstata
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.Testículos
.Pênis
.Cálculos urinários
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HPV na Prática Clínica

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Introduction
Over the past several years, population-based surveys have shown that erectile dysfunction (ED) is an increasingly common condition in aging men.[1-3] Although many men experience mild ED, data indicate that moderate or severe ED occurs in up to 26% of these men.[2] Incidence is further increased in men with specific chronic health conditions, including diabetes, hypertension, cardiovascular disease, and depression.[2,4-6] Although psychological and organic causes are both commonly involved in the etiology and treatment of ED, a more complete understanding of the molecular mechanisms of penile erection have shifted the greater focus to the organic reasons underlying ED and to treatment approaches that target these mechanisms.
Indeed, the successful introduction of a new class of oral agents, the phosphodiesterase (PDE) inhibitors, and namely sildenafil in 1998, paved the way for a substantial increase in men willing to acknowledge and seek treatment for ED. Worldwide, the availability of sildenafil has been associated with a substantial increase in men being diagnosed with ED, compared with rates prior to release of this drug, with data showing a 250% increase in the United States alone.[6] As an indicator of the prevalence of ED and the desire for men to increase their sexual potency, prescription sales of sildenafil topped more than 19 million between 1998 and 1999.[7]
A second generation of PDE agents and other newer drugs are coming to market that will provide men with increased options for successfully treating their problems with sexual function. Satisfactory sexual functioning is a highly individual end point in which psychological and lifestyle approaches remain vital to the overall management of men with ED. However, with increased understanding of the physiologic mechanisms of ED, newer treatments are being developed that target the specific molecular dysfunctions and provide a mechanism of enhanced penile functioning.
After a brief presentation of the epidemiology and etiology of ED, this Clinical Update describes current treatment approaches to ED that focus on first-line therapies with the new PDE agents, other drug treatments for difficult-to-treat ED, future drug options in the pipeline, and behavioral aspects that need to be addressed in helping men to seek and comply with treatment.

Epidemiology and Etiology
A number of population-based surveys show that aging is one of the primary factors associated with increasing incidence of ED. In the Massachusetts Male Aging Study, aging was the predominant risk factor for developing ED, with 52% of 1700 men aged 40-70 years surveyed reporting some degree of ED.[5] Based on updated estimates of that study, which showed that the incidence of ED nearly doubled with each decade of life,[3] it is estimated that the annual incidence of ED for white men between 40 and 70 years is approximately 617,700.[5] Broken down by age, this study showed an annual incidence of ED of 12 per 1000 for those aged 40-49 years and 46 per 1000 for those aged 60-69 years.[2] An increased incidence of ED associated with age was also reported in the Cologne Male Survey,[1] which showed a 19.2% prevalence of ED in 4489 reporting German men aged 30-80 years, with a steep increase in ED associated with age.
Other recent data show increased prevalence of ED in men with specific chronic health problems. In the Cologne Male Survey, the incidence of ED was significantly increased in men with diabetes mellitus, lower urinary tract symptoms, hypertension, and those who had undergone pelvic surgery.[1] In the Multi-National Survey of the Aging Male (MSAM-7), a study of 14,000 men aged 50-80 years in 7 countries (United States, United Kingdom, France, Germany, Italy, Spain, and The Netherlands), Rosen and colleagues[8] found that the severity of high blood pressure was strongly associated with the frequency and severity of sexual problems. Other studies also link depression to increased likelihood of ED.[9]

Pathophysiology
Although there remains debate about whether ED is predominately psychogenic or organic in nature,[10] over the past several years more recognition has been given to the organic nature of ED, with current studies indicating that up to 85% of the causes of ED are organic.[11,12] However, most physicians recognize that both mechanisms are often at play in the same patient.
Vascular disease -- either poor arterial flow (arteriogenic ED) or poor cavernosal trapping of penile blood (veno-occlusive dysfunction) -- accounts for the majority of organic ED currently treated in men aged 40 years and older.[5] In the most common type of vascular ED, erectile failure occurs because of a combination of veno-occlusive dysfunction and arterial insufficiency, which sets off a chain of events that limits the ability of the corporeal smooth muscle to relax, reduces sinusoidal dilation, and thereby limits arterial blood flow.[5]
Other organic causes of ED can result from hormonal conditions, such as low testosterone levels that may interfere with how androgens affect the nitric oxide pathway and mediate erection. Neurologic injuries can also cause ED, particularly from spinal cord injury or non-nerve-sparing radical prostatectomy.[5]
Psychogenic ED can result from a number of psychological issues, including performance anxiety and relationship issues, in which a heightened sympathetic tone inhibits normal vascular relaxation that is essential for erection.

Diagnosis
To determine the causes of ED in a particular man, a thorough medical history should be conducted that includes an evaluation of (1) medical risk factors such as diabetes, hypertension, hypercholesterolemia, cardiovascular disease, spinal cord injury, peripheral vascular disease, endocrine abnormalities, pelvic surgery, depression, arthritis, renal failure, and trauma; (2) lifestyle risk factors that include smoking, alcohol, drug use, and obesity; and (3) usage of prescription drugs including beta-blockers, antidepressants, and thiazide diuretics.[5]
Also needed is a thorough sexual history that should include an evaluation of (1) the severity, nature, and onset of ED; (2) the experience of libido, ejaculation, and orgasm; and (3) psychological and social issues, such as depression and stresses from relationships and jobs.[5]
Assessment of the goals and objectives of the couple is also an important aspect of therapy. In some cases, a genuine desire to fully understand the nature and cause of ED may be present and a physician may want to attempt to offer a more complete investigation to determine the physiologic etiology. In many situations, however, this is not possible.

Treatment
Choice of therapy should be based on the individual needs of the patient and his partner, and should be appropriate for the age of the man and his health condition. For all men, some discussion of psychological and/or lifestyle issues is beneficial to the overall management of ED, and for some men is sufficient for care. For most men, first-line treatment includes oral medications, predominantly sildenafil, which has demonstrated a 69% response rate in men with organic ED and a 80% response rate in men diagnosed with "mixed" organic and psychogenic ED.[13] Other oral agents, including those similar to sildenafil (see discussion below), soon will be licensed and will add to the treatment options for men. For men who are not good candidates for or who do not respond to the PDE medications, other, older drugs administered orally or by injection are available (see discussion below). Other therapies still under investigation hold promise for improving treatment by better targeting therapy for men with specific needs and for those who fail other types of therapy. Table 1 lists future directions for new areas of therapy for ED.
Table 1. Potential Drug Therapies and Areas to Target to Improve Current Therapies[14]

Current Drug Therapies of ED
Current drug therapies include the first generation of PDE5 inhibitors (ie, sildenafil), the second-generation PDE5 inhibitors (ie, vardenafil and tadalafil), dopamine receptor agonists (ie, apomorphine), and drugs for both intracavernous and non-intracavernous administration (eg, prostaglandin E1 [PGE1; alprostadil]).

First-line Treatment: PDE5 Inhibitors
The PDEs play a central role in regulating smooth muscle tone, and control a wide variety of physiologic processes and functions. They can be subdivided into enzymes that are functionally and structurally related, and so far 11 of these PDEs (1-11) have been identified.[14] Of these, PDE5 has been targeted for ED drug therapy. The PDE5 inhibitors increase the physiologic response to sexual stimulation by modulating and affecting the cellular responses responsible for erectile smooth muscle relaxation. Specifically, PDE5 inhibitors inactivate PDEs that normally metabolize the nucleotide cyclic GMP (cGMP). The accumulation of cGMP allows for an enhanced smooth muscle relaxation and improved erection through increased blood flow.

Figure. An illustration of the way in which PDE5 inhibitors increase the physiologic response to sexual stimulation.

Although some concern has been raised over the cardiovascular safety of sildenafil, studies show that sildenafil and the second-generation PDE5 inhibitors soon to be licensed (vardenafil and tadalafil) are safe in most men. In fact, recent studies show that the PDE5 inhibitors may actually improve endothelial function, which is considered the pathologic process common to both ED and vascular disease. Two studies by Halcox[15] and Mahmud[16] recently reported that sildenafil improved relaxation of the arteries (ie, Augmentation Index), improved the constriction response to acetylcholine when endothelial dysfunction was present in the coronary arteries, and that acute and chronic dosing of sildenafil increased brachial artery diameter and thus improved endothelial function.
Other studies also indicate that sildenafil is safe in terms of other cardiac diseases, including congestive heart failure and myocardial infarction. Katz[17] reported that single doses of sildenafil (12.5-50 mg) in patients with Grade II/III heart failure resulted in no major changes in heart rate, blood pressure, or rate-pressure product. Furthermore, sildenafil in doses of 25 mg and 50 mg improved flow-mediated vasodilation.

Sildenafil
For most men, sildenafil is currently the first-line treatment choice. Since it was licensed for use in the United States in 1998, sildenafil has shown in studies that it improves ED in men regardless of disease etiology, severity of disease, or even age.[13] Response rates for men with organic ED and combined psychogenic and organic disease are reported to be 69% and 80%, respectively. For men with severe disease vs mild-to-moderate disease, the response rates are 65% to 87%. Although the response rates start to drop as a man gets older, response rates in men 65 years or older show a 69% improvement.[13]
Studies show that sildenafil also improves sexual functioning in men with chronic health conditions who are at increased risk of developing ED and having ED. In addition, sildenafil has shown efficacy in treating ED in men with diabetes,[4,18] depression,[19] and spinal cord injury.[20]
In terms of safety, data indicate that sildenafil is well tolerated.[21] The most common side effects include facial flushing, headache, nasal congestion, dyspepsia, and dizziness.[21,22] Vision problems, including color differentiation and blurriness, have also been reported.[5,21] Of most concern are the potential cardiac side effects, including sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, myocardial infarction, and hypertension. Because these conditions have been associated with the use of sildenafil in some men, it is suggested that men with specific conditions use this drug with caution. These conditions include a recent history of myocardial infarction, cerebrovascular accident, life-threatening arrhythmia, significantly elevated blood pressure above 170/100 mm Hg or hypotension, a history of unstable angina or cardiac failure, or retinitis pigmentosa. In men taking organic nitrates, sildenafil is absolutely contraindicated.[5,21] Other recent labeling instructions also recommend that men who are taking alpha-blockers to treat their high blood pressure or prostate problems should not take sildenafil in a dose greater than 25 mg within 4 hours of taking the alpha-blocker. Overall, however, cardiac risk is not thought to be a problem for most people taking sildenafil as previously discussed, and the American College of Cardiology and the American Heart Association have reported a joint consensus statement to this effect.[22]

Tadalafil and Vardenafil
The second generation of PDE5s making its way through phase 3 trials in the United States and soon to be licensed for use includes vardenafil and tadalafil, which may provide more versatility in rate of onset and activity duration when compared with sildenafil (Table 2).[14]
Table 2. PDE5 Inhibitors: Variability in Onset and Duration of Activity

Tadalafil. A number of studies show that tadalafil improves ED in men with mild-to-severe ED.[23] Analysis of 5 trials in which patients were randomized to receive placebo, tadalafil 10 mg, or tadalafil 20 mg found that men treated with tadalafil reported increased satisfaction with sexual functioning as measured objectively (maintain an erection until completion to intercourse) and subjectively (increased positive response as determined by global assessment questionnaire).[23] Of the men who received the 20-mg dose, 75% and 81% reported a positive objective and subjective response, respectively, vs 61% and 67% in the 10-mg group and 32% and 35% in the placebo group. Another evaluation, which included of 7 trials, compared efficacy of the 10-mg dose and 20-mg dose against placebo in 1400 patients (average age, 60 years), 90% of whom had ED for more than a year. Clinical and statistical improvement was seen in men in either dose treatment group compared with placebo. Analysis by severity of disease showed that tadalafil was effective for all disease, from mild to severe, with about 80% of study participants reporting a positive response on a global assessment questionnaire.[8]
A number of randomized studies show that tadalafil is effective for treating ED in men regardless of severity of present common comorbid conditions, such as diabetes, hypertension, and cardiovascular disease. In an analysis of patients enrolled in 8 randomized, double-blind, placebo controlled trials, (90% of whom had ED for more than 1 year, and with an average age in the mid-50s), 46% of the men randomized to receive 10-mg tadalafil (n = 141) and 57% of men randomized to receive 20-mg tadalafil (n = 180) reported ability to achieve successful intercourse compared with 20% of the placebo group (n = 157). In terms of quality of erections, the men treated with tadalafil had significantly improved erections compared with the placebo group: 59% for the 10-mg group and 66% for the 20-mg group vs 28% for the placebo group (P < .001).[8]
In an analysis of men taking antihypertensive medications (over 90% of whom had ED for more than 1 year, with an average age in the early 60s), 54% and 65% of sexual attempts made by men taking tadalafil 10 and 20 mg, respectively, were successfully completed compared with 24% of attempts made by men on placebo.[8]
Tadalafil is well tolerated in most patients; the most common side effects include headache, dyspepsia, back pain, nasopharyngitis, and nasal congestion. In an interim analysis of a long-term, open-label safety study, 1173 men were given tadalafil (5-20 mg); treatment duration was up to 18 months. A total of 63 patients (5.4%) discontinued treatment because of reported side effects, of which headache was the most common.[8] Tadalafil also has a similar safety profile in terms of cardiovascular events. Analysis of the incidence of myocardial infarction across all studies shows that of more than 4000 tadalafil-treated patients (including those in double-blind and open-label studies), 6 patients had a myocardial infarction, 5 of whom were enrolled in the open-label studies.[8]
Vardenafil. Several phase 2 and phase 3 studies show that vardenafil is both effective and safe for men with ED.[24,25] A pivotal phase 3 study by Hellstrom and colleagues[26] showed that vardenafil improved erectile functioning in a broad population of men with ED of various severity and etiologies. After 26 weeks of treatment, 85% of men reported improved erections and sexual satisfaction. Up to 89% of men with mild ED and 39% of men with severe ED reported restoration of normal erectile function.
Vardenafil has also been shown to improve sexual functioning in men with health conditions associated with increased risk of ED. A recently published multicenter, double-blind, placebo-controlled study of vardenafil in men with diabetes reported a significant improvement in sexual functioning for men taking vardenafil at all levels of baseline ED severity and for both type 1 and type 2 diabetic patients.[27] Vardenafil also improved sexual functioning in men following radical prostatectomy.[28]
Overall, vardenafil was well tolerated in these studies, with headaches, vasodilation, and rhinitis the most common side effects reported.[24, 26-28] Cardiovascular safety was also demonstrated in a randomized study that assessed cardiovascular response to exercise in patients with coronary artery disease treated with 10 mg of vardenafil or placebo.[24] Compared with placebo, patients treated with vardenafil did not exhibit altered blood pressure, heart rate, or rate pressure at peak exercise.

Dopamine Receptor Agonists (Apomorphine)
Both animal and human studies demonstrate that male sexual behavior is partly regulated by dopamine mechanisms, and that penile erection can be induced by apomorphine, a dopamine receptor agonist that stimulates dopamine D1 and D2.[29] Although early studies of apomorphine showed its ineffectiveness when orally administered and limited effectiveness when injected because of side effects, more recent studies show that sublingual apomorphine is effective with few side effects.
Phase 3 trials of 854 patients receiving 8263 doses of sublingual apomorphine (2 mg or 4 mg) vs a placebo group showed that the men who received apomorphine had significantly more erections, with a time to onset ranging from 10 to 25 minutes.[30] Men included in these trials ranged in age from 18 to 70 years, 74% had moderate-to-severe ED, and many had multiple comorbidities, including hypertension (31%), coronary artery disease (16%), dyslipidemia (16%), and diabetes (16%). Compared with placebo, men receiving 4-mg doses of apomorphine had significantly greater success in achieving an erection suitable for intercourse (54%, vs 34% for placebo; P < .001). Tolerance was also high; mild nausea was the most common, but infrequent, side effect, and there were rare reports of syncope and no reports of cardiac deaths.

Other Treatment Options
For men who do not respond to first-line oral medications, or in whom those medications are contraindicated, drugs for both intracavernous and non-intracavernous administration are available (Table 3).[31]
Table 3. Other Therapies for ED

*Most widely administered drugs for long-term use

Of these drugs, alprostadil is the most widely used for intracavernous, intraurethral, and topical administration.[31]

Alprostadil (PGE1)
Alprostadil is a synthetic PGE1 enzyme that is rapidly metabolized and is useful for diagnostic and treatment testing of ED. Prior to the introduction of sildenafil, alprostadil, administered intracavernously or intraurethrally, was one of the most common drugs used to treat ED. Because of its established efficacy and safety profile in the mid-1990s,[32,33] rates of prescription for alprostadil increased in 1995-1996.[34] However, with the high efficacy rate and successful marketing campaign of sildenafil in 1998, and the predicted similar success rates with the newer PDE5 inhibitors, sales of alprostadil have tapered off. A comparative analysis of the use of alprostadil vs sildenafil shows that from 1998 to 2001, sildenafil was prescribed significantly more frequently than alprostadil for younger men, either in injection or suppository form (P < .0001).[34] Overall, urologists were found to prescribe alprostadil proportionately more frequently than sildenafil, whereas general practitioners and internists were more apt to prescribe sildenafil.
For men who do not respond to sildenafil or the other PDE5 inhibitors, or for men in whom these drugs are contraindicated (eg, men taking nitrates), alprostadil remains a good treatment choice.
Intracavernosal injections. For intracavernosal administration, typical dosing is 1-60 micrograms (mcg) at a concentration of 20-40 mcg/mL. Studies show that alprostadil initiates erection across all etiologies of ED in 60% to 70% of patients, and is superior to papaverine or papaverine-phentolamine. Local side effects include prolonged erection/priapism in 0.35% to 4% of patients, fibrosis in 1% to 23% of patients, and sensations of pain in 11% of patients.[32,33,35,36]
Recently, a prospective, open-label study examined the efficacy of alprostadil in 195 men who failed initial sildenafil. The average age of the participants was 62 years (range, 32-82 years), average duration of ED was 5 years, and 54 (28%) had diabetes. The study found that alprostadil conferred a marked improvement in terms of a range of subjective and objective measurements of erectile function.[8] Side effects, all of which resolved without medical intervention, included penile pain (31%), prolonged erection (6%), and dizziness (2%). Overall, the study showed that intracavernosal alprostadil effectively treated difficult cases of ED (ie, in men with a prior history of nonresponse to sildenafil, men with long-standing ED, men with diabetes, and men who had received prior treatment for prostate cancer).
Intraurethral administration. Intraurethral administration of alprostadil is also widely used with good results, but with less good results in men with difficult-to-treat ED. Studies show that over 60% of men with chronic ED treated by intraurethral alprostadil achieved intercourse.[37] The most common side effect reported is penile pain.
Efficacy of transurethral alprostadil confers an overall response rate of 43%. Among responders, 7 of 10 applications resulted in erection sufficient for intercourse. There was a high drop-out rate -- 75%. Systemic adverse events included dizziness (4%), hypotension (3%-4%), and syncope (0.3%-3%). Local adverse events included penile pain (30%), urethral bleeding (5%), and penile fibrosis (1.4%). Vaginal burning and itching was also reported in sexual partners (5.8%).[8]
In a comparison of intracavernous vs intraurethral alprostadil, intracavernous administration had greater efficacy than intraurethral alprostadil, and either was more efficacious than no treatment at all.[38]
Overall, alprostadil therapy is effective, safe, and highly successful in treating men with ED who do not respond to the newer PDE5 oral agents. Therefore, this may be a first-line treatment option for men in whom sildenafil is not well suited.

Behavioral Perspectives of ED
Although improved pharmaceuticals are increasing the number of men who seek treatment for ED, a large number of men remain untreated or discontinue treatment. In order to provide the best possible care, it is important to address why they do so.
An international study that examined why men fail to seek treatment found that the 2 top reported reasons are the belief that ED is a normal part of aging (reported more often by older men) and that the condition can resolve on its own (reported more often by younger men).[8] Men who do seek treatment are often influenced by their spouse or sex partner.
Studies show that between 50% and 60% of men discontinue treatment, and that a number of psychological reasons may account for this (Table 4).[39,40] Studies indicate that men who are depressed are more likely to discontinue treatment.[9]
Table 4. Potential Factors Responsible for Treatment Discontinuation

For physicians who are becoming increasingly well armed with effective and safe pharmacologic therapies to treat ED, recognition of and attention to the reasons why men fail to seek treatment or discontinue treatment are vitally important for optimizing treatment.

References

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37. Andersson KE. Pharmacology of penile erection. Pharmacol Rev. 2001;53:417-450. Abstract
38. Shabsigh R, Padma-Nathan H, Gittleman M, et al. Intracavernous alprostadil alfadex is more efficacious, better tolerated, and preferred over intraurethral alprostadil plus optional actis: a comparative, randomized, crossover, multicenter study. Urology. 2000;55:109-113. Abstract
39. Althof SE. When an erection alone is not enough: biopsychosocial obstacles in lovemaking. Int J Impot Res. 2002;14(suppl 1):S99-S104. Abstract
40. Sundaram CP, Thomas W, Pryor LE, et al. Long-term follow-up of patients receiving injection therapy for erectile dysfunction. Urology. 1997;49:932-935. Abstract