Introduction
The United States Census Bureau reported that in the year 2000 about 14 million men in the U.S. were over the age of 65. This number is expected to reach over 30 million by 2030. According to the Massachusetts Male Aging Study, over half of men in this age group have at least some degree of erectile dysfunction (ED). 17% of men between the ages of 40 and 70 reported mild ED, 25% reported moderate ED, and 10% reported complete ED. This high disease prevalence is important because ED affects quality of life, influences general health perception of men, represents an unmet medical need, and may be the first sign of other common and important health disorders.
ED shares many risk factors with cardiovascular disease including hypertension, diabetes, dyslipidemia, depression, tobacco use, obesity, and a sedentary lifestyle. The common pathway of these conditions is endothelial cell damage secondary to oxidative stress. Endothelial cell injury, in turn, may lead to vasoconstriction, atherosclerosis, thrombosis, and erectile dysfunction. Endothelial cell dysfunction results in decreased endothelium-dependent relaxation and increased adhesion of leukocytes to the endothelium. Thus, ED may be the first sign of underlying cardiovascular disease.
Current treatment options for Erectile Dysfunction
Medical (hormonal): Androgens
Four commonly used forms of testosterone replacement exist. These include the transdermal patch, intramuscular injections, buccal delivery systems, and topical gels. Each carries with it unique advantages and disadvantages, and these should be discussed with your doctor prior to initiation of therapy. Before initiating therapy, prostate cancer and bladder outlet obstruction should be ruled out. Once therapy has started, hormone levels should be checked at regular intervals, as should PSA, lipid panels, and hemoglobin and/or hematocrit levels. Evidence supporting the role of testosterone replacement in ED includes the fact that hypogonadal men have a diminished response to oral medication, the nitric oxide pathway is testosterone dependent, and treating men with hypogonadism has resulted in improved response rates with oral medications.
Intracavernosal injection
This therapy involves delivery of vasoactive agents directly into the erectile tissue of the penis. Commonly used agents include alprostadil (prostaglandin E1), phentolamine, and papaverine. These agents are packaged and commonly sold under the names of Caverject, Edex, Trimix, Super-Trimix, and Quadmix. Currently, the only FDA-approved products are Caverject and Edex, however, the are expensive and often painful for many patients. Trimix is a combination of papaverine, PGE-1, and phentolamine that must be compounded by an approved facility. Its advantages include minimal pain, improved efficacy, and a synergistic effect of its components. Additionally, it is inexpensive and available in generic form.
Intraurethral suppository
Intraurethral suppositories (MUSE) allow for the delivery of alprostadil into the corporal bodies via direct urethral absorption. This system obviates the use of needles, however, it has not been as effective as originally predicted. Furthermore, erections may be painful secondary to the prostaglandin effect. However, in combination with oral medications, the MUSE has shown better efficacy than oral agents alone in a subset of patients.
Vacuum Constriction Device/Vacuum Erection Device (VED)
VED’s are non-invasive manual devices that pull blood into the corporal bodies via a negative pressure gradient. Once an erection is obtained, a constricting band is placed around the base of the penis to create venous occlusion and maintain the erection after releasing the vacuum pressure. These devices require minimal manual dexterity. Current uses of VED’s also include therapeutic exercises post radical prostatectomy. Engorgement of the corporal bodies results in improved oxygen delivery, stretches the erectile tissue, and allows for early functional use post-operatively. Additionally, VED’s are often used when other treatment modalities fail or when a penile prosthesis is not an acceptable or desirable option.
Penile Prosthesis
Two general types of penile prostheses exist—the malleable and inflatable. Placement of penile prostheses requires surgery with strict adherence to aseptic technique. Generally, the devices may be used starting six weeks post-operatively. Patient satisfaction with penile prostheses is over 75%.
Oral therapy: Phosphodiesterase Inhibitors (PDE5i's)
The mechanism of erection involves vascular engorgement of the lacunar spaces of the corpora cavernosa. Filling of these spaces results in compression of penile veins and venules, prevents venous outflow, and allows for erection.
PDE5i’s work via a cascade of events that begin following sexual arousal with endothelial cell activation by nonadrenergic, noncholinergic neurons. The release of nitric oxide by endothelial cells triggers guanylate cyclase to convert GTP to cGMP, which signals calcium channels to close. Trapping of calcium in the endoplasmic reticulum of smooth muscle cells leads to smooth muscle relaxation, increased penile blood flow, and erection.
PDE isoforms are found in many different tissues, have wide expression patterns, and exert a broad range of functions. PDE5 localizes mainly to the corpus cavernosum, vascular smooth muscle, and platelets. Specific inhibition of PDE5 results in vasodilation and erections.
Currently, three PDE5i’s are available for treatment of ED—sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis). Each of these compounds carries with it different properties including onset time, duration of action, and PDE selectivity. When taken in a fasted state, the time to maximum plasma concentration of sildenafil and vardenafil is about one hour, and about 2 hours for tadalafil. In the presence of a high fat meal, this time for sildenafil and vardenafil increases to about 2 hours, approaching that for tadalafil. The time to eliminate 50% of the administered dose of sildenafil and vardenafil is about 4-5 hours, and about 17 hours for tadalafil.
In addition to PDE5 selectivity, these compounds also show affinity for other PDE isoforms including PDE6, which is found in the retina, and PDE11, which is located in the heart, testis, pituitary, prostate, skeletal muscle and kidney. Compared to tadalafil, sildenafil and vardenafil show strong affinity for PDE6. Conversely, tadalafil shows strong affinity for PDE11 compared to sildenafil and vardenafil. It is important to consider, however, that in vitro data do not always imply a clinical effect.
Numerous studies have examined the efficacy of PDE5i’s, and most use self-administered, standardized questionnaires such as the International Inventory of Erectile Function (IIEF), the Sexual Encounter Profile (SEP), and the Sexual Health Inventory for Men (SHIM). All three available PDE5i’s have been shown to be effective in the treatment of ED. Each agent is effective and well tolerated in diabetic men with ED. Daily use has been reported to improve ED over on-demand use alone. No tachyphylaxis has been seen with sildenafil, and no upregulation of PDE was found with chronic tadalafil exposure.
Studies have shown that all PDE5i’s are efficacious in treating men with ED following radical prostatectomy (RP). Additionally, nightly sildenafil has been shown to improve the return of spontaneous erection following bilateral nerve-sparing RP. The preservation of healthy erectile tissue has been demonstrated at the cellular level from intracorporeal muscle biopsies taken before and after RP with regular PDE5i use.
Side effects of PDE5i’s generally are few and well tolerated. These include headache, dyspepsia, rhinitis, flushing, abnormal vision, and dizziness. Rarely do men discontinue their use because of adverse events.
Pertinent safety information that applies to all PDE5i’s is that any use of nitrates is universally and strictly contraindicated. It is also important to consider the health impact of resuming intercourse in certain populations of at risk men with ED. Also, patients must be aware of the possible, albeit very rare, complication of priapism, which necessitates prompt medical attention.
Drug-specific safety information includes separating any alpha-blocker by 4 hours with sildenafil use; avoiding vardenafil with anti-arrhythmics; and with tadalafil, not using nitrates for 48 hours, avoiding use with “substantial” alcohol intake, and the fact that the drug may cause back pain and myalgia. A recent concern has been the development of nonarteritic anterior ischemic optic neuropathy (NAION) in patients using PDE5i’s. However, because men with ED frequently have risk factors that may also put them at increased risk for NAION, a direct causal relationship has been difficult to establish.
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