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Erectile Dysfunction: Incidence & Standard of Care

Erectile dysfunction (ED) is characterized by the lack of ability to achieve and maintain penile erection for intercourse.  Methods used to quantify ED include the Erectile Function Visual Analog Scale (EF-VAS) and the International Index of Erectile Function (IIEF-5) [11, 12], however clinically it is primarily diagnosed based on symptomology.  In our aging society, ED is becoming an increasing problem. According to one study 39% of men at age 40 experience symptoms of ED, whereas by age 70 the incidence rises to 67% [13]. In this latter age group, it is believed that 50-85% of ED cases are associated with hypertensiom, diabetes, cardiovascular disease and dyslipidemia [14].  Overall, it is estimated that 10-30 million Americans suffer from this condition [15]].

Today, the first line of therapy for ED is a trial of phosphodiesterase (PDE) 5 inhibitors, drugs that augment the physiologic process of tumescence [16].  During penile erection, neuronally derived nitric oxide stimulates cyclic guanosine monophosphate (cGMP) production in vascular smooth muscle cells of the corpus cavernosum[17].  cGMP acts through a series of intracellular pathways to lower the intracellular level of calcium that, in turn, causes cavernosal smooth muscle relaxation and penile arterial vessel dilation.  PDE5 inhibitors, which include sildenafil, vardenafil, tadalafil, and avanafil represent this first-line therapy for various forms of ED including both organic and psychogenic ED.

Unfortunately, up to 50% of patients are either unresponsive to phosphodiesterase-5-inhibitor therapy or do not tolerate adverse effects associated with treatment [18-21].  The primary reason for this unresponsiveness to the PDE5 inhibitors is either the presence of restricted inflow of blood into the cavernosa usually as a result of atherosclerosis of the iliac-pudendal – cavernosal arterial vessels, or nerve damage in which NO cannot be made to initiate the production of cGMP by the corporal smooth muscle, or simply smooth muscle atrophy where the remaining corporal tissue is insufficient to allow tumescence to occur  [22].   Adjunctive and/or additive pro-erectile therapies have been used to try to overcome any less than optimum response from the oral PDE5 inhibitors but these have never been accepted as standard of care [23-25]. In addition, it is believed that a normal circulating testosterone level is necessary for the PDE5 inhibitor to work optimally [26,27].  Simply stated, any defect in either one or a combination of these 4 parameters – the psyche, the nerve, the vascular system (both inflow and outflow), the endocrine (testosterone) system – can lead to ED.

PDE5 inhibitors are known to possess a variety of systemic effects in numerous organ systems; therefore, the long-term effects of PDE5 inhibition are still uncertain.  PDE5 inhibitors can induce a variety of adverse effects such as optic neuropathy [28], headaches [29], and various cardiovascular pathologies [30], especially when taken in combination with nitrate medications[31].  In fact, in 1998, the US Food and Drug Administration published a report on 130 confirmed deaths among men who received prescriptions for sildenafil citrate, where causes of death included arrythmias, sudden cardiac death and hypotension-associated events [32].  Beneficial non-ED uses of PDE5 inhibitors are also known, for example, since PDE5 is expressed in lung tissue, investigators sought to, and succeeded at inhibiting symptomatic pulmonary arterial hypertension in a double blind clinical trial [33] by administration of sildenafil citrate.  However, given the various areas in the body that PDE5 is expressed, such as platelets, kidneys, and pancreas [34], it is the belief of some that systemic inhibition of this enzymatic system may have adverse physiologic consequences in the long-run [35].

In addition to oral phosphodiesterase inhibitors, other treatments for ED are increasingly invasive and include vacuum pumps, penile prostheses, and intracavernosal injections with vasodilators, and vascular surgery. Vacuum pumps may be difficult for some men to use, do not allow for spontaneous, natural erections to occur,and may cause penile trauma if used improperly.  Implantation of penile prostheses is invasive, expensive, and irreversible and can cause penile deformity.  Intracavernosal injections of vasoactive drugs are satisfactory or effective in 30 to 90 percent of men,but they can be associated with pain, priapism, penile hematomas, and fibrosis.  Clinical interest in penile revascularization surgery stems from the widely reported link between ED and atherosclerotic vascular disease (examples in [36, 37]). Unfortunately however, the success rate of vascular surgery has been reported to be highly variable and has raised questions concerning the appropriate means for diagnosis of arteriogenic ED, and the safety and feasibility of stent-based therapies [38].  Hence, there is clearly a need for additional treatments for addressing ED.