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This is also true of the endocrine system, specifically the levels of testosterone production from the Leydig cells of the testicle. Accompanying the decrease in testosterone is a decrease in erections which also has a component in decrease in the blood supply to the penis making erection not as frequent and not as rigid compared with a young man’s erectile function. Although these changes are in itself not life threatening, they can impact a man’s relationship with his partner, and also ED may be a harbinger of other undiagnosed conditions such as coronary artery disease (CAD), hypercholesterolaemia or diabetes mellitus.6. ED is defined as the inability to achieve a full erection or the inability to maintain an erection adequate for sexual intimacy.

Other types of sexual dysfunction such as premature ejaculation and low libido may occur; however, the most common and disruptive problem in men is ED.

Although most men will experience periodic episodes of ED, these episodes tend to become more frequent with advancing age. Medical conditions, such as hypertension, diabetes mellitus, and cardiovascular disease (CVD), and psychological conditions, such as depression and anxiety, also contribute to sexual dysfunction in middle-aged or elderly

men

Men with diabetes are four times more likely to experience ED, and on average, experience ED 15 years earlier than men without diabetes.7 Obesity is also correlated to the development of several types of dysfunction, including a decrease in sex drive and an increase in episodes of ED.8.

There are hundreds of medications that have the side effect of ED and/or decreased libido. Examples of drugs implicated as a cause of ED include hydrochlorothiazides and beta-blocking agents.

Medications used to treat depression, particularly the SSRIs such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Prozac Weekly, Sarafem), fluvoxamine (Luvox, Luvox CR), paroxetine (Paxil, Paxil CR, Pexeva) and sertraline (Zoloft), may also contribute to ED.9 Bupropion (Wellbutrin) which has a predominant effect on blocking the reuptake of dopamine is an antidepressant with lower incidence of ED.10 The side effects of 5ARIs occurring in fewer than 5% of patients can include gynaecomastia, ED, loss of libido and ejaculatory dysfunction.11. Men being treated for prostate cancer with treatments such as radical prostatectomy, radiation therapy or the use of Lutenizing hormone-releasing hormone (LHRH) agonists and antagonists can expect that ED may accompany these treatments.12. Smoking, excessive use of alcohol and illicit drugs are also associated with ED.13 A study in 2005 suggests that ED is not only more likely among men who smoked compared with those who never did, but that in younger men with ED, cigarette smoking is very likely the cause of their impotence.14 15. Also, it is important to remember that there are psychogenic issues such as performance-related issues, traumatic past experiences, relationship problems, anxiety, depression and

stress

The role of the endothelium in ED has been noted for a number of years and the overlapping of ED and other conditions, especially coronary heart disease, CVD, affecting endothelial function/dysfunction, is clearly present.

The endothelial cell is

now

It is important to understand that ED is frequently, if not usually, directly related to endothelial dysfunction, and that the release of NO by the vasculature of the penile arteries is directly related to the function of intact, healthy endothelium. In the face of endothelial dysfunction, the process of erection fails to occur in a normal fashion.16.

The association of ED, CVD and endothelial dysfunction. The pathogenesis of organic ED is related to dysfunction of the endothelium. Endothelial cells can become injured through a variety of mechanisms, most of which cause oxidative stress on the tissues. Many of these causes of oxidative stress are related to lifestyle issues which lead to hypertension, diabetes and dyslipidaemia (figure 1). Endothelial cell dysfunction results in reduction of endothelium-dependent vasorelaxation as well as increased adhesion of leukocytes to the endothelium.

Endothelial cell injury then leads to a variety of sequelae, including ED, other types of vasoconstriction, atherosclerosis and thrombus formation.18.

Download figure Open in new tab Download powerpoint. Link between oxidative stress, endothelial dysfunction and ED.

CVD, cardiovascular disease; ED, erectile dysfunction. The association of CVD and ED was noted in 1997 as one analysed the results of the MMAS. In this landmark study, 1709 men aged 40–70 years were enrolled between 1987 and 1989. A follow-up some 10 years later revealed a striking relationship between ED and CVD.

In this study, it became clear that the risk factors for ED were very similar to those of CVD, such as diabetes mellitus, smoking and dyslipidaemia.18.

Since endothelial dysfunction, CVD and ED are closely associated in epidemiological studies, the question for clinicians is whether to recommend the man presenting with ED undergo a cardiovascular (CV) evaluation.

Clearly, based on numerous studies, ED can be considered at least a ‘marker’ for possible further vascular disease or CVD.15 In their report, Vlachopoulos and coworkers make the point that the man presenting with ED, the clinician, is offered an opportunity to attempt to improve the health of the man by addressing lifestyle modification, and consider further vascular evaluation owing to the clear relationship between endothelial dysfunction, ED and CVD.19. Watts and coworkers, in their review article, make several points about this ED/CAD nexus. Endothelial dysfunction is present in both CVD and ED, and is linked through the NO mechanism.

The authors note that PDE5 inhibitors improve endothelial function and have a salutary effect on both CVD and ED. Both ED and cardiac disease respond to modifications in lifestyle as well as pharmacologic manipulation.

These authors also report that the presence of ED gives the clinician an opportunity to assess CVD and prevention as well.20.

Due to the fact that ED and CVD share many of the same risk factors, it is not surprising that there is a high incidence of ED in men who present with CVD. A study by Montorsi et al found that ED was present in roughly 50% of patients with acute chest pain and confirmed CAD on angiography.21.

In this study, ED proceeded CVD in almost 70% of cases.

Similarly, many men with ED have been found to have pre-existing CVD. A study by Vlachopoulos et al evaluated the incidence of asymptomatic CVD in 50 men with ED.22 These authors found that 19% of men with ED had asymptomatic CVD.

Similarly, Mulhall and colleagues found that 20% of men presenting with ED and vascular insufficiency on penile duplex had asymptomatic CVD.23. These findings suggest that patients who present with ED and CV risk factors should be evaluated for silent CVD and should undergo a thorough CV evaluation.

Men with new onset ED and no signs or symptoms of CVD are at increased risk for experiencing a CV event in the subsequent 3–5 years.24.

Men in their 40s with ED have a 50-fold increased risk of CVD and men in their 20s and 30s have a sevenfold increased CV risk.25.

A meta-analysis of 36 744 men with ED in 12 prospective cohort studies found that the presence of ED significantly increased the risk of CVD, CAD, stroke and all-cause mortality, and the presence of ED was an independent risk factor for CVD. Ponholzer et al found that men with moderate to severe ED had a 65% increased relative risk for developing symptomatic CAD compared with men who did not have ED.26. The Prostate Cancer Prevention Trial was a landmark study by Thompson et al that prospectively assessed the time to developing CVD after the diagnosis of ED. There were 4247 men with no ED at study entry; 2420 developed incident ED (defined as the first report sildenafil lowest price of ED of any grade) over 5 years.

Those men that developed ED had a 1.45-fold higher probability of experiencing a CV event compared with men who did not develop ED.27. The severity of ED has been correlated with the extent of CVD.

Banks et al reported that the risk of future CV events increased progressively according to ED severity.28 This was shown in both men with and without known CVD at baseline and after controlling for confounders. Solomon and colleagues found an inverse correlation between international index of erectile function (IIEF) scores and plaque burden seen on coronary angiography.29 In addition, Yaman et al demonstrated a significant correlation between ED severity on IIEF questionnaires and coronary artery calcification.30. Download figure Open in new tab Download powerpoint. Algorithm for evaluating and managing the patient with ED.

CV, cardiovascular; CVD, cardiovascular disease; ED, erectile dysfunction. On the horizon is gene therapy that would deliver genes that produce products or proteins that may not be functioning properly in the penile tissue of men with ED. Replacement of these proteins may result in improvement in erectile function.

Experimental animal models have demonstrated improvement in erectile function sildenafil lowest price with gene therapy. Human studies may also demonstrate success with this therapy. Gene therapy may take a wholesale sildenafil long time for regulatory approval and

public

At this time, there is a total of 36 published basic studies assessing stem cell therapy for ED, with two clinical

trials

The mechanism of action of stem cells is to generate angiogenesis with subsequent increase in cavernosal smooth muscle cells within the corporal bodies.46. Another potential new treatment consists of penile low-intensity shock wave lithotripsy.

This consists of 1500 shocks twice a week for 3–6 weeks.

The purpose is to stimulate neovascularisation to the corporal bodies with improvement in penile blood flow and endothelial function.