Introduction
Erectile dysfunction (ED) is one of the most distressing conditions a man can experience. It is defined by the National Institutes of Health as 'the inability to achieve and maintain an erection sufficient to permit satisfactory sexual intercourse'. It has a strong negative impact on quality of life, reducing self esteem, compromising well-being and limiting interpersonal relationships.' In 1995, studies estimated erectile dysfunction to affect over 152 million men worldwide. The projection for 2025 is a prevalence of 322 million men worldwide, with the largest increases expected in the developing world, i.e. Africa, Asia and South America. The potential worldwide increase in the prevalence of erectile dysfunction and the social stigma attached to it has prompted a significant amount of research, ranging from establishing pathophysiological mechanisms at the cellular level to defining clinical traits at the population level. This chapter discusses the risk factors associated with the occurrence of organic ED, and provides the foundation for a novel concept that organic erectile dysfunction is a systemic condition with potentially serious manifestations, as opposed to the conventional thought that it is simply a localized problem.
Of 1290 'healthy' men living in towns and cites near Boston, Massachusetts, provided data on the occurrence of erectile dysfunction and its physiological and psychological correlates it identified the high prevalence of ED with 52% of all men between the ages of 40 and 70 years experiencing some degree of erectile dysfunction. This caused investigators throughout the world to evaluate the prevalence and clinical correlates of erectile dysfunction in other continents. Recently, in a Brazilian study of 1286 men aged 18-70 years, 46.20% reported some degree of ED .5 Among 1240 Australian men aged 18 years and older, erectile dysfunction was present in 39.4%. In Thailand, a study with a sample of 1250 men aged 40-70 years demonstrated a prevalence of 37.5%; and in France 39% of men reported erectile dysfunction. In addition, these studies all demonstrated severity and frequency of ED increased to 70% in those approaching 70 years of age. Complete erectile dysfunction increased 10-fold from 1% in men younger than 40 years to 11% in those 70 years in the Brazilian study. The Australian study found that complete erectile dysfunction was present in only 15.7% of men aged 50-69; this figure increased to 47% in greater than 70 years.
In order to appreciate the pathological processes associated with aging, an understanding of the mechanisms occurring in the normal erectile response needs to be established. Penile erection is a neurovascular activity causes the release of neurotransmitters from the cavernous nerve terminals and of relaxing factors from the endothelial cells in the penis. This results in smooth muscle relaxation in the arteries and arterioles supplying the erectile tissue and a several-fold increase in blood flow to the penis. The smooth muscle relaxation is brought about by the release of nitric oxide (NO) from both the endothelial cells and the neural tissue supplying the corpora cavernosa. NO activates a soluble guanylyl cyclase, which raises the intracellular concentration of cyclic GMP which in turn blocks calcium influx by inhibition of calcium channels. This causes a drop in cytosolic calcium concentrations and results in relaxation of smooth muscle, vasodilation, increase in penile blood and subsequent erection.
Studies have shown that the higher prevalence of ED with increasing age is due to a decreased availability of NO in the endothelium of the penis. Haas et al have studied the differences in this neurovascular event in the young (6-month old) and the aged (2.5-3.5 -year- old) rabbit in vitro. They compared the ability of the rabbit cavernosal smooth muscle to relax in an organ bath in response to acetylcholine (Ach, endothelium dependent vasodilator), and sodium nitroprusside (SNP, NO donor). They also examined the endothelial integrity using immunohistochemical techniques. The endothelium was equally well preserved in both age groups, thereby excluding any anatomical deficit in the older animals. Moreover, Ach-mediated relaxation of penile corporal tissue was significantly attenuated from a niaximum of 68.4% in young rabbits to 39.0% in aged rabbits, but no difference was seen in cavernosal relaxation in response to SNP between the young and aged rabbits. They suggested that the inability of the aged rabbit cavernosal smooth muscle to relax was due to a defect in Ach induced NO production and not a defect in NO activity. In other words, erectile dysfunction in the aging rabbit cavernosum is not related to anatomical disturbances, but to endothelial dysfunction through a diminished ability to produce NO, although the response to NO was well preserved.
Many human population-based studies have demonstrated a strong correlation between erectile dysfunction and aging, but why aging per se should be associated with endothelial dysfunction, and hence ED, is not clear. In fact, some investigators suggest that it is not simply the aging process per se which causes a high prevalence of erectile dysfunction in the older population, but it may be the increased presence of co-morbid conditions in the elderly, which are accountable for this relationship. In particular they refer to the increased prevalence of atherosclerosis among the older population.
The association between atherosclerosis and erectile dysfunction has been well established. In the 1920s, Leriche described the well-known syndrome of ED, buttock claudication and aorto-diac atherosclerosis. The earliest vascular manifestations occur with the alteration of arterial endothelium dependent relaxation, followed by the impairment of smooth muscle reactivity. Behr-Roussel et al studied the mechanisms implicated in atherosclerosis induced erectile dysfunction, in addition to, but independently of, its aging associated component. They assessed erectile responses in vivo from young adult (YAD), adult (AD) and age-matched cholesterol-fed, atherosclerotic (ATH) rabbits, by electrically stimulating the left pelvic nerve in the anesthetized state. In addition, they studied endothelium dependent and independent relaxations of corporal strips in vitro from the three groups of animals.
Measurement of intima/media (I/M) ratio on iliac arteries from ATH rabbits determined those with moderate (Mod ATH, 0.5) or severe (Sev ATH, 1.5) atherosclerotic lesions. The electrically stimulated erectile responses were reduced in AD compared with YAD rabbits (51.6 vs 57.5%); they were similar in AD and Mod ATH rabbits (48.1%) but drastically impaired (P<0.05) in Sev ATH rabbits (34.8%). Corporal endothelium-dependent and independent relaxations were comparable in YAD and AD rabbits (maximum relaxation to acetyl choline: 51.3 vs 56.1%) but decreased in ATH rabbits (37.1%, P<0.001).
This study therefore demonstrates that the erectile response is diminished both with age and as a result of the atherosclerotic process, but the atherosclerotic process appears to have a greater effect in causing erectile dysfunction than the aging process. The atherosclerotic process in the coronary artery is associated with a decreased bioavailability of NO, suggesting that the vasculogenic changes in the penile tissue in ED states are similar to those in the coronary arteries.
These studies corroborate the results of previous clinical studies demonstrating the association of erectile dysfunction and atherosclerosis, in particular cardiovascular disease. In the MMAS the probability of erectile dysfunction increased to as much as 56% in patients with established cardiac disease. The suggestion that atherosclerosis is associated with ED is also supported by a meta-analysis of four studies involving 1476 men with heart disease, myocardial infarction or vascular surgery. The incidence of erectile dysfunction ranged from 39 to 64% in each patient group. Furthermore, the severity of erectile dysfunction has been linked to the severity of coronary artery disease. Greenstein et al. assessed the quality of erections in men undergoing coronary angiography and found that men with one-vessel disease had more (W<0.04) and firmer erections (P<0.001) with fewer difficulties in achieving an erection W<0.007) than men with two or three vessel disease.
The presence of ED has in fact been shown to be a marker for the coexistence of occult cardiovascular disease. Pritzker reviewed the results of cardiovascular stress testing, risk profile analysis and angiography in 50 asymptomatic males with erectile dysfunction of presumed vascular origin aged between 40 and 60 years.17 Multiple cardiovascular risk factors were present in 80% and graded exercise testing was electrically positive in 28 of the 50 men. Coronary angiography performed in 20 men revealed left main stem or severe three-vessel disease in six men, moderate two-vessel disease in seven men and significant single-vessel in a further seven. In a Korean study 97 men complaining of erectile dysfunction were given repeated pharmacological tests with 10 mg of prostaglandin E, to try to induce the erectile state. They were divided according to the results of the pharmacological tests as responders (N = 46) or non-responders. Men from both groups also underwent treadmill testing as a screening method for ischemic heart disease. Interestingly, ischemic ST-segment changes on the exercise test were only seen in non-responders (15.7%, P=0.006) but not in responders.
This study suggests that men with ED who do not respond to pharmacotherapy, and hence presumably have a more severe degree of erectile dysfunction, are at a greater risk of occult coronary artery disease than those who do respond. The authors concluded that additional cardiologic evaluations may prove beneficial in a certain subpopulation of patients with erectile dysfunction. The findings from a study by Kawanishi et al also support this theory. They compared the velocity of cavernosal arterial blood flow in 58 men complaining of ED with the presence of ischemic heart disease (IHD). Only six men had a prior history of coronary artery disease. In the remaining 52 men, the diagnosis of IHD was evaluated by either an exercise treadmill test, a thallium exercise scintigram or coronary angiography; 24.1% of men were confirmed as having IHD by these investigations. The mean peak systolic velocity (PSV) in the cavernous artery in patients with IHD was 22.0 cm/sec compared with a PSV of 35 cm/sec in patients without IHD (P<0.01). Furthermore, only 3.7% of patients in whom PSV values exceeded 35 cm/sec had IHD whereas 41.95 of men with a PSV less than 35 cm/sec had IHD (P<0.01). The investigators concluded that in men with erectile dysfunction, the incidence of asymptomatic IHD was high and that men who had low PSV values (indicating a more severe form of erectile dysfunction) should undergo screening for IHD.
Increasingly, more studies are emphasizing the coexistence of ED with cardiovascular disease. Hence, the manifestation of erectile dysfunction should be assumed to be associated with underlying cardiovascular disease until proved otherwise. We have demonstrated that in a cohort of 178 men presenting to a urologist with erectile dysfunction, over 30% of men were at such significant risk of cardiovascular disease that their ED therapy was deferred until further cardiovascular evaluation and treatment could establish them as low risk. We believe that erectile dysfunction may no longer simply represent a condition that is localized to the genital region. The treatment of erectile dysfunction without prior thorough cardiovascular assessment may trigger a cardiac event such as a myocardial infarction and result in significant morbidity or even mortality. Studies with findings similar to those of Pritzker, Kawanishi et al and Solomon et al, give credence to the notion that ED is a manifestation of an underlying systemic vascular disease with potentially serious consequences if not managed appropriately.
Although it is only during the past 10 years that the association of erectile dysfunction and atherosclerosis has received a significant amount of attention, this relation has been documented since 1923. Indeed it was only 20 years ago that the presence of erectile dysfunction was closely linked to arterial risk factors. Virag et al found that whenever two or more arterial risk factors were present, the mean penile blood pressure index (a measure of penile blood flow) was significantly low. ED was present in 49% of men who had no arterial risk factors and increased to 100% in men who had three or more. They concluded that the frequency of erectile dysfunction was related mainly to arteriosclerotic changes within the penile arteries and that these changes were due to the presence of atherosclerotic risk factors. It is now becoming increasingly evident that men with cardiovascular risk factors such as hyperlipidemia, diabetes mellitus, hypertension and a history of smoking are all at an increased risk of developing erectile dysfunction. Unfortunately, medications which are used to combat some of these risk factors also have ED as an unwanted side effect. We discuss the role of each of these risk factors and examine their varying contributions to the manifestation of erectile dysfunction.
Erectile dysfunction and diabetes mellitus