Penile erection is a neurovascular process controlled by numerous tightly regulated events, and occurs in response to the activation of pro-erectile autonomic pathways. It is dependent on an adequate inflow of blood to the erectile tissue through both endothelium-dependent vasodilatation and corporal smooth muscle relaxation. Pathologic alteration in the endothelium of penile vasculature and/or erectile tissue and/or impairment of neurovascular processes can result in erectile dysfunction (ED). Both cardiovascular disease (CVD) and ED have been linked to endothelial dysfunction. Endothelial dysfunction is a vascular condition resulting in a diminished vasodilatory response to pharmacologic and physiologic stressors. Endothelial dysfunction may be a pathophysiologic mechanism underlying both ED and CVD, forming a unifying link between these two conditions. Furthermore, in the general population and in men with diabetes or obesity, ED may be a valuable early marker for serious subclinical CVD, coronary artery disease and atherosclerosis.
Physiology of penile erection and the role of the endothelium
The physiology and biochemical mechanisms involved in penile erection have been extensively studied and a wealth of published information is available. Therefore, a brief summary, focusing on the key mechanisms relevant to erectile and endothelial dysfunction is provided below. For further information, the reader is referred to several excellent reviews.1, 2, 3
Normal physiology of penile erection
The penis is a neurovascular organ in which achieving an erectile response depends on the successful interaction of a sequence of neural and vascular events. Penile erection involves three synergistic and simultaneous processes: increased penile arterial inflow mediated neurologically, relaxation of the cavernosal smooth muscle and restriction of the venous outflow.2
The penis is innervated by both somatic and autonomic nerves. The cavernous nerves (sympathetic and parasympathetic autonomic nerves) innervate the smooth muscles of the arterioles, and the trabeculae regulate penile blood flow during erection and flaccidity. Neurotransmitter release from the penile nerve endings leads to relaxation of the arteriolar smooth muscle. As a result of arteriolar dilatation, the blood flow increases rapidly into the sinusoidal spaces within the trabeculae, leading to penile engorgement. Simultaneously, the trabecular smooth muscles relax, compressing the subtunical venous plexi around the trabecular spaces. This compression significantly reduces venous outflow whereas arterial inflow continues and results in erection of the penis. These events are reversed in detumescence, that is neurotransmitter release ceases, the trabecular smooth muscle contracts, expelling the trapped blood from the sinusoids through the veins and the penis becomes flaccid.3
Critical to the process of initiating and maintaining an erection are adequate arterial vasodilatation and sinusoidal smooth muscle relaxation. Research has shown that these processes are dependent on the normal functioning of the vascular endothelium and the cavernosal endothelium, respectively.3, 4, 5
The vascular endothelium: a key role in normal physiology
The vascular endothelium is a thin layer of cells lining the interior surface of blood vessels forming an interface between circulating blood and the rest of the vessel wall, thereby providing a physical barrier. However, the endothelium is not merely a passive barrier for arterial and venous blood. The obligatory role of the endothelium in regulating local and basal control of vessel tone, and therefore blood flow, was first reported almost 30 years ago.6 In response to humoral, neural and mechanical stimuli, the vascular endothelium releases a variety of factors that affect the contractile and relaxatory behavior of the underlying vascular smooth muscle. These changes control the vascular tone, thereby altering the blood flow.4, 5 Similarly, the cavernosal endothelium has a fundamental role in regulating the tone of the cavernosal smooth muscle.4
In addition to regulating vascular tone, the normal endothelium also has a pivotal role in several other key biological processes. These activities include regulation of inflammation, platelet aggregation and leukocyte adhesion, inhibition of smooth muscle cell migration and proliferation, acting as a barrier to low-density lipoprotein cholesterol and degrading very low-density lipoprotein cholesterol and chylotriglyceride.7
Abnormalities in the vascular endothelium occur frequently as a result of certain disease states. The resulting disruption of the functional integrity of the endothelium affects its ability to respond to controlling signals, a condition known as endothelial dysfunction.7, 8 This term refers to several pathologic conditions, including vasoconstriction, altered anticoagulation and anti-inflammatory activities, impaired modulation of vascular growth, dysregulation of vascular remodeling, altered lipid deposition and/or clearance.7, 8 However, endothelial dysfunction most commonly refers to decreased endothelium-dependent smooth muscle relaxation resulting from reduced vascular nitric oxide (NO) production. Examples of conditions associated with endothelial dysfunction are hypertension, diabetes, hypercholesterolemia, cigarette smoking and obesity. Interestingly, such conditions are also associated with erectile dysfunction (ED).9, 10
Penile erection: key role of endothelial NO
Nitric oxide is an intercellular messenger with numerous physiologic roles, including endothelium-dependent smooth muscle relaxation and penile erection.11 During sexual arousal, NO is synthesized from L-arginine and oxygen, a reaction catalyzed by NO synthase (NOS). This process occurs in both non-adrenergic, non-cholinergic nitrergic neurons (nNOS), and in vascular endothelial cells (eNOS) of the corpora cavernosa within the penis. Subsequently, NO diffuses to the adjacent smooth muscle cells activating guanylate cyclase. This enzyme converts guanosine triphosphate to its active form cyclic guanosine monophosphate (cGMP), which triggers a complex intracellular biochemical cascade. Through the activation of protein kinase G, cGMP induces a substantial decrease in intracellular calcium levels, which relaxes the vascular smooth muscle cells resulting in penile vasodilatation, increased arterial blood flow, expansion of erectile tissues and trapping of blood through the compression of emissary veins.3, 4, 5 The active cGMP molecule is metabolized to GMP through the action of the enzyme phosphodiesterase-5, the predominant phosphodiesterase in the penis. This enzyme is a target for phosphodiesterase-5 inhibitors, which are successfully used to encourage and maintain erections in patients with ED (for example, sildenafil citrate, tadalafil, vardenafil HCl).12
It is now evident that the activities of nNOS and eNOS play different roles in erectile function (Figure 1). A model has been proposed in which neural signals trigger a rapid, brief activation of nNOS that initiates the erectile process. The NO of neuronal origin induces vasorelaxation causing increased blood flow and physical expansion of penile vasculature and sinusoidal spaces. The resulting shear force on the endothelium of these structures triggers the phosphatidylinositol 3-kinase (PI3)/serine/threonine protein kinase (Akt)-dependent phosphorylation and activation of eNOS, causing a more sustained NO release, vasorelaxation and maximal erection.13
In summary, the penis is a neurovascular organ, and the processes involved in the initiation and maintenance of an erection are numerous and tightly regulated. Pathologic alterations in either the penile vasculature or in any of the neurovascular interactions can result in ED3 by impairing the release of NO. Although this applies to NO from both neural and/or endothelial origins, ED is predominantly a disease of vascular origin.4
Erectile and endothelial dysfunction in advancing age
Epidemiology of ED: age is a critical factor
The long-established definition of ED is ‘the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance’.14 This condition is common; for example, in the United States, up to 30 million men suffer from ED, and the worldwide estimate is approximately 150 million.15 Thus, the prevalence of this disorder is widespread, affecting the sexual well-being of many men.
There is a relative paucity of epidemiologic studies of ED evaluating its associated risk factors and the published data are heterogeneous because of the wide range of different populations evaluated.16 However, there are clearly several risk factors for ED, and a consistent finding between the studies is that age is a key factor in ED and that it is independent of comorbidities. Indeed, as the world population ages, the prevalence of ED in 2025 is projected to be approximately 300 million worldwide.17 ED is a particularly common condition in middle-aged and older men, and its reported prevalences range from 2% in men aged 40 years to 86% in men older than 80 years.18, 19 A recent US study reported that the most prevalent sexual problems in men (n=1455, aged 57–85 years) were erectile difficulties.20
However, many studies evaluating the prevalence of ED have focused on patients in the community or on those attending specialty clinics. An important question for the primary care physician is: what is the actual prevalence of ED among the patients whom they commonly see? This question was recently addressed in a survey of almost 4000 Canadian men, aged 40–88 years, in the primary care setting.21 The overall prevalence of ED was 49.4%. As expected, the prevalence and severity of ED increased with advancing age. For example, the percentage of men with no ED in each age category was approximately 70% (40–49 years), 59% (50–59 years), 38% (60–69 years) and 14% (⩾70 years). In contrast, severe ED was reported in 5% of men aged 40–49 years and in 60% of men aged 70 years or more (Figure 2).21
Endothelial dysfunction increases with advancing age
Various studies have shown an association between aging and endothelial dysfunction, and as detailed earlier, the vascular endothelium plays a crucial role in erectile function. Thus, the increased prevalence of ED in older men could be explained by the link between age and endothelial dysfunction.
Non-invasive techniques are available to evaluate peripheral endothelial function; for example, assessment of brachial artery diameter using high-resolution ultrasound.22 In this method, local ischemia is induced by interrupting arterial blood flow with an inflated blood pressure cuff. Releasing the pressure induces reactive hyperemia resulting in the local release of NO, a key function of the endothelium. The magnitude of change in vessel diameter between baseline and the observed peak during reactive hyperemia is indicative of the degree of endothelial function.
The effect of age on the endothelial responsiveness in the forearm vessels of a group of normotensive subjects (n=53) was evaluated by Taddei and colleagues.23 Acetylcholine, an endothelium-dependent vasodilator, induced a dose-dependent increase in forearm blood flow. Interestingly, the acetylcholine-induced increase in blood flow was negatively correlated with age, that is, as age increased, vascular endothelial function was significantly decreased.23 This association between aging and endothelial dysfunction provides a plausible explanation for the increased prevalence of ED in older men.
ED: the close link with cardiovascular disease (CVD)
A recent US clinical research study of 2126 men ⩾20 years old in the general population clearly showed that ED was particularly prevalent in those with one or more cardiovascular risk factors, even after adjustment for age.10 Examples of ED prevalence by cardiovascular risk factors include: 20% (obesity, body mass index >30); 39% (diabetes); 17% (hypercholesterolemia); 28% (treated hypertension); 15% (untreated hypertension); 19% (former smokers) and 21% (current smokers). Thus, there is a close correlation between ED and CVD as they share the same risk factors.
Traditionally, owing to its high prevalence in men with CVD, ED was viewed as a secondary complication of this disorder. However, a more recent hypothesis is that ED is an early marker for CVD24 (see Jackson paper in this supplement on page S9). Various evaluations have examined support for this hypothesis, the largest of which to date used data collected during the Prostate Cancer Prevention Trial (PCPT).
The PCPT was a prospective, blinded, randomized and placebo-controlled trial (n=18 882; 1994–2003) to assess whether prophylactic finasteride decreased the prevalence of prostate cancer.25 Participants were regularly monitored for overall health, including cardiovascular events and sexual function (for example, ED). ED was graded as follows: grade 0, absent; grade 1, decrease in normal function, but able to achieve vaginal penetration with difficulty; grade 2, no erections. CVD was defined as any of the following events: myocardial infarction or surgical treatment of coronary artery disease (CAD; coronary artery bypass or angioplasty), angina, cerebrovascular accident, transient ischemic attack, congestive heart failure, fatal cardiac arrest or non-fatal cardiac arrhythmia.
Data from the placebo group (n=9457 men aged 55 years or older) in this trial were analyzed to assess the hypothesis that ED is an early marker or sentinel symptom of patients with occult CVD.26 At study entry, 8063 (85%) men had no CVD. Interestingly, 3816 (47%) of these patients reported some level of ED at baseline and were excluded from the analyses. After 5 years, 57% of men (2420 of 4247) without this condition at baseline reported ED, and this incidence increased to 65% at 7 years. Incident ED was statistically significantly associated with subsequent angina, myocardial infarction or stroke; hazard ratio after adjustment was 1.25 (95% confidence interval (CI): 1.02–1.53; P=0.04).26
The analysis also provided estimates of incident CVD in men who developed incident ED during the study and before any cardiovascular event (at risk population=2495 men). One and 5 years after initially reporting ED, 2% and 11% of men, respectively had their first cardiovascular event. Further analyses showed that incident ED had an equal or greater effect on subsequent cardiovascular events as traditional risk factors such as a family history of myocardial infarction, smoking or hyperlipidemia.
These findings from the PCPT provide the first evidence of a strong association between ED and the subsequent development of clinical cardiovascular events. Thus, ED can be considered to be a ‘sentinel’ of cardiovascular events in some men. Consequently, the presenting symptom of ED should prompt an assessment of cardiovascular risk factors and appropriate intervention (see Jackson paper in this supplement on page S9).
Endothelial dysfunction: a unifying link between ED and CVD
As detailed above, penile erection is dependent on the normal functioning of the vascular endothelium and endothelial dysfunction is associated with ED. Furthermore, ED is closely associated with CVD, and both disorders have similar risk factors. Disruption of normal endothelial function has also been reported in association with other factors that confer increased ED risk such as aging,23 hypertension, diabetes, hyperlipidemia, atherosclerosis and smoking.9, 27 Thus, it can be plausibly argued that endothelial dysfunction may be a unifying alteration underlying the pathogenesis of CVD, aging and ED (Figure 3).
Erectile and endothelial dysfunctions: potential markers for CVD in patients with diabetes or obesity
ED as a potential marker for heart disease in patients with diabetes
ED is a frequent complication of both type I and type II diabetes,9, 10, 27 but it is more common in type I diabetes. The association between overt CAD and ED is well recognized. However, the diabetic population has a high prevalence of silent CAD, a condition that precedes coronary events and premature death. An early marker of silent CAD in this population would be of value in identifying patients requiring treatment for this serious condition. In the first evaluation of its kind, Gazzaruso and colleagues28 analyzed the association of ED with asymptomatic CAD in type II diabetic patients.
A wide range of potential risk factors was compared in patients with uncomplicated type II diabetes with and without silent myocardial ischemia. Patients were age- and weight-matched, and the duration of diabetes was similar for both groups. Significant risk factors identified for silent CAD included: ED, apolipoprotein(a) polymorphism, smoking, microalbuminuria and abnormal high-density lipoprotein and low-density lipoprotein levels. Interestingly, of all the risk factors, ED was the strongest predictor of silent CAD (odds ratio 14.8; 95% CI: 3.8–56.9). The prevalence of ED was 33.8% in patients with silent CAD compared with only 4.7% for patients in the control group (no CAD) (P=0.000)28 (Table 1). Although these findings need to be confirmed in more patients, ED should be considered as a potential predicator of silent CAD requiring early intervention.
ED is associated with endothelial dysfunction in obese men
There is a growing body of evidence correlating ED with obesity. Indeed, being obese or even overweight can increase the risk of ED by 30–90%.10, 29, 30 In contrast, epidemiologic studies suggest that modifiable health behaviors, including physical activity and leanness, are associated with a reduced risk for ED. Obesity is also a recognized independent risk factor for CVD.
The potential association between ED and endothelial function in obese men with and without ED has been evaluated (n=80, age range 35–55 years).29 Compared with non-obese, age-matched men (n=50), all of the obese men had impaired indices of endothelial function (for example, blood pressure, platelet aggregation responses to L-arginine and serum levels of pro-inflammatory cytokines). Moreover, endothelial function showed a greater impairment in obese men with ED compared with those without ED.29 As the incidence of obesity is reaching epidemic levels in the western world, and considering its link with ED and CVD (which are also interrelated), obesity is a modifiable risk factor, which, if tackled, could provide great benefits in both sexual and cardiac health.
Erectile and endothelial dysfunctions: potential markers for atherosclerosis
Another manifestation of endothelial dysfunction is atherosclerosis, a serious clinical condition leading to increased cerebrovascular and cardiovascular morbidity. Atherosclerosis is also a common cause of vascular ED.9, 27, 31
Currently, little is known about the prevalence, extent and causes of coronary artery atherosclerosis in ED patients without symptomatic CAD. However, a recent study, although limited by the number of patients, has attempted to address this knowledge gap.32 Traditional coronary risk factors, endothelial function (measured by brachial artery flow-mediated dilation) and coronary artery calcification (measured by multi-slice computed tomography) were compared in patients with vascular ED (n=70; mean age 50.9±6.7 years) and in men without ED (n=73; mean age 50.1±6.2 years), all without a history of CAD. Flow-mediated dilation of the brachial artery was significantly lower in ED patients compared with controls (2.36±1.75 vs 3.92±2.2; P<0.001). The prevalence of coronary artery calcification was higher in ED patients than in men without ED (odds ratio: 2.57; 95% CI: 1.26–5.26, P=0.01). Furthermore, calcification occurred at a younger age and increased over time at a faster rate in patients with ED compared with controls. The results were not predicted by the presence of traditional risk factors for CVD. Further confirmation of these results is required, although an initial conclusion is that ED is potentially an additional early warning sign of coronary atherosclerosis.
The normal penile erectile response depends on the numerous tightly regulated interactions of many neural and vascular events. ED is a widespread condition that is likely to increase in prevalence as the global population ages. Although there are many causes of ED, its main etiology is of vascular origin. The endothelium plays a fundamental role in erectile physiology, so it is perhaps not surprising that endothelial dysfunction is closely associated with ED. Moreover, endothelial dysfunction occurs in many other clinical conditions associated with ED, such as hypertension, diabetes, hypercholesterolemia, atherosclerosis, and also as a result of lifestyle issues such as cigarette smoking and obesity. This supports the hypothesis that endothelial dysfunction is a common underlying link between ED and many other common conditions.
CVD and its related conditions produce significant morbidity and mortality. As the prevalence of CVD is increasing worldwide, there is an urgent need to improve methods of prevention and early detection. There are many cardiovascular risk factors that have a prognostic value for CVD, and such factors are also associated with ED. In fact, clinical presentation with ED may have valuable prognostic value as an early marker for CVD (Figure 4) rather than as a secondary complication.
The recognition of ED as an early sign of CVD provides an opportunity for prevention, particularly in high-risk and underserved minority populations. This realization is being put to practical use; for example, a Minority Health Institute Expert Advisory Panel has proposed a practice algorithm to assess ED in all men ⩾25 years regardless of sexual dysfunction.33 Moreover, screening of patients older than 40 or 50 years for ED in the primary care setting is an inexpensive way to provide valuable information regarding cardiovascular status. The role of ED in CVD prevention is expanded in this supplement by Dr Jackson on page S9.
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The author would like to acknowledge medical writing support by Jackie Phillipson of Gardiner-Caldwell Communications; this support was funded by Eli Lilly and Company. Diane Stothard (Eli Lilly and Company) provided support by reviewing this article.
The author is a paid consultant for Pfizer, Eli Lilly and Company and an investigator for Pfizer and Bayer.
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Giuliano, F. New horizons in erectile and endothelial dysfunction research and therapies. Int J Impot Res 20, S2–S8 (2008). https://doi.org/10.1038/ijir.2008.46
International Journal of Impotence Research (2010)
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International Journal of Impotence Research (2009)