Phil Bach1 and Robert E. Brannigan2
(1)
Division of Urology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
(2)
Department of Urology, Feinberg School of Medicine, Northwestern University, Galter Pavilion, Suite 20-150, 675 N Saint Clair, Chicago, IL 60611, USA
Robert E. Brannigan
Email: r-brannigan@northwestern.edu
Keywords
Erectile dysfunctionLifestyleCardiovascular diseaseHypertensionObesityMetabolic syndromeDiabetesSmokingPhysical activity
8.1 Introduction
Major insights into the physiology of erections and the pathophysiology of erectile dysfunction (ED) were gleaned from work during the 1980s and 1990s. Most notably, the discovery of nitric oxide (NO) as a signaling molecule responsible for erection was crucial in not only helping understand the role of endothelial dysfunction in ED but also in driving the development of phosphodiesterase-5 (PDE-5) inhibitors as a first-line treatment for ED. Since then, numerous studies have linked ED with disease states that also affect endothelial function, such as cardiovascular disease (CVD), hypertension, diabetes mellitus, metabolic syndrome, and obesity [1, 2]. Furthermore, an increased prevalence of ED has been associated with lifestyle issues such as smoking, lack of physical activity, and psychosocial factors including depression [1, 2]. This chapter will examine the links between lifestyle and ED and explore the impact of lifestyle modifications in improving ED.
8.2 Risk Factors for ED
While it is difficult to definitively establish causality between various comorbidities and ED, there are clear and strong associations between ED and other health factors (Fig. 8.1). The Massachusetts Male Aging Study (MMAS) was an observational, community-based survey of men aged 40–70 conducted between 1987 and 1989 in and around Boston, Massachusetts. Investigators found that after adjusting for age, there was a higher probability of ED in men with a history of heart disease, hypertension, diabetes, and cigarette smoking [1]. Subsequent studies have reaffirmed these findings. A recent cross-sectional, population-based survey study of 108,477 men aged 45 years and older in New South Wales also found a higher risk of moderate-to-severe ED in men with high body mass index (BMI), smoking history, heart disease, and hypertension [2].
Fig. 8.1
Pathogenic factors contributing to penile endothelial dysfunction/ erectile dysfunction.
8.2.1 Links Between ED and CVD
Numerous studies have documented strong links between ED and CVD, with many now considering ED and CVD to be different manifestations of the same pathophysiology. Montorsi et al. [3] studied 300 men with angiographically documented coronary artery disease (CAD) and found that 49 % had ED using the International Index of Erectile Function (IIEF) , a validated survey measure of erectile function [3]. Of the 147 men with coexisting ED and CAD, 67 % reported having ED symptoms an average of 39 months prior to the onset of CAD symptoms, suggesting a relatively short interval between the onset of the two conditions [3]. Montorsi’s findings were corroborated by a prospective study in which 19 % (9/47) of men with vasculogenic ED were found to have angiographically, documented, but clinically asymptomatic, CAD [4].
Two meta-analyses have evaluated whether ED could be used as a predictor of CVD in men. Vlachopoulos et al. [5] conducted a meta-analysis of 14 studies comprising 92,757 patients with a mean follow-up of 6.1 years and demonstrated that men with ED had a 44 % increased risk for total cardiovascular events, 62 % increased risk for myocardial infarction, 39 % increased risk for cerebrovascular events, and a 25 % increased risk for all-cause mortality [5]. Similarly, a smaller meta-analysis of 12 prospective cohort studies comprising of 36,744 men found that those with ED had a significantly increased risk of 48 % for CVD, 46 % for coronary heart disease (CHD), 35 % for stroke, and 19 % for all-cause mortality [6]. The results from both studies support the hypothesis that ED is an important marker of silent CVD.
Theories aiming to explain the strong association between ED and CVD are based on similarities in the pathophysiologies of the two conditions. The physiology of penile erections is heavily dependent on the integrity of the endothelium, whose ability to release nitric oxide (NO) and other factors promotes relaxation of corporal smooth muscle, an increase in penile arterial inflow, and a decrease in penile venous outflow. This cascade contributes to corporal cavernosal engorgement, with resultant increases in the intracavernosal pressures and, ultimately, penile erection. Disruptions in normal endothelial function result in decreased secretion of NO, impaired vasodilatation, and, ultimately, decreased penile blood flow during erection. Similarly, the pathophysiology of CVD is thought to be related to endothelial dysfunction, leading to decreased NO release and, ultimately, atherosclerosis and decreased blood flow (see Fig. 8.1). While the pathophysiology of both ED and CVD is systemic, penile arteries (1–2 mm) are much smaller than coronary arteries (3–4 mm) and may therefore manifest endothelial dysfunction and atherosclerosis prior to the coronary circulation, resulting in much more significant reductions in blood flow in the penis than in the heart [7].
8.3 Impact of Lifestyle Modification on ED
It is well established that modifying CVD risk factors can improve CVD symptoms and risk profile, raising the possibility of a benefit from therapeutic lifestyle interventions in the setting of ED as well (Table 8.1).
Table 8.1
Summary of studies examining lifestyle modifications and effect on ED
|
Author |
Study design |
Intervention |
Effect on ED |
|
Esposito et al. [10] |
Single-blind prospective randomized controlled trial |
Increased physical activity and reduced caloric intake |
Improvement in ED (IIEF scores 13.9–17) |
|
Lamina et al. [11] |
Prospective cohort study in hypertensive patients |
Eight-week exercise program |
Improvement in ED (IIEF scores 11.5–15.1) |
|
Cheng et al. [12] |
Meta-analysis |
Physical activity |
Dose-dependent improvement in erectile function with increased physical activity |
|
Wessells et al. [20] |
Prospective randomized controlled trial in type 1 DM men |
Intensive glycemic control |
Decreased rates of ED with better glycemic control |
|
Cordero et al. [24] |
Cross-sectional observational study |
Treatment of HTN with beta-blocking agent for ≥6 months |
Blood pressure control associated with lower prevalence of ED |
|
Pourmand et al. [30] |
Prospective cohort study |
Smoking cessation |
Improvement in ED in 25 % of men who stopped smoking |
8.3.1 ED and Obesity/Physical Activity
A number of studies have described a strong association between ED and obesity. The MMAS found that men with baseline obesity and a sedentary lifestyle have a significantly higher incidence of ED [8]. However, obese men who had initiated regular moderate to vigorous exercise were able to decrease their risk of developing ED [8]. In a multivariate analysis conducted in the Health Professionals Follow-Up Study, a cohort study of 22,086 American men aged 40–75, obesity was found to increase the risk of developing ED as a function of BMI [9]. Compared to men with BMI under 25 kg/m2, those with a BMI 25–26.9 kg/m2 had a 19 % increased risk of developing ED, while those with a BMI 27–29.9 kg/m2 had a 33 % increased risk of developing ED [9]. In contrast, physical activity was inversely associated with ED [9].
Esposito et al. [10] conducted a randomized, single-blind trial of 110 men with a mean BMI of 36 kg/m2 and with ED (mean IIEF score 13.7). Men with other comorbidities such as hypertension, diabetes, and hyperlipidemia were excluded from the study. The intervention group was given specific advice on how to lose at least 10 % of their body weight through increased physical activity and by reducing caloric intake, whereas the control group was simply given general information about healthy food choices and exercise. After 2 years, the intervention group had a statistically significant decrease in BMI (36.9–31.2 kg/m2) compared with the controls (36.4–35.7 kg/m2) and statistically significant increases in physical activity (48–195 min/week vs. 51–84 min/week) and IIEF scores (13.9–17 vs. 13.5–13.6) when compared to the control group [10]. Approximately one third of men in the intervention group had IIEF scores above 22, suggesting that they had regained their erectile function [10]. Multivariate analysis revealed that changes in body mass and physical activity were independently associated with changes in IIEF scores [10]. More recently, Lamina et al. [11] conducted a prospective cohort study examining the effects of exercise on ED in hypertensive patients. Twenty-two hypertensive patients with ED aged 50–70 were assigned an 8-week exercise program and compared to age-matched controls. Similar to the prior study, the authors found a significant improvement in IIEF scores in the exercise group compared to the control group (IIEF 11.50 ± 5.30–15.14 ± 4.92 vs. 8.10 ± 4.02–8.95 ± 3.90) [11]. A meta-analysis examining seven cross-sectional studies found not only a negative correlation between physical activity and ED (OR 0.53, 99 % CI 0.31-0.91) but also identified a dose–response relationship between physical activity and ED, with higher levels of activity resulting in a lower incidence of ED (OR 1 for low activity, OR 0.63, 99 % CI 0.43-0.93 for moderate activity, and OR 0.42, 99 % CI 0.22-0.82 for high activity) [12].
The explanation for the relationship between ED and obesity revolves around the effect of inflammation on endothelial function. Chronic inflammation contributes significantly to the pathogenesis of obesity and the metabolic syndrome ; excessive calorie intake and physical inactivity lead to overproduction of pro-inflammatory cytokines including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) [13]. In turn, these cytokines lead to a persistent state of low-grade inflammation that impairs endothelial function, most notably by decreasing the bioavailability of endothelial NO and initiating a cascade of events ultimately leading to atherosclerosis [14]. Support for this hypothesis can be found in the significantly higher CRP levels detected in men with ED compared to those without when controlled for age and comorbidities [15], as well as the association between CRP levels and penile arterial disease severity as measured via penile Doppler ultrasound in men with ED [16]. Furthermore, in Lamina et al.’s [11] study, men in the exercise group with significantly higher IIEF scores after exercise also had significantly lower CRP levels when compared to the control group [11].
8.3.2 ED and Diabetes Mellitus
The prevalence of ED among diabetic men ranges from 35 to 90 % [17]. In a multivariable regression analysis from the Health Professionals Follow-Up Study, men with type 1 and 2 diabetes were both at significantly higher risk of developing ED compared to nondiabetic men (RR 3.0, 95 % CI 1.5–5.9 for type 1, and RR 1.3, 95 % CI 1.1–1.5 for type 2) [18]. Additionally, risk of ED in type 2 diabetics increased with duration of diabetes (RR 1.7, 95 % CI 1.1–2.7 in men with >20 years of disease) [18]. In their cross-sectional study of diabetic men in Israel, Kalter-Leibovici et al. [19] observed severe ED in 30.5 % of diabetic men and found association between worsening ED severity and both advancing patient age and diabetes duration [19].
While no published trials directly comparing the impact of glycemic control on ED are available, numerous studies offer indirect evidence that good glycemic control may improve ED symptoms. In the Diabetes Control and Complications Trial , 761 type 1 diabetic men were randomized to either intensive glycemic control or conventional glycemic control between 1983 and 1989 and treated until 1993. The men were divided into two cohorts: the primary prevention cohort, which consisted of 366 men who had a disease duration of 1–5 years without evidence of microvascular complications, and the secondary intervention cohort, which consisted of 395 men who had a disease duration of 1–15 years and evidence of nonproliferative retinopathy and/or microalbuminuria. In 2003, an ancillary study using a validated ED questionnaire was conducted on 571 men (295 men from the primary prevention cohort and 280 men from the secondary intervention cohort) and found a significantly decreased rate of ED in the intensive glycemic control group compared to the conventional glycemic control group for the secondary intervention cohort (12.8 vs. 30.8 %, p = 0.001) [20]. Of note, on multivariate analysis, the risk of developing ED was significantly associated with mean hemoglobin A1c (HbA1c); with a 55 % increased adjusted odds of ED symptoms in the secondary intervention cohort and a 21.5 % increased adjusted odds of ED symptoms in the primary prevention cohort for every 10 % increase in mean HbA1c [20]. Used as a measure for glycemic control, another small study of 78 men with type 2 diabetes found a significant inverse relationship between HbA1c levels and erectile function and identified HbA1c as an independent predictor of erectile function [21].
The pathophysiology of ED in diabetes is thought to be multifactorial. Beyond the endothelial dysfunction that presages macrovascular atherosclerotic disease, microvascular complications lead to nerve ischemia and subsequent damage, causing both autonomic and peripheral neuropathy. Penile innervation via the dorsal and perineal nerves includes not only sympathetic and parasympathetic nerves, but also motor and sensory somatic nerves. Impaired parasympathetic stimulation from autonomic neuropathy impedes smooth muscle relaxation within the corpora cavernosa and can lead to ED [17]. Diabetic peripheral neuropathy can impair the transmission of both sensory impulses from the penile shaft and glans to the reflexogenic erectile center and motor impulses to the bulbocavernosus and ischiocavernosus muscles responsible for preventing venous outflow from the cavernous bodies during erection [17]. Finally, diabetes is frequently associated with hypogonadism, with 20 % of diabetic men having a low total testosterone level below 8 nmol/L and 31 % of diabetic men having a borderline low testosterone level between 8 and 12 nmol/L [22].
8.3.3 ED and Hypertension
As an important risk factor for CVD and a contributor to systemic endothelial dysfunction, hypertension is also a risk factor for ED. The MMAS found hypertension to be directly associated with an increased risk of ED [1] while a cross-sectional analysis of the 2126 American men in the National Health and Nutrition Examination Survey (NHANES) found the age-adjusted prevalence of ED to be 27.7 % in men with treated hypertension and 15.1 % in men with untreated hypertension [23].
In contrast, in a cross-sectional, observational study of 1242 hypertensive men, Cardero et al. [24] assessed the impact on ED of treating hypertension for over 6 months with beta-blockade and found that blood pressure control resulted in a lower prevalence of ED independent of age, medical treatments, and CVD [24]. The favorable impact of beta-blockade on ED was most pronounced with nebivolol, especially in younger patients [24]. A separate study of 1007 patients also found that treatment of hypertension with nebivolol specifically resulted in a lower prevalence of ED [25]. The improvement in ED seen in the two studies may be related to nebivolol’s unique ability to function as a vasodilator by potentiating NO release.
The higher prevalence of ED found in men with treated hypertension compared to those with untreated hypertension in the NHANES study shows how antihypertensive medications can contribute to ED. Many antihypertensive medications, such as diuretics, nonselective beta-blockers, and alpha-2 blockers, are known to contribute to ED, whereas angiotensin-converting enzyme inhibitors and calcium channel blockers typically do not have adverse effects on erectile function [26].
8.3.4 ED and Smoking
Various clinical and epidemiological studies have identified a relationship between smoking and ED. Prospective results from the MMAS found that after adjusting for age and other covariates, baseline cigarette smokers had a significantly higher risk of developing moderate or complete ED (24 vs. 14 %, p = 0.01) when compared to non-smokers [27]. In this study, cigar smoking and passive exposure to cigarette smoke were also significant predictors of ED [27]. A secondary analysis of a cross-sectional survey of 4462 Vietnam War veterans also found a significant association between smoking and ED that held even after accounting for confounders (adjusted OR 1.5, 95 % CI 1.0–2.2) [28]. A recent meta-analysis of eight studies including 28,856 patients found an overall odds ratio of ED of 1.51 (95 % CI 1.34–1.71) in current smokers and 1.29 (95 % CI 1.07–1.47) in former smokers when compared to non-smokers [29].
Pourmand et al. [30] conducted the first prospective trial examining the beneficial impact of smoking cessation on ED. Smokers with ED who requested nicotine replacement therapy (NRT) and who had no concurrent risk factors (such as hypertension, dyslipidemia, diabetes, psychiatric disorders, or illicit drug history) were assessed with IIEF questionnaires before initiating NRT and after 1 year of follow-up. While a significant correlation between ED severity and level of exposure to smoking was observed, an improvement in ED in 25 % of men who stopped smoking compared to none in those who continued smoking was also seen [30].
A more recent study compared penile tumescence using penile plethysmography in men who were able to successfully stop smoking during an 8-week smoking cessation program with those who relapsed and found a significant improvement in both penile tumescence response and time to reach maximum sexual arousal in those men with successful cessation who did not relapse [31].
The etiology of smoking’s deleterious effects on erectile function is not entirely understood, but is thought to be secondary to endothelial dysfunction. Smoking causes an increase in reactive oxygen species that are directly detrimental to endothelial cells, leading to an exacerbation in oxidative stress and a decreased bioavailability of NO required for smooth muscle relaxation in the corpora cavernosa [32].
8.3.5 ED and Psychosocial Factors
Psychosocial factors such as anxiety and depression have been closely associated with ED and are thought to contribute to up to 40 % of cases, though it is unclear whether ED is the cause or result of these psychosocial factors [33, 34]. In the MMAS, a strong association was found between men with depressive symptoms and ED (OR 2.03, 95 % CI 1.39–2.96) [1]. Even after multifactorial regression analysis controlling for confounding factors such as age, CVD, medical conditions, and physical activity, men with depressive symptoms were 1.82 times more likely to have moderate-to-severe ED compared to those without depressive symptoms [1]. A prospective Finnish study of 1683 men aged 50–70 years attempted to assess the relationship between ED and depressive symptoms and found the relationship to be bidirectional [35]. The study found a higher incidence of ED in men with depressive symptoms (59/1000 person-years, 95 % CI 39–90) than in those without depressive symptoms (37/1000 person-years, 95 % CI 32–43) as well as a higher incidence of depression in men with ED (20/1000 person-years, 95 % CI 13–30) than in those without ED (11/1000 person-years, 95 % CI 8–14) [35].
While there appears to be a strong relationship between depression and ED, there is a paucity of robust data on the effects of lifestyle modifications in depression and ED. In fact, a major repercussion of the medical therapies used in managing depression is ED. A prospective study examining the effects of various selective serotonin reuptake inhibitors (SSRIs) on sexual function in 344 men with normal baseline sexual function found de novo ED incidence rates of 16.8 %, 34.1 %, 9.5 %, and 15.8 % for men taking fluoxetine, paroxetine, fluvoxamine, and sertraline, respectively [36].
Although the evidence consists of a few small studies with significant heterogeneity, sex therapy and psychotherapy do appear to have a positive impact on ED. Sex psychotherapy focuses on treating anxiety and psychosocial factors by utilizing a number of techniques such as desensitization, sex education, interpersonal therapy, rational-emotive therapy, and communications training. A prospective trial of 23 couples presenting with a primary complaint of ED found a significant improvement in ED following implementation of sex psychotherapy that was sustained after 6 months [37], while a recent systematic review and meta-analysis of 100 patients showed that group psychotherapy and sex group therapy were effective in reducing ED when compared to no treatment (RR 0.40, 95 % CI 0.17–0.98, p = 0.05) [38]. Furthermore, evidence from the meta-analysis suggests that psychotherapy may have synergistic effects in reducing ED when combined with commonly used medical therapies such as sildenafil citrate (RR 0.46, 95 % CI 0.24–0.88, p = 0.02 compared to sildenafil citrate-only group) [38].
8.4 Summary and Conclusion
While difficult to definitively establish causality, numerous studies have shown strong correlations between ED and lifestyle diseases such as CVD, obesity, diabetes, hypertension, and smoking. The common link between these clinical entities appears to be endothelial dysfunction that, due to the smaller size of the penile arteries, manifests as ED prior to the onset of symptomatic CVD. Obesity, diabetes, hypertension, and smoking, which are all risk factors for CVD, double as risk factors for ED and contribute to endothelial dysfunction through chronic low-grade inflammation.
Modifications of risk factors related to obesity, diabetes, hypertension, smoking, and psychosocial factors have been shown to improve or have been associated with improved erectile function. The links between ED and lifestyle diseases open an important avenue for healthcare professionals to explore in managing ED. Lifestyle modifications and a multidimensional approach that incorporates psychosocial factors represent important interventions that can improve ED and should be among first-line recommendations for the treatment of ED.
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