Oxidative stress and inflammation, which disrupt nitric oxide (NO) production directly or by causing resistance to insulin, are central determinants of vascular diseases including ED. Decreased vascular NO has been linked to abdominal obesity, smoking and high intakes of fat and sugar, which all cause oxidative stress. Men with ED have decreased vascular NO and circulating and cellular antioxidants. Oxidative stress and inflammatory markers are increased in men with ED, and all increase with age. Exercise increases vascular NO, and more frequent erections are correlated with decreased ED, both in part due to stimulation of endothelial NO production by shear stress. Exercise and weight loss increase insulin sensitivity and endothelial NO production. Potent antioxidants or high doses of weaker antioxidants increase vascular NO and improve vascular and erectile function. Antioxidants may be particularly important in men with ED who smoke, are obese or have diabetes. Omega-3 fatty acids reduce inflammatory markers, decrease cardiac death and increase endothelial NO production, and are therefore critical for men with ED who are under age 60 years, and/or have diabetes, hypertension or coronary artery disease, who are at increased risk of serious or even fatal cardiac events. Phosphodiesterase inhibitors have recently been shown to improve antioxidant status and NO production and allow more frequent and sustained penile exercise. Some angiotensin II receptor blockers decrease oxidative stress and improve vascular and erectile function and are therefore preferred choices for lowering blood pressure in men with ED. Lifestyle modifications, including physical and penile-specific exercise, weight loss, omega-3 and folic acid supplements, reduced intakes of fat and sugar, and improved antioxidant status through diet and/or supplements should be integrated into any comprehensive approach to maximizing erectile function, resulting in greater overall success and patient satisfaction, as well as improved vascular health and longevity.
It is remarkable that a compound as unstable as nitric oxide (NO) evolved as the critical factor determining the capacity for an erection,1 and therefore perpetuation of our species. NO lasts only a few seconds in tissues due to its unbalanced electrons, and its production and stability depend on extensive antioxidant protection.
Antioxidant defenses are reduced in men with ED. In a study of levels of reduced glutathione (GSH), an important intracellular antioxidant, men with and without diabetes had significant decreases of GSH if they also had ED (1931±581 versus 2269±232 and 1671±438 versus 2084±118, mean±s.d. (μmol l−1), respectively, both P<0.001); diabetic men, as expected, had significantly lower levels than men without diabetes (Figure 1).2 In a study of young men with ED, serum levels of paraoxonase-1 activity were markedly lower (mean±s.d. 119±62 versus 185±56, P<0.001) compared with men without ED. Both low paraoxonase-1 activity and low high-density lipoprotein (HDL) cholesterol were independent predictors of ED in this population.3 Paraoxonase-1 is an HDL cholesterol-associated circulating antioxidant enzyme that appears to at least partially mediate many positive and negative atherogenic factors.4 These lower levels of both cellular and circulating antioxidants in men with ED are most likely due to oxidative stress and/or low antioxidant intake, rather than to inherent abnormalities of antioxidant protection. Oxidative stress5 and inflammatory factors such as C-reactive protein6 are increased in men with ED.
ED is associated with reduced NO production in the systemic vasculature. In normal weight men, mean±s.e. flow-mediated dilation (FMD) was 2.4±0.21% in the men with ED compared with 3.9±0.26% in the men without ED (P<0.001).7 This review will discuss various lifestyle and metabolic factors influencing vascular NO and erectile function, with an emphasis on the role of oxidative stress and inflammation, and specific interventions available to maximize erectile and vascular health.
Obesity is associated with increased pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6.6 Obese individuals require more calories to maintain their weight and the burning of that extra fuel generates more reactive oxygen species.8 Men with ED with and without obesity have higher levels of C-reactive protein compared to men with normal erectile function.6, 7, 9 Tumor necrosis factor-α, interleukin-6, C-reactive protein and reactive oxygen species all cause insulin resistance. Insulin is an integral stimulator of vascular NO and thereby increased skeletal muscle glucose disposal. Insulin resistance therefore reduces vascular NO, causing increased circulating glucose, and hyperglycemia itself impairs insulin action and also increases the formation of advanced glycation end products, which increase reactive oxygen species and further impair NO production.10 Antioxidants increase NO and insulin sensitivity; for example, ingestion of cocoa has been shown to increase insulin sensitivity in various animal and human studies,11 and a potent polyphenolic antioxidant in green tea increases endothelial NO and insulin sensitivity in vitro and in vivo.12 In 110 obese men without diabetes, hypertension or dyslipidemia, ED was strongly correlated with waist/hip ratio and was significantly improved with weight loss and increased activity, which lowered glucose, insulin, waist/hip ratio, blood pressure and triglycerides, and increased endothelial NO production.13 In obese men, increased insulin sensitivity, induced by diet and vigorous activity and reflected by reduced circulating insulin, was very strongly correlated with increased NO production (r=0.83).14
The most important lifestyle factor influencing ED is exercise,15 both systemic and penile (coital). Physical exercise causes increased systemic endothelial NO production through shear stress caused by the mechanical effect of increased blood flow,15, 16, 17 and with erection the increase of penile blood flow is many times greater than with physical exercise. In a study of men aged 55–75 years, more frequent coitus was associated with about a 50% reduction of ED, although establishing cause and effect would require a randomized study.18 ‘Penile rehabilitation’ is increasingly used to preserve erectile function following radical prostatectomy, using either a vacuum device19 or PDE-5 inhibitors.20 In a randomized, crossover study, pelvic floor exercises also reduced ED, most likely by reducing venous outflow from the penis.21
A sedentary lifestyle increases ED by 2–10-fold,22, 23, 24 whereas ‘moderate’ activity has been reported to reduce ED by two-thirds and ‘high’ activity by over 80% (unfortunately, these degrees of activity were not defined).25 Because penile blood flow presumably does not increase with physical exercise, the principal mechanism whereby physical exercise improves ED may be the pronounced effect of increased systemic NO on glucose disposal and insulin sensitivity (reviewed above). However, physical exercise also increases PON-1 activity,26 a circulating HDL-associated antioxidant enzyme reported to be lower in men with ED.3 The effect of exercise on NO is influenced by frequency as well as intensity. In an animal model, acute exercise increased NO release for 48 h, whereas daily exercise induced fourfold higher levels of NO production that lasted for a week.27 Moderate exercise may be preferable to extreme exercise. FMD is improved with moderate exercise, but extreme exercise increases oxidative stress and reduces FMD.15 Athletes also burn more calories and commonly load up with sugar and carbohydrates before participating in extreme exercise, which would further worsen those effects.
Reduced fat intake
A high fat meal increases oxidative stress and decreases FMD.28, 29 These effects were not observed in physically active compared to inactive adults.29 A high fat meal also increases inflammatory markers and soluble adhesion molecules.30 The increases of oxidative stress and inflammatory markers decrease vascular NO by interfering with insulin action,10 and also activate endothelial production of adhesion molecules, which may further contribute to atherosclerosis.30 Subjects with diabetes or the metabolic syndrome have exaggerated effects of a high fat meal on inflammation and endothelial activation.29, 30 Elevations of inflammatory markers and adhesion molecules were significantly decreased by high doses of vitamin C (1000 mg) and vitamin E (800 IU),30 suggesting that oxidative stress is involved in these adverse effects of postprandial hyperlipidemia. The safest dose of vitamin E will be discussed later in this manuscript.
Reduced blood sugar/sugar intake
Elevations of blood glucose raise interleukin-6, tumor necrosis factor-α and interleukin-18 in normal subjects and to a greater extent in individuals with impaired glucose tolerance.31 The increases were prevented by an infusion of GSH, showing that glucose stimulates circulating inflammatory markers through an oxidative mechanism. Ingesting antioxidants together with loading of fat and/or sugar may therefore help to reduce their adverse vascular effects. ED in diabetics is negatively correlated with better glycemic control and physical activity.32
Angiotensin receptor blockers
Short-acting angiotensin II receptor blockers have been reported to improve erectile function.16 In a randomized, double-blind, crossover study of men with type 2 diabetes and hypertension, an angiotensin II receptor blocker significantly decreased a marker of oxidative stress (P<0.001) and caused a significant increase of FMD compared with an angiotensin II-converting enzyme inhibitor (P=0.01).33
Circulating levels of testosterone correlate with NO production.34 Testosterone treatment can reduce central adiposity and insulin resistance,35 which may contribute to its beneficial effects on vascular NO and ED. Raising low testosterone levels improves ED35 and can restore erectile function in response to PDE-5 inhibitors.36
Both smoking and second-hand smoke increase the incidence of ED.37 Oxidative stress induced by smoking and cigarette smoke extract has been shown to uncouple endothelial NO synthase, which results in the production of superoxide and conversion of NO to peroxynitrite,38 a potent pro-oxidant that reduces endothelial NO synthase bioactivity.39 Antioxidants can recouple endothelial NO synthase39 and protect NO from destruction by these potent oxidants.40 The complete reversal of the effect of smoking on NO by high daily doses of vitamins C (1000 mg) and E (800 IU) (Figure 2) demonstrates that even these weak antioxidants can effectively counteract oxidative stress, provided the doses are sufficiently high.38 Besides efforts at quitting, early and aggressive supplementation with antioxidants may prevent ED and progressive vascular disease in these men.
Polyphenols are potent antioxidants found in high amounts in certain foods. Pomegranate has been shown to increase endothelial NO and prevent its breakdown.40 Chocolate has been extensively examined for its favorable vascular effects.11 The effects of 22 g of cocoa with and without 45 g of sugar were examined on FMD. The cocoa, equivalent to a 40 g portion of chocolate with only 55% cocoa, had a markedly favorable effect on FMD (Figure 3).45 Sugar (45 g, an amount present in many 12 ounce sodas) abolished about two-thirds of that benefit. Dark chocolate with low sugar content (for example, 5–6 g per 40 g portion) is available with good flavor and would provide the maximum benefit on NO and vascular health. Tea increases NO46 and tea drinkers were shown to have a reduction of almost 50% of a second myocardial infarction.47 Red wine increases NO,48 but its antioxidant effects are confounded by the positive effects of alcohol (above). Fruits and vegetables contain varying amounts of antioxidants. Blueberries have been extensively touted for their antioxidant content, but strawberries and raspberries have similar amounts and cranberries have 50% more and blackberries almost 100% more compared to blueberries; some spices have up to 50-fold or more per weight than berries. Almost without exception, cooking increases the antioxidant content of foods.49 Pycnogenol is a commercial preparation of polyphenolic compounds that has been extensively investigated, is well standardized and improves erectile function at a dose of 80–120 mg per day.50 Ginseng has also been shown in a randomized trial to improve ED compared with placebo.50 Vitamin C increases vascular NO; a dose of 500 mg daily was shown to have a pronounced beneficial effect on blood pressure in patients with uncomplicated hypertension compared with placebo.51
Folic acid and hyperhomocysteinemia
Folic acid stimulates NO and deficient intake is common; the recommended daily intake is 400 μg.52 Homocysteine levels are increased in men with ED, in some cases due to methylenetetrahydrofolate reductase gene polymorphisms,53 in which case higher than usual doses of folic acid may be necessary to normalize serum homocysteine levels.
Omega-3 fatty acids
Omega-3 fatty acids are associated with lower pro-inflammatory markers and increased anti-inflammatory markers,54 stabilize heart rhythm,55 lower serum triglycerides and directly increase NO production by endothelial cells. Addition of eicosapentaenoic acid to human endothelial cells caused an immediate, threefold increase of NO.56 All of these effects may contribute to the decrease of sudden cardiac death observed with omega-3 intake.57 Because the American Heart Association recommends 1000 mg of omega-3 fatty acids daily for individuals with established coronary artery disease, and these levels are ‘Generally Recognized As Safe’ by the United States Food and Drug Administration,57 500–1000 mg is a reasonable daily intake to maximize erectile and vascular health, particularly for men with ED under age 60 years or with diabetes or hypertension, who are at markedly increased risk for serious cardiac events.16
Approximately 70% of men with chronic kidney disease have ED, in part due to diabetes and depression.58 The lower incidence of ED in renal transplant patients compared to men having dialysis suggests that metabolic factors may play a role in the ED of men with chronic kidney disease.59 Decreased quality of life is strongly correlated with ED in men having dialysis,60 emphasizing that more attention should be paid to treating ED in these men.
Multiple population studies have documented the increase of ED with age, although the incidence with each advancing decade is much lower in the absence of coronary artery disease.61 Age-related increases of weight, insulin resistance, and oxidative stress and inflammation,8 and decreases of GSH synthesis,62 and coital frequency18 may be some of the mechanisms underlying the association of ED with age in men without coronary artery disease.
Calcium supplementation causes a small but significant decrease of blood pressure, the effect being greater in individuals with insufficient dietary intake.63 Vitamin E is a weak antioxidant that increases the circulating levels of vitamin C.64 Vitamin E should be limited to 200 IU and should not be taken with aspirin.16 Substituting green tea for other beverages, together with 1000 mg of vitamin C and 200 mg of vitamin E daily, would be the least expensive choice for achieving good levels of antioxidants. L-Arginine has been disappointing as a supplement for ED or heart disease, probably because it is extensively metabolized in the gut wall and liver. Only a very large dose (5 g per day) has been reported to have some benefit on ED,65, 66 whereas smaller doses such as 1.5 g are ineffective (although commonly promoted).67
Response to PDE-5 inhibitors
NO causes penile muscle relaxation by increasing cyclic GMP.1 Consequently, all of the factors discussed above that increase NO would be expected to increase the response to PDE-5 inhibitors, which improve erectile function by inhibiting cyclic GMP breakdown and by enabling more frequent and sustained penile-specific exercise. PDE-5 inhibitors also can markedly improve antioxidant status. At peak blood levels following administration of 20 mg of tadalafil to men with ED, serum antioxidants rose 45%, serum oxidants declined 33% and serum paraoxonase-1 activity increased 50% (Figure 4, all P<0.0001).68 The magnitude of increase of PON-1 was great enough to reverse the reduction of PON-1 observed in men with ED (inset, Figure 4).3 This same dose given to men with cardiovascular risk factors caused a greater than twofold increase of FMD at the end of 4 weeks and continuing for 2 weeks after cessation of tadalafil (both P<0.01), whereas no changes were observed with placebo.16, 69 These marked increases of antioxidant status and vascular NO may be due to increased cyclic GMP reducing vascular superoxide levels and nicotinamide adenine dinucleotide phosphate oxidase expression;70 NO production requires both adequate antioxidant levels and nicotinamide adenine dinucleotide phosphate as a specific cofactor. This ancillary effect of PDE-5 inhibitors may contribute to blood pressure control. Systolic and diastolic blood pressures were lowered by 10 and 6 mm of mercury, respectively, in untreated hypertensive subjects given 50 mg of sildenafil three times daily for 16 days (P<0.01).71
Reduction of inflammation improves endothelial function and ED
More direct proof of a link between inflammation and ED is provided by experimentally producing and removing inflammation with concomitant assessment of endothelial and erectile function. When periodontal inflammation, which has been linked to cardiovascular disease, was aggressively treated, acute elevations of inflammatory markers were associated with a decrease of FMD. As the inflammation resolved over time, inflammatory markers regressed and FMD significantly increased.72 When periodontal inflammation was created in an animal model, inflammatory markers increased and intracavernosal pressure, NOS activity and cyclic GMP all significantly decreased.73 Minimizing infection and inflammation throughout the body, including avoiding fat accumulation, should improve both vascular and erectile health.
Table 1 summarizes the lifestyle and metabolic factors having positive and negative effects on ED and/or vascular NO. In some cases, randomized controlled trials are not possible, such as with smoking, excessive alcohol or hyperhomocysteinemia, but others, such as the effect of omega-3 fatty acids on ED, are entirely possible and are conspicuously lacking. Further randomized trials are needed, including various combinations of the listed interventions,50 such as the favorable effects on ED of combining testosterone and sildenafil,36 or of the Mediterranean diet, which increases intakes of omega-3's, antioxidants and folic acid.74
Lifestyle and nutritional counseling
Lifestyle modification should be included in any clinical management of ED. To aid practitioners in providing this information, three of the authors (DRM, JCG and MAM) have established a website, http: //www.erectile-function.com,75 which provides information regarding erectile function and a healthy lifestyle, and a PowerPoint presentation and a more extensive reference list for healthcare professionals free of charge.
Oxidative stress, decreased antioxidant defenses and inflammation are prevalent in men with ED and play major roles in reducing vascular NO. Poor lifestyle choices increase oxidative stress, inflammation and ED, and reduced oxidative stress and inflammation occur with multiple interventions that increase NO and improve erectile function. Understanding the influence of lifestyle and metabolic factors on erectile health will help practitioners to integrate a more comprehensive approach into their treatments of impotence, resulting in greater overall success and a higher level of satisfaction and vascular health for their patients.
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DRM, JCG and MAM are shareholders of Sexuality EDucation Network, which operates the website http: //www.erectile-function.com.
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Meldrum, D., Gambone, J., Morris, M. et al. Lifestyle and metabolic approaches to maximizing erectile and vascular health. Int J Impot Res 24, 61–68 (2012). https://doi.org/10.1038/ijir.2011.51
- inflammatory markers
- nitric oxide
- oxidative stress
- PDE-5 inhibitors
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