Aldemir M, Okulu E, Neselioglu S, Erel O, Ener K, Kayigil O. Evaluation of serum oxidative and antioxidative status in patients with erectile dysfunction. Andrologia 2011 30 June e-pub ahead of print.

 

     Men with ED had a higher oxidative stress and lower antioxidant capacity compared to men without ED. In these men, average age 48, the PON-1 level was markedly decreased with ED, confirming the study by Cifti et al in younger men.

 

Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Goswin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet 2009;373:1849-1860.

 

     Use of aspirin for primary prevention of heart attacks was not supported by this large study, as it increases bleeding complications, counterbalancing the benefit of aspirin on cardiac blood vessels. It is much more logical to alter lifestyle factors that increase NO, and NO inhibits platelet aggregation.

 

Aydinoglu F, Yilmaz SN, Coskun B, Daqlioglu N. Oqulener N. Effects of ethanol treatment on the neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle in the mouse. Pharmacol Rep 2008;60:725-34.

 

     This study of the corpus cavernosum of the mouse found that alcohol reduced endothelial NO release, but neural NO release remained intact.

 

Aytac IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999;84:50-6.

 

     Mild, moderate and severe ED is projected to affect over 600 million men by the year 2025. Assuming that questionnaires underestimate the incidence of ED (Akkus, above), probably close to a half billion men in the world currently have some degree of ED.

 

Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB, Rimm EB. Sexual function in men older than 50 years of age: results from the health professionals follow-up study. Ann Int Med 2003;139:161-8.

 

     In this study of health professionals, smoking was correlated with ED. Television viewing, as a surrogate for inactivity, was associated with more ED. In men with depression, a 70% increase in ED was observed.

 

Baumhakel M, Schlimmer N, Bohm M; DO-IT Investigators. Effect of Irbesartan on erectile function in patients with hypertension and metabolic syndrome. Int J Impot Res 2008;20:493-500.

A short-acting angiotensin II receptor blocker significantly improved erectile function in men with ED and metabolic syndrome (irbesartan).

 

Block G, Mangels AR, Norkus BP, Patterson BH, Levander OA, Taylor PR. Ascorbic acid status and subsequent diastolic and systolic blood pressure. Hypertension 2001;37:261-267.

 

     This study indicated a positive relationship of an antioxidant (vitamin C) to blood pressure.

 

Bohm M, Baumhakel M, Teo K, Sleight P, Probstfield J, Gao P. Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: The ONgoing Telmisartan

Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials. Circulation 2010;121:1439-1446.

 

     ED predicts a doubling of the risks of myocardial infarction and cardiac death in hypertensive men.

 

Bolland MJ, Avenell A, Baron JA, Grey A, Maclennan GS, Gamble GD. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:c3691.

 

     In women who were already consuming 800 mg or more of calcium in their diets, calcium supplements (usually 1.000 to 1,200 mg daily) were associated with increased heart attacks. Calcium supplements should be adjusted according to dietary intake.

Bonaa KH, Bjerve KS, Straume B, Gram IT, Thelle D. Effect of eicosapentaenoic and docosahexaenoic acids on blood pressure in hypertension. N Engl J Med 1990;322:795-801.

 

     Omega-3’s were shown in this study to decrease blood pressure.

 

Boulanger C, Luscher TF. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest 1990;85:587-590.

 

     NO relaxes vascular muscle tone directly but also by suppressing endothelin, a vasoconstrictor produced by the endothelium.

 

Buga GM, Gold ME, Fukuto JM, Ignarro LJ. Shear stress-induced release of nitric oxide from endothelial cells grown on beads. Hypertension 1991;17:187–93.

 

     This study was the first to show increased NO release due to the shear stress effect on endothelial cells. This appears to be triggered by calcium flux across the cell membrane.

 

Buijsse B, Feskens EJM, Kok FJ, Kromhout D. Cocoa intake, blood pressure, and cardiac mortality. The Zutphen Elderly study. Arch Intern Med 2006;166:411-417.

 

     This study related cocoa (chocolate) intake to reduced blood pressure.

 

Cayan S, Bozlu M, Canpolat B, Akbay E. The assessment of sexual functions in women with male partners complaining of erectile dysfunction: does treatment of male sexual dysfunction improve female partner's sexual functions? J Sex Medical Ther 2004;30:333-41.

 

     This study showed marked decreases in sexual function in female partners of men with ED and dramatic improvements with successful treatment of ED. It shows that ED is generally not secondary to female sexual dysfunction, and that the female responds very well to better erectile performance.

 

Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study. BJU Int 1999;83:269-73.

 

     This study showed that that 5 gm per day of L-arginine improved ED in men with reduced NO production.

 

Cheng C, van Haperen R, de Waard M, van Damme LCA, Tempel D, Hanemaaijer R, et al. Shear stress affects the intracellular distribution of eNOS: direct demonstration by a novel in vivo technique. Blood 2005;106:3691-8.

 

     This study elegantly demonstrated the marked induction of eNOS in endothelial cells by shear stress, using eNOS green fluorescent protein as a marker.

 

Cheng JYW, Ng EML, Chen RL, Ko JSN. Alcohol consumption and erectile dysfunction: meta-analysis of population-based studies. Int J Impot Res 2007;19:343-352.

 

     In a large collection of studies, mild to moderate alcohol decreased ED by 21%.

 

Chiurlia E, D'Amico R, Ratti C, Granata AR, Romagnoli R, Modena MG. Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. J Am Coll Cardiol 2005;46:1503-6.

 

     Men with ED develop coronary artery calcification at a younger age than controls, leading these investigators to call ED “penile angina”

 

 

Christensen BS, Gronbaek M, Pedersen BV, Graugaard C, Frisch M. Associations of unhealthy lifestyle factors with sexual inactivity and sexual dysfunctions in Denmark. J Sex Med 2011; 8:1903-1916.

 

     Excessive alcohol increases premature ejaculation, but studies clearly documenting increased ED are lacking.

 

Ciftci H, Yeni E, Savas M, Verit A, Celik H. Paraoxinase activity in patients with erectile dysfunction. Int J Impot Res 2007;19:517-520.

 

     Men with ED had a marked decrease of paraoxinase-1 (PON-1), a HDL-associated antioxidant enzyme.

 

Derby CA, Mohr BA, Goldstein I, Feldman HA, Johannes CB, McKinlay JB. Modifiable risk factors and erectile dysfunction: can lifestyle changes modify risk? Urology 2000;56:302-6.

 

     ED was associated with obesity and baseline and initiated physical activity. ED remained associated with obesity after weight loss. Physical activity appears to be of greater importance than weight loss, but the two usually go together, making it difficult to say which is more important.

 

Deutsch S, Sherman L. Previously unrecognized diabetes mellitus in sexually impotent men. JAMA 1980;244:2430-2.

 

     Twelve percent of men with ED were found to have unrecognized diabetes. Health screening of blood sugar, blood pressure, and blood lipids will often turn up unrecognized health problems in these men.

Dorey G, Speakman MJ, Feneley RCL, Swinkels A, Dunn CDR. Pelvic floor exercises for erectile dysfunction. B J U Int 2005; 96:595-597.

 

     This is a very well-designed study showing that highly structured pelvic floor exercises (PFE) significantly improved erectile function in men with ED, probably by impeding outflow of blood from the penis. The ideal approach for improving erectile function should be to maximize inflow by enhancing NO production, while decreasing outflow using PFE.

 

Duffy SJ, Gokce N, Holbrook M, Huang A, Frei B, Keaney JF, Vita JA. Treatment of hypertension with ascorbic acid. Lancet 1999;354:2048-2049.

 

     In this study, 500 mg of vitamin C daily was shown to reduce blood pressure.

 

Dulloo A, Duret C, Rohrer D, Girardier L, Mensi N, Fathi M, at al. Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Amer J Clin Nutr 1999;70:1040-5.

 

     In this study green tea extract increased energy expenditure (EE) by 4%. Caffeine at the amount present in the extract had no effect. Fat oxidation was also increased, showing that fat was being utilized for thermogenesis. The increased EE observed, for an average adult would translate to 50 calories daily and 5 pounds of weight loss per year.

 

Doumas M, Tsakiris A, Douma S, Grigorakis A, Papadopoulos A, Hounta A, Tsiodras S, Dimitriou D, Giamarellou H. Factors affecting the increased prevalence of erectile dysfunction in Greek hypertensive compared with normotensive subjects. J Androl 2006;27:469-477.

 

     This is a very good summary of the relationship of ED to hypertension, including the effect of antihypertensive medications on erectile function.

 

Eaton CB, Liu YL, Mittleman MA, Miner M, Glasser DB, Rimm EB. A retrospective study of the relationship of biomarkers of atherosclerosis and erectile dysfunction in 988 men. Int J Impot Res 2007;19:218-25.

 

     ED was associated with a reduced HDL/LDL ratio. Exercise, alcohol and a low fat diet will improve this ratio. Oxidation of LDL is a major contributor to atherosclerosis. Statins are very effective in lowering LDL cholesterol and thereby reducing cardiovascular disease.

 

El MiedanyY, El Gaafari M, El Aroussy N, et al. Sexual dysfunction in rheumatoid arthritis patients: arthritis and beyond. Clin Rheumatol 2011 Nov 24 Epub ahead of print.

 

     ED is increased in men with rheumatoid arthritis.

 

Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, et al. Inflammatory Cytokine Concentrations are Acutely Increased by Hyperglycemia in Humans: Role of Oxidative Stress. Circulation 2002; 106:2067-2072.

 

     Raising blood sugar increases inflammatory markers, and to a greater extent with glucose intolerance. These effects were blocked by antioxidant, indicating the oxidative stress caused by glucose is at least partially mediating this effect.

 

Esposito K, Giugliano F, Di Palo C, Giugliano G, Marfella R, D’Andrea F, et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled study. JAMA 2004;291:2978-84.

 

     ED was strongly associated with an increased waist/hip (W/H) ratio. ED was significantly improved with weight loss and increased activity. These interventions lowered glucose, insulin, W/H ratio, blood pressure, triglycerides, and increased endothelial NO release.

 

Esposito K, Giugliano F, Martedi E, Feola G, Marfella R, D’Armiento M, Giugliano D. High proportions of erectile dysfunction in men with the metabolic syndrome. Diabetes Care 2005;28:1201-1203.

 

     This study found a strong correlation between ED and the metabolic syndrome. Obesity appears to influence erectile function through insulin resistance, diabetes, hypertension, and abnormal blood lipids. Exercise, omega-3 supplements, and a high daily antioxidant load my prevent most of the adverse effects of obesity on erectile and vascular function.

 

Esposito K, Ciotola M, Giugliano F, De Sio M, Giugliano G, D’Armiento M, et al. Mediterranean diet improves erectile function in subjects with the metabolic syndrome. Int J Impot Res 2006;18:405-10.

 

     In a randomized study, men with MetS who followed the Mediterranean diet had significant reductions of systolic blood pressure, LDL, triglycerides, CRP, glucose, and insulin, and significant increases of HDL, endothelial function and ED score. The intervention group significantly increased their intake of healthy oils, omega-3 fats, and vegetables/fruits/nuts/legumes. 37% of the treatment group achieved an ED score of greater than 22. These men with MetS and severe ED may not have had as poor a diet at baseline as that of the typical American, as this study took place in Italy. It does illustrate that a multifaceted approach is necessary to achieve a marked improvement of ED, particularly when it is severe.

 

Esposito K, Ciotola M, Sasso FC, Cozzolino D, Saccomanno F, Assaloni R, et al. Effect of a single high-fat meal on endothelial function in patients with the metabolic syndrome: role of tumor necrosis factor-alpha. Nutr Metab Cardiovasc Dis 2007; 17:274-279.

 

     A high fat meal increases oxidative stress and inflammatory markers and decreases vascular NO.

 

Esposito K, Ciotola M, Giugliano F, et al. Endothelial microparticles correlate with erectile dysfunction in diabetic men. Int J Impot Res. 2007;19:161-166.

 

     Endothelial microparticles correlated highly with ED in men with diabetes, reinforcing the extreme endothelial dysfunction in these individuals resulting in large part from decreased NO. Increased blood sugar is probably the single worst insult to the endothelium.

 

Giugliano F, Maiorino M, Bellastella G, Gicchino M, Giugliano D, Esposito K. Determinants of erectile dysfunction in type 2 diabetes. Int J Impot Res 2010; 22:204-209.

 

     ED in diabetics is negatively correlated with better glycemic control and physical activity.

 

Fagard RH, Cornelissen VA. Effect of exercise on blood pressure control in hypertensive patients. Eur J Cardiovasc Prev Rehabil 2007;14:12-17.

 

     This study documented a beneficial effect of exercise in lowering blood pressure.

 

Faridi Z, Njike VY, Dutta S, Ali A, Katz DL. Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial. Am J Clin Nutr 2008;88:58-63.

 

     Cocoa (22 gm, an amount equivalent to a 40 gm portion of chocolate with only 55% cocoa) had a markedly favorable effect on NO production. Sugar (45 gm, the amount present in a many 12 oz sodas) abolished about two-thirds of that benefit.

 

Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massechusettes Male Aging Study. J Urol. 1994;151:54-61.

 

      This study found that the incidence of ED in men ages 40 to 70 was 52%. Questionnaires probably underestimate the incidence of this sensitive function. In another study the patients were interviewed by a physician and the incidence was 69% (Akkus).

 

Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med 2000;30:328-38.

 

     Smoking doubled the risk of ED in this study, and second-hand smoke also increased the risk. The risk estimates have not been as high in other studies on smoking and ED, but the relationship to ED might be one further factor that could convince a smoker to kick the habit.

 

Fernandes GV, dos Santos RR, Soares W, de Lima LG, de Macedo BS, da Fonte JE, et al. The impact of erectile dysfunction on the quality of life of men undergoing hemodialysis and its association with depression. J Sex Med 2010; 7:4003-4010.

 

     ED correlates with decreased quality of life in men having dialysis, suggesting more attention should be paid to treating ED in these men.

 

Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F, et al. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab 2006; 91:439-446.

 

     Higher circulating omega-3’s are related to decreased inflammatory markers.

 

Fisher ND, HughesM, Gerhard-Herman, Hollenberg NK. Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation in healthy humans. J Hypertens 2003;21:2281-6.

 

     Cocoa ingested four times daily for 5 days increased vasodilation and this was blocked by L-NAME, an inhibitor of NO production. A further acute response was seen 90 minutes after a single dose on day 5. This study was in normal individuals, indicating that NO can be further stimulated in people without any overt signs of cardiovascular disease. The amounts of flavinols ingested would be equivalent to the amount of anti-oxidant recommended on this web site (lots of fruits and vegetables, 3 cups of green tea per day, 50-100 mg of pycnogenol, and 1 oz. of no sugar dark chocolate.

 

Fitzpatrick DF, Bing B, Rohdewald P. Endothelium-dependent vascular effects of Pycnogenol. J Cardiovasc Pharmacol 1998;32:509-15.

 

     Pycnogenol increases eNOS in vascular endothelium.

 

Flammer AJ, Hermann F, Wiesli P, Schwegler B, Chenevard R, Hurlimann D, Sudano I, Gay S, Neidhart M, Riesen W, Ruschitzka F, Luscher TF, Noll G, Lehmann R, Lehmann R. Effect of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension. J Hypertens 2007;25:785-791.

 

     In a randomized, double-blind, cross-over study of men with type 2 diabetes and hypertension, the angiotensin II receptor blocker losartan caused a significant increase of FMD compared with an angiotensin converting enzyme inhibitor (p = 0.01) and also significantly decreased a marker of oxidative stress (p< 0.001).

 

Fogari R, Zoppi A, Poletti L, Marasi G, Mugellini A, Corradi L. Sexual activity in hypertensive men treated with valsartan or carvedilol: a crossover study. Am J Hypertens 2001; 14:27-31.

 

      A short-acting angiotensin II receptor blocker significantly improved coital frequency in men without ED (valsartan).

 

Forman JP, Stampfer MJ, Curhan GC. Diet and lifestyle factors associated with incident hypertension in women. JAMA 2009;302:401-411.

 

     In a large population of women followed for many years, normal BMI, 30 minutes of vigorous exercise daily, folic acid, and a healthful diet reduced incident hypertension, and their effects were additive.

 

Foster GD, Wyatt HR, Hill JO, Makris AP, Rosenbaum DL, Brill C, et al. Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low fat diet: A randomized trial. Ann Intern Med 2010;153:147-157.

 

     In a well designed study, a low carbohydrate diet lowered blood pressure more than a low fat diet; sugar appears to have worse effects on vascular NO than fat.

 

Fung MM, Bettencourt R, Barrett-Connor E. Heart disease risk factors predict erectile dysfunction 25 years later: the Rancho Bernardo Study. J Am Coll Cardiol 2004;43:1405-11.

 

     Coronary risk factors in mid-life predicted the later development of ED

 

Gazzaruso C, Solerte SB, Pujia A, Coppola A, Vezzoli M, Salvucci F, Valenti, C, Giustina A, Garzaniti A. Erectile dysfunction as a predictor of cardiovascular events and death in diabetic patients with angiographically proven asymptomatic coronary artery disease. A potential role for statins and 5-phosphodiesterase inhibitors. J Am Coll Cardiol 2008;51:2040-2044.

 

     ED predicts CAD major adverse cardiac events in men with type 2 diabetes who have established, asymptomatic CAD (hazard ratio 2.1, p < 0.001).

 

Giovannucci E, Liu Y, Platz EA, Stampfer MJ, Willett WC. Risk factors for prostatic cancer incidence and progression in the health professionals follow-up study. Int J Cancer 2007; 121:1571-1578.

 

     High calcium intake (over 1,500 mg per day) has been linked to increased advanced and aggressive prostate cancers. Most prostate cancers grow very slowly. Aggressive ones are much more crucial to avoid.

 

Giugliano D, Giugliano F, Esposito K. Sexual dysfunction and the Mediterranean diet. Public Health Nutr 2006;9:1118-1120.

 

     ED is decreased by the Mediterranean diet.

 

Giugliano F, Esposito K, Di Palo C, Ciotola M, Giugliano G, Marfella R, et al: Erectile dysfunction associates with endothelial dysfunction and raised proinflamatory cytokines in obese men. J Endocrinol Invest 2004;27:665-9.

 

     The title says it all.

 

Giugliano F, Maiorino M, Bellastella G, Gicchino M, Giugliano D, Esposito K. Determinants of erectile dysfunction in type 2 diabetes. Int J Impot Res 2010;22:204-209.

 

     In diabetic men the prevalence of ED is increased three-fold, 18 and ED is positively correlated with metabolic syndrome, hypertension and dyslipidemia, and is negatively correlated with better glycemic control and physical activity.

 

Goldstein I, Fisher WA, Sand M, Rosen RC, Mollen M, Brock G, et al. Women's sexual function improves when partners are administered vardenafil for erectile dysfunction: a prospective, randomized, double-blind, placebo-controlled trial. J Sex Med 2005;2:819-32.

 

      Treatment of ED markedly improved arousal, lubrication, orgasm, and sexual satisfaction in the female partner.

 

Goldstein I, Lue TF, Padma-Nathan H, Rosen, RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. New Engl J Med 1998;338:1397-404.

 

      Over 500 men with ED were treated with sildenafil (Viagra) or placebo. Although highly efficacious, treatment only allowed the men to achieve 4 fully rigid erections per month.

 

González-Correa JA, Arrebola MM, Guerrero A, Muñoz-Marín J, Ruiz-Villafranca D, Sánchez de La Cuesta F, De La Cruz JP. Influence of vitamin E on the antiplatelet effect of acetylsalicylic acid in human blood. Platelets 2005;16:171-179.

 

     Vitamin E was shown to markedly increase the platelet anti-aggregation effect of aspirin.

 

Gur S, Kadowitz PJ, Trost L, Hellstrom WJ. Optimizing nitric oxide production by time dependent L-Arginine administration in human corpus cavernosum. J Urol 2007;178:1543-8.

 

     L-arginine was found to potentiate the response of human corpus cavernosum tissue to sildenafil in vitro.

 

Halvorsen BL, Carlsen MH, Phillips KM, Bohn SK, Holte K, Jacobs DR, et al. Content of redox-active compounds (ie, antioxidants) in foods consumed in the United States. Am J Clin Nutr 2006; 84:95-135.

 

     This is a remarkably detailed study of the antioxidant capacity of various foods consumed in the U.S. Almost without exception, cooking increases the antioxidant content of foods.

 

Hambrecht R, Adams V, Erbs S, Linke A, Krankel N, Shu Y, et al. Regular physical activity improvesendothelial function in patients with coronary artery disease by increasingphosphorylation of endothelial nitric oxide synthase. Circulation 2003;107:3152–8.

 

     Diseased arteries also respond to exercise with increased NO production.

 

Hamilton IM, Gilmore WS, Benzie IF, Mulholland CW, Strain JJ. Interactions between vitamins C and E in human subjects. Br J Nutr 2000;84:261-7.

 

     Ingestion of either Vitamin C or vitamin E leads to higher serum levels of the other vitamin. This observation may underlie the finding of synergism in other studies regarding the effect of these two vitamins on NO production.

 

Haram PM, Adams V, Kemi OJ, Brubakk AO, Hambrecht R, Ellingsen O, et al. Time-course of endothelial adaptation following acute and regular exercise. Eur J Cardiovasc Prev Rehabil 2006;13:585-91.

 

     A single episode of exercise increased vascular NO production for 48 hours, whereas regular daily exercise caused four-fold higher vascular NO production that lasted for about a week. We recommend moderate to vigorous activity every day for men with ED.

 

Harrison DG, Widder J, Grumbach I, Chen W, Weber M, Searles C. Endothelial mechanotransduction, nitric oxide and vascular inflammation. J Intern Med 2006;259:351-363.

 

     Shear stress from increased blood flow causes an immediate release of NO due to influx of calcium into the endothelial cell and phosphorylation of eNOS, and a sustained release by increasing eNOS messenger RNA transcription and stability.

 

Hayashi T, Juliet PA, Matsui-Hirai H, Miyazaki A, Fukatsu A, Funami J, et al. l-Citrulline and l-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc Natl Acad Sci 2005;102:13681-6.

 

     Either L-arginine or L-citrulline increased NO production by blood vessels in rabbits on a high cholesterol diet. When both amino acids were given together with Vitamin C and vitamin E, atherosclerosis was dramatically lessened compared with controls.

 

Hecker M, Sessa WC, Hayley J, Harris J, Anggard EE, Vane JR. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: Cultured endothelial cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci 1990;87:8612-6.

 

     L-citrulline is a byproduct of NO production and is recycled to L-arginine within the cell. Other studies have shown that intracellular L-arginine is the critical precursor for NOS.

 

Hong B, Ji YH, Hong JH, Nam KY, Ahn TY. A double-blind crossover study evaluating the efficacy of korean red ginseng in patients with erectile dysfunction: a preliminary report. J Urol 2002;168:2070-73.

 

     Ginseng was shown to benefit ED in a well designed study. However, ginseng comes from many sources, so there is no standardization of antioxidant potency among different products.

 

Hong P, Hope JE, Ouimet JM et al. Erectile dysfunction associated with scleroderma: a case control study of men with scleroderma and rheumatoid arthritis. J Rheumatol 2004;31:508-513.

 

     ED is increased in men with rheumatoid arthritis or scleroderma.

 

Inman BA, St. Sauver JL, Jacobson DL, Mcgree ME, Nehra A, Lieber MM, Roger VL, Jacobsen SJ. A population-based, longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc 2009;84:108-113.

 

     In this prospective studyED in men ages 40 to 49 was associated with a fifty-fold increase in the incidence of CAD (including sudden death) over the following ten years, whereas the predictive value fell with increasing age as expected (5.4 fold for ages 50-59, 2.2 fold for ages 60-69, and 1.3 fold for ages 70 and over).

 

Ignarro LJ, Balertrieri ML, Napoli C. Nutrition, physical activity, and cardiovascular disease: An update. Cardiovasc Res 2007;73:326-40.

 

     A good review of this topic and well referenced.

 

Ignarro LJ, Byrns RE, Sumi D, de Nigris F, Napoli C. Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biologic actions of nitric oxide. Nitric Oxide 2006;15:93-102.

 

     Pomegranate juice is a very potent antioxidant, and protects NO from oxidative destruction. However, Pomegranate juice is very bitter and therefore commercial products have added sugar. This may be why a controlled trial of Pomegranate juice versus placebo did not reach statistical significance in treating men with ED.

 

Jackson G, Rosen RC, Kloner RA, Kostis JB. The second Princeton consensus on sexual dysfunction and cardiac risk: new guidelines for sexual medicine. J Sex Med 2006;3:28-36.

 

     The correlation of ED with cardiovascular disease and risk factors is so strong that: “…a man with ED and no cardiac symptoms is a cardiac (or vascular) patient until proven otherwise.”

 

Janszky I, Mukamal KJ, Ljung R, Ahnve S, Ahlbom A, Hallkvist J. Chocolate consumption and mortality following a first acute myocardial infarction: the Stockholm Heart Epidemiology Program. J Intern Med 2009;266:248-257.

 

     Chocolate consumption two or more times per week was associated with a two-thirds reduction of mortality following an initial myocardial infarction.

 

Jian L, Xie LP, Lee AH, Binns CW. Protective effect of green tea against prostate cancer: A case-control study in southeast China. Int J Cancer 2004;108:130-5.

 

     Prostate cancer is very uncommon in China. In this study the adjusted odds ratio for Chinese men drinking more than 3 cups daily was 0.27, and for consumption for more than 40 years the ratio was 0.12. In addition to its vascular benefits, green tea appears to be highly protective against development of prostate cancer.

 

Johnson BD, Padilla J, Harris RA, Wallace JP. Vascular consequences of a high-fat meal in physically active and inactive adults. Appl Physiol Nutr Metab 2011; 36:368-375.

 

     A high fat meal decreased vascular NO in inactive, but not in physically active, adults.

 

Jones TH, Saad F. The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process. Atherosclerosis 2009;207:318-327.

 

      This article is a very thorough review of the role of low testosterone levels in the aging male on the metabolic syndrome and atherosclerosis.

 

Kalea AZ, Clark K, Schuschke DA, Kimis-Zacas DJ. Vascular reactivity is affected by dietary consumption of wild blueberries in the Sprague-Dawley rat. J Med Food 2009 12:21-8.

 

      Blueberries were shown to increase vascular NO production. The health benefits of blueberries have been widely promoted, but in one study, strawberries had the same antioxidant content, and blackberries had almost twice the amount of antioxidant compared to blueberries.

 

Katz D, Doughty K, Ali A. Cocoa and chocolate in human health and disease. Antioxid Redox Signal 2011;15:2779-2811.

 

      This review is a very detailed treatise on the effects of cocoa and chocolate on health with emphasis on its cardioprotective properties.

 

Klotz T, Mathers MJ, Braun M, Bloch W, Engelmann U. Effectiveness of Oral L-Arginine in First-Line Treatment of Erectile Dysfunction in a Controlled Crossover Study. Urol Int 1999;63:220-3.

 

     At a dose of 1.5 gm daily, this well-designed study showed no benefit on ED. Only about one-third of oral L-arginine is absorbed intact. Other studies have shown that 5 gm has a beneficial effect on ED.

 

Koskimaki J, Shiri R, Tammela T, Hakkinen J, Hakama M, Auvinen A. Regular Intercourse Protects Against Erectile Dysfunction: Tampere Aging Male Urologic Study. Amer J Med 2008;121:592-6.

 

     These investigators found a two-fold increase of ED with less frequent coitus in men between ages 55 and 75. Use it or lose it!

 

Kostis JB, Jackson G, Rosen R, Barrett-Connor E, Billups K, Burnett AL, et al. Sexual dysfunction and cardiac risk (the second Princeton Consensus Conference). Amer J Cardiol 2005;96(12B):85M-93M.

 

     This is an excellent, comprehensive review on the risks of sexual activity in various cardiac conditions, the risks of PDE-5 inhibitor use in cardiac patients, and interactions of PDE-5 inhibitors with cardiac drugs.

 

Kris-Etherton PM, Harris WS, Appel LJ. American Heart Association Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-2757.

 

     This review summarizes the conclusions of the Nutrition Committee of the American Heart Association on omega-3’s and health. Omega-3’s decrease sudden cardiac deaths, stabilize the myocardium, are anti-inflammatory, decrease serum triglycerides, and increase endothelial nitric oxide.

 

Kupelian V, Shabsigh R, Araujo AB, O'Donnell AB, McKinlay JB. Erectile dysfunction as a predictor of the metabolic syndrome in aging men: results from the Massachusetts Male Aging Study. J Urol 2006;176:222-6.

 

     In this study ED was highly correlated with the metabolic syndrome.

 

Lopez-Jaramillo P, Gonzalez MC, Palmer RMJ, Moncada S. The crucial role of physiologic Ca2+ concentrations in the production of endothelial nitric oxide and the control of vascular tone. Br J Pharmacol 1990;101:489-493.

 

     This paper showed that changes of calcium concentrations within the physiologic range influenced NO production by the endothelium.

 

Lugg J, Rajfer J, Gonzalez-Cadavid NF. Dihydrotestosterone is the active androgen in the maintenance of nitric-oxide-mediated penile erection in the rat. Endocrinology 1995;136:1495-501.

 

     Castration reduced the nerve-stimulated erectile response in the rat. Erectile response was restored by testosterone, and this effect was mediated by conversion of testosterone to dihydrotestosterone and by nitric oxide.

 

Ma R C-W, So W-Y, Yang Z, Yu LW, Kong AP, Ko GT, Chow CC, Cockram CS, Chan JC, Tong PC. Erectile dysfunction predicts coronary heart disease in type 2 diabetes. J Am Coll Cardiol 2008;51:2045-2050.

 

     ED predicts CAD events in diabetic men with no evidence of CAD

 

Mathers JC. Folate intake and bowel cancer risk. Genes Nutr 2009;4:173-178.

 

     This review presents findings suggesting that excessive intake of folic acid could stimulate established colon cancer.

 

Meldrum DR, Gambone JC, Morris MA, Ignarro LJ. A multifaceted approach to maximize erectile function and vascular health. Fertil Steril 2010;94:2514-2520.

 

     This review describes lifestyle and nutritional changes affecting vascular NO, ED, testosterone levels, and sperm quality and argues for an approach combining several modalities to have maximum benefits.

 

Meldrum DR, Gambone JC, Morris MA, Meldrum DAN, Esposito K, Ignarro LJ. The Link Between Erectile and Cardiovascular Health: The Canary in the Coal Mine. Amer J Cardiol 2011; 108:599-606.

 

     This review emphasizes that NO is reduced in both ED and cardiovascular disease, and details the lifestyle interventions that can improve both erectile and cardiovascular health.

 

Meldrum DR, Gambone JC, Morris MA, Giuliano D, Esposito K, Ignarro LJ. Lifestyle and metabolic approaches to maximizing erectile and vascular health. Int J Impot Res. 2011 Nov 10 Epub ahead of print.

 

     This review emphasizes the role of oxidative stress, inflammation, and other metabolic abnormalities on vascular NO and ED

 

Meldrum DR, Gambone JC. Survival of the Firmest. Charleston, South Carolina: CreateSpace, 2012.

 

     This book details the lifestyle factors that influence the chance of a man having ED and gives specific recommendations that are based on evidence of improved NO production or decreased ED.

 

Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dose vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.

 

     In this large collection of smaller studies, people taking 400 IU or more of vitamin E had an increase of all-cause mortality. Vitamin E is a weak antioxidant. Berries, dark chocolate and green tea are much better choices.

 

Moens AL, Vrints CJ, Claeys MJ, Timmermans JP, Kass DA. Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease. Am J Physiol Heart Circ Physiol 2008;249:H1971-7.

 

     Folic acid is integrally involved in NO production. Dietary intake and supplements should assure the recommended daily allowance (RDA) of 400 micrograms. Green tea depletes folic acid, so a 400 ug supplement is suggested for men emphasizing this source of antioxidant.

 

Montorsi F, Briganti A, Salonia A, Rigatti P, Margonato A, Macchi A, et al. Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 2003;44:360-4.

 

     In men with angiographically proven atherosclerotic heart disease, symptoms of Ed had begun an average of 39 months previously. This study showed that intervention must occur before the actual diagnosis of ED, as 39 months would be too short a time to expect that lifestyle interventions could prevent this extent of vascular disease.

 

Mukamal KJ, Maclure M, Muller JE, Sherwood JB, Mittleman MA. Tea consumption and mortality after acute myocardial infarction. Circulation 2002;105:2476-2481.

 

     Tea drinkers were shown to have a reduction of almost 50% of a second heart attack.

 

Muniyappa R, Quon MJ. Insulin action and insulin resistance in vascular endothelium. Curr Opin Clin Nutr Metab Care 2007;10:523–530.

 

     This is an excellent review of the involvement of insulin and insulin resistance in vascular disease.

 

Murad F. Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med 2006;395:2003-2011.

 

     Ferid Murad shared the Nobel Prize with Lou Ignarro for the discovery of NO. This lecture describes his major contribution in defining cyclic GMP as the cellular messenger causing muscle relaxation in response to NO.

 

Napoli C, Lerman LO, de Nigris F, et al. Glycoxidized low-density lipoprotein downregulates nitric oxide synthase in human coronary cells. J Am Coll Cardiol. 2002;40:1515-1522.

 

      Both oxidized and glycoxidized LDL suppress NO production in coronary vessels.

 

Napoli C, Ignarro LJ. Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases. Arch Pharm Res 2009;32:1103-1108.

 

    This is an excellent review of the importance of NO in the development of vascular diseases.

 

Nappo F, Esposito K, Cioffi M, Giugliano G, Molinari AM, Paolisso G, et al. Postprandial Endothelial Activation in Healthy Subjects and in Type 2 Diabetic Patients: Role of Fat and Carbohydrate Meals. J Am Coll Cardiol 2002; 39:1145-1150.

 

     A high fat meal increases inflammatory markers and soluble adhesion molecules and to a greater extent in men with diabetes. These effects were reduced by a high load of antioxidants, indicating that oxidative stress plays a role in these adverse effects.

 

Navaneethan SD, Vecchio M, Johnson DW, Saglimbene V, Graziano G, Pellegrini F, et al. Prevalence and correlates of self-reported sexual dysfunction in CKD: a meta-analysis of observational studies. Am J Kidney Dis 2010;56:670-685.

 

     Approximately 70% of men with chronic kidney disease (CKD) have ED, in part due to diabetes and depression.The title says it all.

 

Okuda Y, Kawashima K, Sawada T, Tsurumaru K, Asano M, Suzuki S, et al: Eicosapentaenoic acid enhances nitric oxide production by cultured human endothelial cells. Biochem Biophys Res Commun 1997;232:487-91.

 

     A very prompt and marked three-fold increase of NO production was observed when EPA, one of the two main omega-3 fatty acids, was exposed to human endothelial cells.

 

Oliver JJ, Melville VP, Webb DJ. Effect of regular phosphodiesterase type 5 inhibition in hypertension. Hypertension 2006;48:622-627.

 

     In untreated hypertensive subjects, 50 mg of sildenafil three times daily for 16 days lowered systolic and diastolic blood pressures by 10 and 6 mm of mercury respectively (p < 0.01). This is a further study showing favorable vascular effects of the PDE-5 inhibitors.

 

Pace G, Del Rosso A, Vicentini C. Penile rehabilitation therapy following radical prostatectomy. Disabil Rehabil 2010; 32:1204-1208.

 

     Both vacuum therapy and PDE-5 inhibitors have been used for “penile rehabilitation” following surgery for prostate cancer.

 

Palmer RMJ, Ferrige AG, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988;333:664-666.

 

     This was the original article showing that L-arginine (an amino acid from ingested protein) is the raw material from which NO is made.

 

Palmieri V, Russo C, Pezzullo S, et al. Relation of flow-mediated dilation to global arterial load: Impact of hypertension and additional cardiovascular risk factors. Int J Cardiol. 2011;152:225-230.

 

     Endothelial NO is decreased in men with hypertension.

 

Peluffo G, Calcerrada P, Piacenza L, Pizzano N, Radi F. Superoxide-mediated inactivation of nitric oxide and peroxinitrite formation by tobacco smoke in vascular endothelium: studies in cultured cells and smokers. Am J Physiol Heart Circ Physiol 2009; 96:H1781-1792.

 

     Smoking and cigarette smoke extract markedly decrease NO in vitro and in vivo by generation of the potent oxidants, superoxide and peroxinitrite. The marked decrease of vascular NO in smokers was completely reversed by a high daily load of antioxidants for 6 months.

 

Peppa M, Uribarri J, VlassaraH. Glucose, advanced glycation end products and diabetes complications: What is new and what works. Clinical Diabetes. 2003;21:186-187.

 

     This is a good review of the role of advanced glycation end products in diabetic vascular disease.

 

Persson IA, Josefsson M, Persson K, Andersson RG. Tea flavinols inhibit angiotensin-converting enzyme activity and increase nitric oxide production in human endothelial cells. J Pharm Pharmacol 2006;58:1139-44.

 

     Tea flavinols increase vascular NO production. , but also inhibit angiotensin-converting enzyme activity.

 

Potenza MA, MarasciuloFL, Tarquinio M, Tiravanti E, Colantuono G, Federici A, et al. EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial I/R injury in SHR. Am J Physiol Endocrinol Metab 2007; 292:E1378-1387.

 

     The title says it all; SHR = spontaneous hypertensive rat. EGCG is the main polyphenol in tea.

 

Radomski MW, Palmer RMJ, Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacycline and nitric oxide. Br J Pharmacol 1987;92:639-646.

 

NO increases the platelet anti-aggregation effect of prostacyclin. Lifestyle factors that increase NO will keep platelets from adhering to the endothelium, most likely making aspirin prophylaxis unnecessary.

 

Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ: Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. New Engl J Med 1992;326:90-4.

 

This landmark study showed that neural stimulation resulting in increased penile blood flow and erection is mediated by NO and in turn by the stimulation of cyclic GMP. Because the increase was blocked by a PDE-5 inhibitor, this study led to the development of Viagra.

 

Richard C, Couture P, Desroches S, Charest A, Lamarche B. Effect of the Mediterranean diet with and without weight loss on cardiovascular risk factors in men with the metabolic syndrome. Nutr Metab Cardiovasc Dis 2011;21:628-35.

The Mediterranean diet with weight loss decreased blood pressure. The Mediterranean diet alone improved blood lipids.

 

Roberts CK, Vaziri ND, Barnard J. Effect of diet and exercise intervention on blood pressure, insulin, oxidative stress, and nitric oxide availability. Circulation 2002;106:2530-32.

 

Obese men underwent a program of vigorous daily exercise. The decrease in circulating insulin, reflecting increased insulin sensitivity, correlated with increased NO production. The increased NO production could have been due to improved insulin action, as insulin stimulates NO, but it also could have been due to reduced circulating glucose.

Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther 2002;40:158-68.

 

This is a good review of the pharmacology of pycnogenol. This procyanidin is a potent antioxidant in the general class of polyphenols also present in red wine, chocolate, blueberries and green tea. Procyanidins have 20 to 50 times the antioxidant content compared to vitamin C and vitamin E.

 

Rosano GMC, Aversa A, Vitale C, Fabbri A, Fini M, Spera G. Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk. Eur Urol 2005;47:214-222.

 

In men with cardiovascular risk factors, 20 mg of tadalafil every other day for 4 weeks doubled flow-mediated dilation, indicating increased vascular NO production, and the effect lasted for 2 weeks.

Rosen RC, Wing RR, Scneider S, Wadden TA, Foster GD, West DS, et al. Erectile dysfunction in type 2 diabetic men: relationship to exercise fitness and cardiovascular risk factors in the Look AHEAD trial. J Sex Med 2009;6:1414-22.

In men with type 2 diabetes cardiovascular fitness was associated with 40% less ED.

 

Rosenthal BD, May NR, Metro MJ, Harkaway RC, Ginsberg PC. Adjunctive use of Androgel (testosterone gel) with sildenafil to treat erectile dysfunction in men with acquired androgen deficiency syndrome after failure using sildenafil alone. Urology 2006;67:571-4.

 

In 24 men with hypogonadism who failed to have adequate erections with either sildenafil or testosterone therapy alone, 92% regained potency with the two agents combined.

 

Safarinejad MR, Safarinejad S, Shafiei N. Role of methylenetetrahydrofolate reductase gene polymorphisms (C677T, A1298C, and G1793A) in the development of early onset vasculogenic erectile dysfunction. Arch Med Res 2010; 41:410-422.

 

Homocysteine levels are increased in men with ED, in some cases due to methylenetetrahydrofolate reductase gene polymorphisms, in which case higher than usual doses of folic acid may be necessary to normalize serum homocysteine levels.

 

Saldeen P, Saldeen T. Women and omega-3 fatty acids. Obstet Ginecol Surv 2004;59:722-30.

 

This review refers to the evidence that increased dietary intake of omega-3 fatty acids shifts the balance away from vasoconstricting toward vasodilating prostaglandins. In this way, omega-3’s act similarly to penile injections or urethral suppositories of prostaglandin E1 that are prescribed by urologists when other less invasive treatments for ED fail.

 

Schafer A, Fraccarollo D, Pfortsch S, Flierl U, Vogt C, Pfrang J, Kobsar A, Renné A, Eigenthaler M, Ertl G, Bauersachs J. Improvement of vascular function by acute and chronic treatment with the PDE-5 inhibitor sildenafil in experimental diabetes mellitus. Br J Pharmacol 2008;153:886-893.

 

     In diabetic rats, daily sildenafil reduced vascular superoxide levels and nicotinamide adenine dinucleotide phosphate(NADPH) oxidase expression.NO production requires both adequate antioxidant levels and NADPHas a specific co-factor. These factors may explain the improved vascular NO observed with PDE-5 inhibitors.

 

Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol 2008;65:51-9.

 

     The circulating levels of L-arginine, the direct precursor of NO, are over twice as high after ingestion of L-citruline compared to ingestion of L-arginine. L-citrulline also acts within the cell as a precursor of L-arginine. Because 5 gm of L-arginine orally per day benefits ED, 2-3 gm of L-citrulline should have a similar effect.

 

Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for erectile dysfunction in the US. Am J Med 2007;120:151-7.

 

     The incidence of ED was found to be three-fold higher in diabetic men. Endothelial dysfunction is worse in men with diabetes because elevated circulating glucose inhibits NO production by inducing mitochondrial dysfunction with release of oxidation products that inactivate NO. High glucose levels also promote production of advanced glycation end-products (AGE’s), that accumulate with age and are potent oxidation products contributing to vascular oxidative stress. The high sugar intake of the current American diet would cause similar negative effects on NO release.

 

Senti M, Tomas M, Anglada R, Elosua R, Marrugat J, Covas MI, et al. Interrelationship of smoking, paraoxinase activity, and leisure time physical activity: a population-based study. Eur J Intern Med 2003; 14:178-84.

 

     Physical activity increases PON-1, a circulating antioxidant shown to be decreased in men with ED.

Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Glynn RJ, Gaziano JM. Vitamins C and E in the prevention of cardiovascular disease in men: the Physicians Health Study II randomized controlled trial. JAMA 2008; 300:2123-2133.

 

     Physicians who were given 400 IU of vitamin E every other day had an increase of hemorrhagic stroke. Although aspirin use was not recorded, many older physicians take low dose aspirin for cardiac prophylaxis, and vitamin E markedly increases the platelet anti-aggregation effect of aspirin (see González-Correa).

 

Shamloul R, Ghanem HM, Salem A, Elnashaar A, Elnaggar W, Darwish H, et al. Correlation between penile duplex findings and stress electrocardiography in men with erectile dysfunction. Int J Impot Res 2004;16:235-7.

 

     These investigators found a correlation of penile systolic velocity and ischemic heart disease.

 

Shindel AW, Nelson CJ, Naughton CK, Ohebshalom M, Mulhall JP. Sexual function and quality of life in the male partner of infertile couples: prevalence and correlates of dysfunction. J Urol 2008;179:1056-9.

 

     The incidence of sexual disfunction was found to be 20-25% in infertile couples.

 

Soltesz P, Kerekes G, Der H, et al. Comparative assessment of vascular function in autoimmune rheumatic diseases: Considerations of prevention and Treatment. Autoimmunity Reviews. 2011;10:416-425.

 

     Vascular NO is reduced in rheumatic diseases. This is yet another indication that inflammation interferes with NO production.

 

Soran H, Jounis NN, Charlton-Menys V, Durrington P. Variation in paraoxonase-1 activity and atherosclerosis. Curr Opin Lipidol 2009;20:265-274.

 

     PON-1, a circulating antioxidant enzyme found to be lower in men with ED, appears to at least partially mediate many positive and negative atherogenic factors.

 

Stanislavov R, Nikolova V. Treatment of erectile dysfunction with pycnogenol and L-arginine. J Sex Marital Ther 2003;29:207-13.

 

     Men with ED showed no improvement on an ineffective dose of L-arginine (1.5 gm daily), but over a further two month period with addition of 80 to 100 mg of the procyanidin, pycnogenol, 93% had improved ED scores.

 

Stanislavov R, Nikalova V, Rohdewald P. Improvement of erectile function with Prelox: a randomized, placebo-controlled crossover trial. Int J Impotence Res 2008;20:173-80.

 

      This study showed a highly significant benefit of a four week treatment of 80 mg of pycnogenol and 3 gm of L-arginine daily. The use of two supplements makes it difficult to determine which contributed to the results. One must assume that each contributed to the effects observed. Interestingly, the treatment also significantly raised testosterone levels.

 

Stanworth RD, Jones TH. Testosterone for the aging male: current evidence and recommended practice. Clin Interv Aging 2008;3:25-44.

 

     This is an excellent review of the correlation of low/low/normal testosterone levels with central obesity, insulin resistance, cardiovascular risk factors, and other adverse changes such as cognition, and the evidence that a proper level of testosterone treatment can improve these adverse effects, including diabetes control and may reduce the risk of Alzheimer’s.

 

Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, et al. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A 2004; 101:3381-3386.

 

     Glutathione synthesis decreases with age and therefore may contribute to increasing ED with age. This finding, together with the reduced cellular levels of reduced glutathione in men with ED, suggests a prominent role of oxidative stress in ED.

 

Tagliabue M, Pinach S, Di Bisceglie C, Brocato L, Cassader M, Bertagna A, et al. Glutathione levels in patients with erectile dysfunction, with or without diabetes mellitus. Int J Androl 2005;28:156-162.

 

     Levels of red cell reduced glutathione (GSH) were lower in men with ED. The very narrow standard errors of GSH levels indicated this is a consistent finding in these men, most likely reflecting reduced intake of antioxidants.

 

Tomasian D, Keaney JF, Vita JA. Antioxidants and the bioactivity of endothelium-derived nitric oxide. Cardiovasc Res 2000;47:426-435.

 

     This is a good review of the actions of vitamins C and E on vascular NO production. These two vitamins may play specific roles in NO production.

 

Traish AM, Munarriz R, Oconnell L, Choi S , Kim SW, Kimm NM, et al. Effects of medical or surgical castration in an animal model. J Androl 2003;24:381-7.

 

     Castration led to a reduced intracavernosal blood pressure, but NOS activity was unchanged. There was decreased smooth muscle content of erectile tissue. This finding, and the finding that testosterone replacement prevents effects of castration on erectile function suggest that part of the effect of androgen deficiency is via changes over time of cavernosal smooth muscle content.

 

Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl 2009;30:10-22.

 

     This is a very thorough review of the strong relationship of the metabolic syndrome (MetS) and both low testosterone levels and erectile dysfunction. Also cited is evidence that testosterone therapy improves both ED and some aspects of MetS. The authors propose that T deficiency contributes to MetS and that MetS contributes to lower T levels. In men with low T levels, T replacement improves ED as well as MetS.

 

Travallai SA, Mirzamani M, Heshmatzade BA, Assari S, Khoddami Vishteh HR, Hajarizadeh B, et al. Sexual function: a comparison between male renal transplant recipients and hemodialysis patients. J Sex Med 2009; 6:142-148.

 

     ED is less frequent after renal transplant, suggesting metabolic factors cause further ED in men on dialysis.

 

Ungvari Z, Parrado-Fernandez C, Csiszar A, de Cabo R. Mechanisms underlying caloric restriction and life span regulation: implications for vascular aging. Circ Res 2008; 102:519-528.

 

     Lower body weight is associated with less oxidative stress. As weight increases, more fuel is required to support a larger body, which generates more free oxygen radicals.

 

van Mierlo LAJ, Arends LR, Streppel MT, Zeegers MPA, Kok FJ, Grobbee DE, et al. Blood pressure response to calcium supplementation: a meta-analysis of randomized controlled trials. J Hum Hypertens 2006;20:571-80.

 

     Meta-analysis of randomized trials showed a small but significant effect of calcium supplementation on blood pressure. Multiple points in the synthesis of NO are calcium dependent. In men with deficient calcium intake, increasing dietary calcium or taking supplements may aid NO synthesis.

 

Verit A, Savas M, Ciftci H, Aksoy N, Taskin A, Topal U. Assessment of the acute effects of tadalafil on the cardiovascular system based on examination of serum oxidative status and paraoxonase activity in men with erectile dysfunction: a preliminary study.

 

     At peak serum levels of tadalafil (Cialis), total serum antioxidants increased by 45%, serum oxidant oxidants declined 33%, and levels of paroxonase1 (PON1), an important HDL-associated antioxidant enzyme, increased by 50% over baseline. All of these changes were highly statistically significant (p < 0.001). PON1 appears to at least partially mediate many positive and negative atherogenic factors. Long-acting PDE-5 inhibitors such as tadalafil may therefore play a role in enhancing vascular as well as erectile health.

 

Wallerath T, Poleo D, Li H, Forstermann U. Red wine increases the expression of human endothelial nitric oxide synthase: a mechanism that may contribute to its beneficial cardiovascular effects. J Am Coll Cardiol 2003;41:471-8.

 

     The polyphenols in red wine are probably responsible for the French paradox and the increased longevity of people living in the southwestern part of France and Sardinia. Resveratrol is probably less important due to its lower concentration in wine than other polyphenols and because of its reduced bioavailability. Interestingly, the benefits of red wine are inconsistent. In one study German red wine did not produce the same vascular effect as French wine, and some regions of France produce wine with higher a content of polyphenols.

 

White JR, Case DA, McWhirter D, Mattison AM. Enhanced sexual behavior in exercising men. Arch Sex Behav 1990;19:193-209.

 

     In normal men, exercise led to increased sexual behavior.

 

Woodman CR, Muller, JM, Laughlin MH, Price, EM. Induction of nitric oxide synthase mRNA in coronary resistance arteries isolated from exercise-trained pigs. Am J Physiol 1997;273:H2575-9.

 

     Exercise training increased eNOS mRNA in coronary arteries.

 

Xiao YF, Sigg DC, Leaf A. The antiarrythmic effect of n-3 polyunsaturated fatty acids: modulation of cardiac ionic channels as a potential mechanism. J Membr Biol 2005; 206:141-154.

 

     Omega-3’s have a stabilizing effect on the heart muscle, which probably contributes to their known effect in decreasing sudden cardiac death.

 

Yang AL, Su CT, Lin KL, Chao JI, You HP, Lee SD. Exercise training improves insulin-induced and insulin-like growth factor-1-induced vasorelaxation in rat aortas. Life Sci 2006;79:2017-21.

 

     Exercise increased the sensitivity of NO production in response to insulin, manifested by increased eNOS expression and activity.

 

Yuan J, Hoang AN, Romero CA, Lin H, Dai Y, Wang R. Vacuum therapy in erectile dysfunction- science and clinical evidence. Int J Impot Res 2010; 22:211-219.

 

     This paper reviews the evidence for use of a vacuum device to improve erectile function. It has been used as a form of “penile rehabilitation” for men following surgery for prostate cancer.

 

Zorgniotti AW, Lizza EF. Effect of large doses of the nitric oxide precursor, l-arginine, on erectile dysfunction. Int J Impot Res 1994;6:33-35.

 

     In men with mild ED, a well-designed study showed a benefit with 5 gm daily of L-arginine.