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This Month's Question:

Phosphodiesterase type 5 (PDE5) inhibitors are an effective first-line oral therapy for erectile dysfunction (ED). Chronic use of PDE5 inhibitors has improved erectile function further and fostered endothelial rehabilitation. Lifestyle modification has improved erectile function and endothelial function and diminished markers of systemic vascular inflammation. What might persuade clinicians that PDE5 inhibitors plus lifestyle modification can improve erectile function and endothelial function in patients?

Response by Vivian A. Fonseca, MD, Posted 08/16/06:

PDE5 inhibitors not only effectively treat ED, but also have demonstrated favorable effects on endothelial dysfunction.^1,2 According to recent studies, chronic therapy with PDE5 inhibitors enhances erectile function more than on-demand therapy does³ and does not cause side effects.² Notably, in men with increased cardiovascular risk, chronic use of tadalafil imparts improvements in endothelial function that remain after discontinuation of therapy.⁴ Studies with patients with coronary artery disease⁵ and type 2 diabetes⁶ suggest that sildenafil improves endothelial function. Additionally, PDE5 inhibitors have demonstrated efficacy for treating ED in men with diabetes.⁷ Finally, PDE5 inhibitors have been found to be effective in the treatment of pulmonary hypertension, a serious condition with high mortality.^4,8,9

Endothelial dysfunction links ED and cardiovascular disease (CVD),³ and the severity of ED increases with the number of vascular risk factors.¹⁰ ED may serve as the first sign of endothelial damage in men with vascular risk factors and as the earliest clinical presentation of vascular comorbidities, such as hypertension, diabetes, and hyperlipidemia.¹⁰ CVD and ED share many common risk factors.⁸

Lifestyle risk factors associated with ED and CVD include obesity,^8,11,12 particularly when associated with the metabolic syndrome,^13,14 sedentary lifestyle,^8,12 and smoking.^8,11,12,15 Particularly among patients with diabetes, smoking has been shown to increase the risk of ED, with greater duration and intensity of the smoking habit conferring higher risk.¹⁶ Lifestyle modifications may improve sexual function and endothelial function among men in certain risk categories.¹⁷ Reduced calorie intake and increased exercise have been shown to improve erectile function in obese men by mitigating endothelial dysfunction and markers of systemic vascular disease.^7,13,17 Sedentary men may reduce their risk of ED by beginning regular exercise at a level of at least 200 kcal/day, which corresponds to a brisk 2-mile walk.¹³ In a study by Esposito and colleagues, about one third of obese men with ED regained sexual function after 2 years of following such lifestyle modifications.¹³ These findings correspond with epidemiologic data demonstrating that physical activity is associated with a 30% lower risk of ED, whereas obesity is associated with a 30% higher risk of ED.^13,17

Endothelial progenitor cells (EPCs) from bone marrow proliferate and differentiate into endothelial cells that support endothelial repair and neovascularization.^18,19 Studies have demonstrated that administration of either vardenafil or tadalafil significantly raises the number of circulating EPCs.¹ Additional studies are examining whether long-term use of PDE5 inhibitors improves biochemical markers of endothelial dysfunction.⁷ Increasing EPCs may offer vascular protection against initiation and progression of endothelial dysfunction.¹ Higher EPC levels are associated with fewer cardiovascular events, and because CVD and ED are linked by endothelial dysfunction, these findings are clinically relevant for patients with ED.¹

In summary, PDE5 inhibitor therapy and lifestyle modification may improve endothelial function for men with ED, thus contributing to improved sexual function and overall health. PDE5 inhibitors enhance endothelial function by increasing the number of circulating EPCs, which promote endothelial repair.¹

References

1. Foresta C, Ferlin A, De Toni L, et al. Circulating endothelial progenitor cells and endothelial function after chronic tadalafil treatment in subjects with erectile dysfunction. Int J Impot Res. In press.

2. Schwarz ER, Kapur V, Rodriguez J, Rastogi S, Rosanio S. The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems. Int J Impot Res. In press.

3. Sommer F, Schulze W. Treating erectile dysfunction by endothelial rehabilitation with phosphodiesterase 5 inhibitors. World J Urol. 2005;23:385-392.

4. 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.

5. Halcox JPJ, Nour KRA, Zalos G, et al. The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Cardiol. 2002;40:1232-1240.

6. Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA. Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes Care. 2002;25:1336-1339.

7. Fonseca V, Jawa A. Endothelial and erectile dysfunction, diabetes mellitus, and the metabolic syndrome: common pathways and treatments? Am J Cardiol. 2005;96(suppl):13M-18M.

8. Kloner RA. Erectile dysfunction and cardiovascular risk factors. Hosp Pract. 2001;36:41-51.

9. Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001;104:1218-1222.

10. Kendirci M, Nowfar S, Hellstrom WJG. The impact of vascular risk factors on erectile function. Drugs Today. 2005;41:65-74.

11. Barrett-Connor E. Cardiovascular risk stratification and cardiovascular risk factors associated with erectile dysfunction: assessing cardiovascular risk in men with erectile dysfunction. Clin Cardiol. 2004;27(suppl 1):I-8–I-13.

12. Nusbaum MRH. Erectile dysfunction: prevalence, etiology, and major risk factors. J Am Osteopath Assoc. 2002;102:S1-S6.

13. Esposito K, Giugliano D. Obesity, the metabolic syndrome, and sexual dysfunction. Int J Impot Res. 2005;17:391-398.

14. Matfin G, Jawa A, Fonseca VA. Erectile dysfunction: interrelationship with the metabolic syndrome. Curr Diab Rep. 2005;5:64-69.

15. Lewis RW, Fugl-Meyer KS, Bosch R, et al. Epidemiology/risk factors of sexual dysfunction. J Sex Med. 2004;1:35-39.

16. Bortolotti A, Fedele D, Chatenoud L, et al. Cigarette smoking: a risk factor for erectile dysfunction in diabetics. Eur Urol. 2001;40:392-397.

17. Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA. 2004;291:2978-2984.

18. Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353:999-1007.

19. Foresta C, Lana A, Cabrelle A, et al. PDE-5 inhibitor, vardenafil, increases circulating progenitor cells in humans. Int J Impot Res. 2005;17:377-380.