Is erectile dysfunction a low-grade systemic inflammatory condition?

Low-grade systemic inflammation is present in insulin resistance, obesity, type 2 diabetes mellitus, hypertension, hyperlipidaemia, and metabolic syndrome X, which predispose to the development of coronary heart disease (CHD),1,2 conditions in which endothelial dysfunction is present, implying that reduced production of nitric oxide (NO) by endothelial cells could be a common denominator. NO, produced by endothelial cells, is responsible for penile erection. Hence, obesity, type 2 diabetes mellitus, hypertension, hyperlipidaemia, and metabolic syndrome X are likely to be associated with erectile dysfunction. The findings of Montorsi et al.3 and Vlachopoulos et al.4 are not only in support of this but also suggest that erectile dysfunction could be a disease of low-grade systemic inflammation. Increase in the levels of inflammatory markers—high-sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), IL-1β, tumour necrosis factor-α (TNF-α), endothelial-prothrombotic markers/mediators, von-Willebrand factor (vWF), tissue plasminogen factor (tPA), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen noted in patients with erectile dysfunction4—suggests that low-grade systemic inflammation is present in these subjects, similar to those seen in insulin resistance, obesity, type 2 diabetes mellitus, hypertension, hyperlipidaemia, and metabolic syndrome X. These findings coupled with the observation that there is a close association between erectile dysfunction and coronary artery disease3 indicate that all these diseases are due to decreased endothelial NO (eNO) generation. Oral phosphodiesterase-5 inhibitor tadalafil, used for the treatment of erectile dysfunction, significantly decreased hypoxia-induced upregulation of TNF-α and IL-1β expression in pulmonary artery,5 indicating that NO has anti-inflammatory actions. Ageing is associated with decreased expression of eNO synthase (eNOS) and vascular endothelial growth factor (VEGF), whereas that of endothelin-1, a potent vasoconstrictor, increased.6 VEGF increases the ability of endothelial cells to produce NO,7 and its stimulatory effect on penile erection involves phosphorylated eNOS.8 Furthermore, VEGF enhances prostacyclin (PGI2) production,9 eNO overexpression attenuates myocardial reperfusion injury, and VEGF is essential for NO-mediated angiogenesis.10 These evidences suggest that a co-ordinated expression and synthesis of eNO, VEGF, and PGI2 and suppression of TNF-α, IL-1, endothelin-1, and other pro-inflammatory molecules are essential to prevent erectile dysfunction, which calls for healthy endothelium. It is likely that under normal physiological conditions, a balance is maintained between pro- and anti-inflammatory molecules such that optimal NO, PGI2, and VEGF production occurs to prevent erectile dysfunction and to ensure normal blood flow to vital organs, including heart. When endothelial cells fail to produce adequate amounts of NO, PGI2, and VEGF, it could lead to increased secretion of endothelin-1, free radicals (normally NO quenches superoxide anion, whereas excess free radicals inactivate NO and PGI2), and pro-inflammatory cytokines (since NO suppresses the production of TNF, and IL-1) and decreased production and action of VEGF that impair vasodilatation and angiogenesis and cause erectile dysfunction. Hence, measurement of NO, PGI2, VEGF, hsCRP, IL-6, IL-1β, TNF-α, vWF, tPA, PAI-1, and fibrinogen in subjects who are at high risk of developing insulin resistance, type 2 diabetes mellitus, hypertension, hyperlipidaemia, and metabolic syndrome X and those with erectile dysfunction may help early detection of low-grade systemic inflammation and in the prevention, prediction, and prognosis of CHD.