Lower urinary tract symptoms and erectile dysfunction: a role for PDE-5 inhibitors?

Abstract

It is well established that lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are multifactorial and involve many pathophysiologic mechanisms. Until recently, the association between LUTS and ED has been attributed to the age link with a huge impact in the QoL at older ages. However, a large variety of large-scale epidemiological studies documented an age-independent relationship between LUTS and ED leading to a new research paradigm in search for the causal link. In fact, the MSAM-7 study (Multinational Survey of The Aging Male) revealed that erection problems (IIEF validated) were significantly more common in men with LUTS, and were strongly related to the severity of LUTS (IPSS validated), independently of the effects of age and other comorbidities. However, even if there is a link between LUTS and ED from an epidemiological perspective, the fact is that the causal relationship must be shown to have biological plausibility before acceptance is possible. Four pathophysiological mechanisms currently support this relationship: • The Nitric Oxide Synthase (NOS) / nitric oxide (NO) theory • Reduction in the NOS-containing nerves in the prostate, bladder and penis (in the presence of common risk factors for ED), suggests a possible increase in smooth muscle cell proliferation which may result in structural changes in the prostate and bladder leading to LUTS. • The autonomic hyperactivity and metabolic syndrome hypothesis • LUTS as a part of the metabolic syndrome which includes glucose intolerance, insulin resistance, obesity, dyslipidaemia and hypertension, all known risk factors for ED. These factors are associated with an increased sympathetic activity that can be involved in prostate growth, LUTS and DE with noradrenaline representing the common link. • The Rho-kinase activation/endothelin pathway • Increased Rho-kinase activity upregulates smooth muscle tone. Endothelin (a potent vasoconstrictor), is possibly involved in the increased smooth muscle activity found in both LUTS and ED and is dependent on Rhokinase activity that acts downstream from these receptors. • Pelvic atherosclerosis • Pelvic ischaemia can induce fibrosis, smooth muscle atrophy and non-compliance of the bladder. It also results in stromal fibrosis, glandular cystic atrophy and increases in smooth muscle contractility of the prostate, and penile fibrosis in the corpus cavernosum tissue. The increased production of TGF-s1 impairs neurogenic relaxation of the prostate and erectile tissue, involving a downregulation of the NO pathway. Recent studies suggest that PDE-5 inhibitors (PDE5-I) might have a beneficial effect on LUTS probably through the NO pathway. Under this treatment, both the International Prostatic Symptom Score (IPSS) and the International Index of Erectile Function (IIEF) improved from baseline. As NO and PDE5 enzymes have been identified in the human prostate, the improvement of both LUTS and ED might be mediated by an increased NO activity which leads to smooth muscle cell relaxation. Although placebo-controlled trials are needed to confirm the impact of these drugs on both LUTS and ED, the preliminary results reinforce the need for a common approach to managing these two highly prevalent and bothersome conditions.