Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: Pathophysiology and mechanism(s) of action

Authors


  • Dirk De Ridder led the review process.

  • Conflicts of interest: KEA, consultant for Eli Lilly and Company (Lilly) and Pfizer; WCdG, equity interest in Pfizer and consultant for Lilly; KTM, consultant, speaker honoraria, and research grants from Lilly/ICOS, Allergan; TFL, consultant for Lilly, Allergan, GSK, Watson, and speaker honoraria from Lilly, Watson and GSK; MM, consultant, speaker honoraria, clinical investigator and research grants from Lilly and Bayer-Schering, and fellowship or travel grants from Lilly; CGR, consultant and contractor for Lilly; JJW, consultant for Lilly and Pfizer, and speaker honoraria and clinical investigator for Pfizer; TM, acting as employee of Lilly via joint venture; LV, employee and equity interest in Lilly.

Abstract

Background

The PDE5 inhibitor tadalafil is investigation for the treatment of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). Several clinical studies of tadalafil and other PDE5 inhibitors have reported significant symptom reduction but limited urinary flow rate improvement. This manuscript reviews the published literature describing the pathophysiology of male LUTS, with an emphasis on mechanisms that may be modulated or improved by phosphodiesterase type 5 (PDE5) inhibition.

Methods

Literature (through March 2010) was obtained via Medline searches and from the individual reviewers files. Articles were selected for review based on describing in vitro, preclinical, or clinical studies of pathological processes contributing to LUTS, or possible effects of PDE5 inhibition in the lower urinary tract.

Results

Major mechanisms contributing to LUTS include: reduced nitric oxide/cyclic guanosine monophosphate signaling; increased RhoA kinase pathway activity; autonomic overactivity; increased bladder afferent activity; and pelvic ischemia. Tadalafil and other PDE5 inhibitors have demonstrated beneficial effects on smooth muscle relaxation, smooth muscle and endothelial cell proliferation, nerve activity, and tissue perfusion that may impact LUTS in men.

Conclusions

The pathophysiology of male LUTS is complex and not completely understood. LUTS may occur independently of BPH or secondary to BPH but in both cases involve obstructive or irritative mechanisms with substantial pathophysiological overlap. While the precise mechanism remains unclear, inhibition of PDE5 seems to have an effect on several pathways that may impact LUTS. Neurourol. Urodynam. 30:292–301, 2011. © 2011 Wiley-Liss, Inc.

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