Tadalafil for the Treatment of Benign Prostatic Hyperplasia: When the Moment Does Not Add Up

Abstract

Over the past few years, the urologic literature has been replete with clinical studies suggesting that phosphodiesterase type 5 inhibitors (PDE5-Is) improve lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). More recently, tadalafil, a drug widely used to treat erectile dysfunction (ED), has gained regulatory approval for the treatment of men with BPH [1–3]. However, enthusiasm for tadalafil has been diminished by the lack of objective improvement (ie, maximum flow rate [Qmax]). In addition, urodynamic parameters did not change. This lack of objective change is common to all currently approved drugs used to treatmale LUTS, including a-blockers, 5a-reductase inhibitors, and antimuscarinic agents. Furthermore, no overarching scientific rationale has been presented to coherently explain the disconnect between subjective and objective findings. In this month’s edition of European Urology, Giuliano et al. present a scholarly review that proposes putative mechanisms of action for PDE5-Is, including localization of phosphodiesterase type 5 (PDE5) isoenzymes throughout the lower urinary tract [4]. This localization results in smooth muscle relaxation, improved bladder and prostate tissue oxygenation, and alterations and modulation in afferent activity in animal bladder models. Taken in toto, these proposed mechanisms of action suggest that smooth muscle relaxation along the lower urinary tract and, more specifically, at the bladder neck, prostate, and urethra leads to improved LUTS secondary to BPH. What I found striking is that in many of the same experiments, receptor localization and conclusions have been touted for a-blockers, yet a-blockers in the treatment of BPH–LUTS do result in objective improvement. Stated otherwise about PDE5-Is for BPH, if it walks like a duck and talks like a duck, how come it isn’t a duck? Moreover, it is troubling that there seems to be a continuation of unsupported scientific rationales and excuses for why tadalafil is the only drug approved for BPH that does not lead to objective improvement. Disavowing the clinical correlation between Qmax and symptoms or debating their clinical relevance is not an explanation, it is an excuse. What has been troubling about the PDE5 story is that, frankly, there is no story to explain this discrepancy between subjective and objective findings. The authors propose a panoply of sites in the lower urinary tract where PDE5 isoenzymes exist and may work, but ultimately, where is the sweet spot? Do they work on the bladder? That is unlikely, given that both storage symptoms, albeit minimally, and voiding symptoms improvewith tadalafil, as opposed to antimuscarinic agents, which only alleviate storage symptoms. Do PDE5 isoenzymes work on the prostate? If so, then why doesn’t flow rate increase or detrusor pressure at maximum flow decrease? Even antimuscarinics result in urodynamic changes. A third possibility is that, in fact, these drugs do not work to improve LUTS. The purported changes in symptoms may be driven by trial design rather than by actual physiologic effect. Given that these agents improve erectile function, there may be a compromise to patients being unblinded, that is, when a man notices that his erections improve, he would bemore likely to suspect that he is on the active drug. Moreover, a clinical trial giving free tadalafil for a minimum of 3 mo may be a powerful force for creating new-onset LUTS. E U RO P E AN URO L OG Y 6 3 ( 2 0 1 3 ) 5 1 7 – 5 2 0