Investigational agents for benign prostatic hyperplasia

This review focuses on the clinical evidence supporting three nonsurgical treatments for BPH/LUTS in development: phosphodiesterase type-5 inhibitors, the intraprostatic instillation of onabotulinumtoxinA (BTA [Botox]), and gonadotropin-releasing hormone (GnRH) antagonists.

Benign prostatic enlargement (BPE) results from this hyperplastic/proliferative process. For decades it was thought that BPE caused bladder outlet obstruction (BOO) via dynamic and static components. The dynamic component is due to the tone of the smooth muscle elements of the prostate, whereas the static component is due to anatomic obstruction. BOO promotes bladder dysfunction and thereby causes the sequelae of BPH: lower urinary tract symptoms (LUTS), urinary retention, detrusor instability, urinary tract infection, and renal insufficiency. Today, it is well recognized that this paradigm is an oversimplification for the clinical entity of LUTS/BPH.

Indications for treating BPH

The primary reason for treating BPH is to relieve bothersome LUTS. The AUA Symptom and Bothersome Indices are reliable and reproducible instruments for quantifying LUTS. The International Prostate Symptom Score (IPSS) consists of the AUA Symptom Index (AUA-SI) along with a single bothersome question. Symptom severity has been categorized as mild (score of 0-7), moderate (score of 8-18), and severe (score of >18) based on responses to the AUA-SI. Importantly, some men with severe symptoms may not be bothered at all, while others with mild symptoms may be incapacitated. Therefore, the decision to treat BPH/LUTS must be guided by bother and not simply the presence of symptoms.

The mechanism by which BPH causes LUTS is still poorly understood; while the concept that BPE causes BOO leading to LUTS was the foundation for alpha-blocker and 5-alpha-reductase inhibitor therapy, this is an oversimplification. There is little doubt that the prostate plays a central role in LUTS, since the majority of men experience dramatic improvement in symptoms following a transurethral or radical prostatectomy. However, the mere fact that there are alpha-receptors, LHRH receptors, nerve endings, phosphodiesterase, and 5-alpha-reductase in the prostate does not adequately explain the mechanism by which these therapies treat BPH.