Future Strategies

Medical therapies provide improvement over watchful waiting for most patients (Hutchison et al 2007). The therapeutic response to medical therapy is less than that of prostatectomy. As Clifford and Farmer (2000) noted in a meta-analysis of α-adrenergic blocker and finasteride studies, “neither finasteride nor α-blockers approach the efficacy of prostatic surgery in terms of improvement in either symptoms or flow rates….” Therefore opportunities exist to develop novel strategies that may be more effective than existing therapies. The development of “pharmacogenetics” and molecular biologic testing may allow “personalized” medication so that α_1A-adrenergic receptor–predominant men get tamsulosin and α_1D-adrenergic receptor–predominant men get naftopidil, for instance. Developing different classes of drugs to relax smooth muscle and further targeting nonprostatic factors are further potential opportunities.

Endothelins are potent vasoconstrictors. Langenstroer and associates (1993) reported that human prostate contains endogenous endothelin and that endothelin elicits a very potent contraction in the human prostate. The contractile response elicited by endothelin in the human prostate is not abolished by pretreatment with selective α₁-adrenergic blockers. These observations suggest that relaxation of prostatic smooth muscle in BPH may also be achieved by endothelin antagonists. The pharmaceutical industry is actively engaged in efforts to synthesize selective endothelin antagonists. Kobayashi and colleagues (1994) have characterized the binding properties of endothelin receptor subtypes in the human prostate. Both endothelin-A and endothelin-B receptors are present in the human prostate. These receptors are localized primarily in the stroma and glandular epithelium, respectively. Preliminary studies suggest that both types of endothelin receptors mediate the tension of prostate smooth muscle. Endothelin antagonists may emerge as another treatment for BPH.

It is generally assumed that the clinical manifestations of BPH are the result of BOO. Therefore pharmacologic strategies have been directed toward reducing BOO. Several observations suggest that nonprostatic factors may also contribute to clinical BPH. The severity of clinical prostatism as captured by symptom scores is poorly correlated with measurement of BOO. In addition, the changes in symptom scores after therapy for BPH are poorly correlated with changes in PFR and obstruction grade. The discordance between symptom severity and measures of obstruction suggests that nonprostatic factors may be contributing to clinical BPH. Clearly several factors including aging, the hormonal milieu, nonurologic diseases, and prostatic growth affect bladder morphometry, neurologic innervation, BOO, and renal function, and these factors collectively contribute to clinical BPH. Our present understanding of the pathophysiology of clinical BPH is rudimentary. It is therefore imperative to develop a more comprehensive understanding of the pathophysiology of symptoms. This knowledge will result in more effective use of existing therapies and will provide the rationale for the next generation of therapeutic modalities.

Key Points

Evaluation and Nonsurgical Management of Benign Prostatic Hyperplasia

• Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms (LUTS) in men beyond middle age.

• Evaluation requires a history and symptom score (IPSS) and a careful physical examination including a digital rectal examination.

• Uroflowmetry and ultrasound estimation of PVR urine volume are often helpful, and determination of the PSA level is requested when a diagnosis of prostate cancer would alter the management of the individual patient.

• Medical therapy is now the usual first-line management of uncomplicated BPH with either an α-adrenergic receptor blocker or (if the prostate is large) a 5α-reductase inhibitor.

• Combination therapy with both an α-adrenergic receptor blocker and a 5α-reductase inhibitor has been demonstrated to be the most effective means of preventing disease progression and seems likely to become the standard of care in appropriate cases.

• Antimuscarinic agents and PDEIs are useful adjuncts for men with “storage” symptoms or ED. Their true importance will become clearer with time.