Historical Overview of Medical Therapy for Benign Prostatic Hyperplasia

The treatment of benign prostatic hyperplasia (BPH) has undergone tremendous re-evaluation over the last decade. The seeds for medical therapy were planted in the late 1960s and early 1970s, as single-center, small, uncontrolled studies suggested a role for α-blockers and hormonal therapy for the treatment of BPH. In 1976, Caine and associates reported on the efficacy of α-adrenergic blockers in the treatment of BPH, but it was not until the late 1980s that randomized, double-blind, multicenter, placebo-controlled studies reported the safety and effectiveness of 5α-reductase inhibitors and α1-blockers for the treatment of BPH. These studies demonstrated that both therapies were well tolerated and that α1-blockers were generally more effective. Reported in 1996, the Veterans Affairs Cooperative Studies Benign Prostestic Hyperplasia Study was the first study to compare an α1-blocker (terazosin), a 5α-reductase inhibitor (finasteride), and combination therapy with both drugs to placebo. Terazosin was shown to be significantly more effective in improving lower urinary tract symptoms (LUTS) and increasing peak urinary flow rates compared to placebo or finasteride. In this study, the combination arm did not prove to be superior to terazosin alone. Although the effect of terazosin on symptoms and flow rate was independent of prostate volume, finasteride-treated patients exhibited clinically relevant symptomatic improvement only in a subset of men with larger prostates. However, even in those patients, terazosin alone was more effective compared to finasteride. Another important study in the treatment of BPH was the Proscar Long-Term Efficacy and Safety Study (PLESS), which was sponsored by Merck & Co and reported its initial results in 1996. This large-scale, long-term (4 year), multicenter, randomized, double-blind, placebo-controlled trial demonstrated that the modest efficacy of finasteride was durable and that finasteride decreased the probability of developing acute urinary retention and the requirement for surgical intervention. Several randomized, placebo-controlled studies were subsequently conducted in the United States in the mid-1990s, investigating tamsulosin (Flomax®, Boerhinger Ingelheim, Ridgefield, CT), one of the four α1-blockers that have been extensively investigated for the treatment of BPH. These studies represented the foundation for the U.S. Food and Drug Administration's approval of tamsulosin for the treatment of BPH in 1997. Boehringer Ingelheim subsequently entered into a licensing agreement with Yamanouchi Pharmaceuticals to market tamsulosin in the United States. Tamsulosin is currently the most widely prescribed medical therapy for the treatment of BPH in the United States and throughout the world. There is a significant database supporting the short-term and long-term safety and effectiveness of tamsulosin for the treatment of BPH. Tamsulosin has unique clinical properties that are related to its slow release formulation and modest receptor subtype selectivity. Tamsulosin has no clinically significant effect on blood pressure. Therefore, there is no need to titrate tamsulosin to a clinically effective dose. Tamsulosin has been shown to be extraordinarily well tolerated at clinically effective doses. The European Prospective European Doxazosin and Combination Therapy (PREDICT) study, reported in January 2003, comparing the α1-receptor blocker, doxazosin, to finasteride monotherapy, combination therapy, and placebo, reported similar findings. In this study, the prostate volume was not assessed by ultrasound or MRI, doxazosin was superior to placebo and finasteride, and the combination therapy arm did not prove to be superior compared to the arm treated with doxazosin alone. In the mid-1990s, the National Institutes of Health initiated a 7-year, randomized, double-blind, placebo-controlled study examining how medical therapy influences the natural history of BPH. The Medical Therapy of Prostate Symptoms (MTOPS) study was completed in April 2002. MTOPS provides important insights into the long-term effectiveness of α1-blockers and 5α-reductase inhibitors, and also answers the question of whether—in the entire population or a subset of the population—combination therapy with α1-blockers and 5α-reductase inhibitors is superior concerning an improvement in lower urinary tract symptoms (LUTS), peak flow rates, and/or in the prevention of outcomes. Further, the study sheds light on the natural history of BPH disease progression by providing 5-year data on the placebo-treated cohort. Given these new data, we feel that the timing is optimal to prepare a supplement to Reviews in Urology addressing medical therapy of BPH for the urological community. In the 1990s, BPH was a disease that received tremendous attention and the concept of nonsurgical management became widely accepted. The urological community is no longer bombarded with information on the topic of BPH. We hope the urological community finds this state-of-the-art review by internationally recognized experts in the field to be informative and clinically applicable. We are grateful for the generous support provided by Boehringer Ingelheim to bring a group of experts together to discuss and debate issues related to medical management of BPH. We are also indebted to MedReviews for organizing the opinion leader roundtable meeting and for preparing the supplement. We hope the readership of Reviews in Urology finds the proceedings of the expert opinion roundtable meeting focusing on medical therapy of BPH to be an informative and useful reference.