Introduction: 5-Alpha-Reductase Inhibition in the Treatment of LUTS and BPH: Update and Importance of Dual Inhibition of Types 1 and 2
INTRODUCTION 5-Reductase Inhibition in the Treatment of LUTS and BPH: Update and Importance of Dual Inhibition of Types 1 and 2 Claus G. Roehrborn, MD Supplement Editor, 5-Reductase Inhibition in the Treatment of LUTS and BPH: Update and Importance of Dual Inhibition of Types 1 and 2; Department of Urology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX [Rev Urol. 2004;6(suppl 9):S1-S2] © 2004 MedReviews, LLC he articles in this supplement issue of Reviews in Urology illuminate the role of one pivotal metabolic step in the etiology and pathophysiology of benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS), and specifically the 2 isoenzymes catalyzing this step: the conversion of the main androgenic steroid testosterone to dihydrotestosterone (DHT) by the 5-reductase isoenzymes Types 1 and 2. The presence of functioning testes at the time of puberty together with the aging process is undoubtedly a prime condition for the development of histologic hyperplasia of the prostate, or BPH. Interesting anthropomorphic studies have demonstrated the permissive role of androgens in the past century, none more convincing than the examination of elderly eunuchs serving at the Imperial Palace, the Forbidden City, in Beijing. These men were castrated prior to puberty, and after the fall of the last emperor, foreign physicians were given access to some of these eunuchs, verifying that indeed none of them had any perceptible prostate enlargement or any palpable prostate tissue. Clearly, the growth of the prostate under the influence of androgenic steroids alone is not enough to create the conditions commonly referred to as LUTS, most often associated with BPH. As Dr. Lepor elegantly points out, there is no direct correlation between prostate size or growth and presence or severity of symptoms, and in fact there are similar symptoms found both in women and in men after a total prostatectomy. Nonetheless, the enlarged prostate is as much part of the LUTS/BPH complex as the bothersome, irritative, and obstructive symptoms that prompt men to seek medical attention in the first place. T VOL. 6 SUPPL. 9 2004 REVIEWS IN UROLOGY S1 Introduction continued It took an experiment of nature, a genetic defect, to unravel some of the mysteries surrounding intraprostatic androgen metabolism. The fascinating review by Dr. Marks illustrates the scientific path, starting with the recognition of a group of individuals affected by a congenital absence of the enzyme 5-reductase, located in the prostate and responsible for the conversion of testosterone to dihydrotestosterone. These individuals are phenotypically female, but genetic XY males, and at the time of puberty the functioning testes produce enough testosterone that the enzymatic block is overcome and virilization, and thus a gender assignment change, takes place. It took nearly another decade to learn that in fact 2 isoenzymes are present in the human body. Type 1 is most prevalent in the liver and the skin, with minimal amounts found in the prostate, whereas Type 2 is most prevalent in the prostate. Coincidentally, the first drug developed to mimic this genetic defect, finasteride, exclusively inhibited Type 2 5-reductase, and thus proved to be an effective drug in the treatment of BPH by shrinking the S2 VOL. 6 SUPPL. 9 2004 prostate, alleviating the symptoms, and preventing outcomes such as retention of urine and need for surgery. A second compound, dutasteride, was developed as a non-specific dual inhibitor of both isoenzymes Type 1 and 2, and, as expected, it proved to reduce serum DHT by more than 90% in contrast to the 70% reduction induced by finasteride. Intraprostatic DHT was reduced to an even greater degree. The phase III trial program and a direct comparative study verified that dutasteride was indeed at least equally as effective as finasteride in terms of improvement in symptoms, flow rate, and prevention of retention and need for surgery, with an earlier onset of improvement in some of the measured parameters. Of note was the finding that after the first 2 years on the drug there was an ongoing and sustained improvement in both symptoms and flow rate in the patients treated for an additional 2 years with dutasteride, as elaborated by Dr. Nickel and me in this supplement. Dutasteride was found to be well tolerated and efficacious at 48 months, suggesting that it is an effective long-term treatment for men with symptomatic BPH. A potential expla- REVIEWS IN UROLOGY nation for this phenomenon could be the fact that patients were chosen to have a prostate volume of at least 30 mL and a prostate-specific antigen level of > 1.5 ng/mL (ie, patients who are likely to respond favorably to 5-reductase therapy). As Dr. Kuritzky points out, the aging of the population and the large number of men presenting with LUTS and BPH to healthcare providers underscores the need for primary care providers, family physicians, and internists to evaluate these patients and provide therapy for them based on a rational assessment of their presentation. The AUA guidelines, as discussed by Dr. Kaplan, and readily available nomograms, discussed by Drs. Slawin and Kattan, should help physicians choose appropriate patients for a watchful waiting strategy (ie, those with little risk for progression), for monotherapy with an -blocker or a 5-reductase inhibitor, or for combination medical therapy. It is our hope that this supplement, with contributions from some of the most prominent opinion leaders in the field of LUTS and BPH, will be helpful to those managing such patients in their daily practice.