Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia

Objective: The development of the human benign prostatic hyperplasia clearly requires a combination of testicular androgens and aging. Although the role of androgens as the causative factor for human benign prostatic hyperplasia is debated, they undoubtedly have at least a permissive role. The principal prostatic androgen is dihydrotestoaterone (DHT). Although not elevated in human benign prostatic hyperplasia, DHT levels in the prostate remain at a normal level with aging, despite a decrease in the plasma testosterone. Results: DHT is generated by reduction of testosterone. Two isoenzymes of 5 alpha-reductase have been discovered. Type 1 is present in most tissues of the body where Sa-reductase is expressed and is the dominant form in sebaceous glands. Type2 5 alpha-reductase is the dominant isoenzyme in genital tissues, including the prostate. Finasteride is a 5 alpha-reductase inhibitor that has been used for the treatment of benign prostatic hyperplasia and male-pattern baldness. At doses used clinically, its major effect is through suppression of type 2 5 alpha-reductase, because it has a much lower affinity for the type 1 isoenzyme. Finasteride suppresses DHT by about 70% in serum and by as much as 85-90% in the prostate. The remaining DHT in the prostate is likely to be the result of type 1 Scc-reductase. Suppression of both 5 alpha-reductase isoenzymes with G1198745 result in greater and more consistent suppression of serum dihydrotestosterone than that observed with a selective inhibitor of type 2 5 alpha-reductase. Physiological and clinical studies comparing dual 5 alpha-reductase inhibitors, such as G1198745, with selective type 2, such as finasteride, wi II be needed to determine the clinical relevance of type 1 5 alpha-reductase within the prostate. Two large international multicenter, phase III trials have been published documenting the safety and efficacy of finasteride in the treatment of hu man benign prostatic hyperplasia. Combining these two studies, randomized, controlled data are available for 12 months. Noncontrolled extension of these data from a subset: of patients, who elected to continue drug treatment for 3, 4 or 5 years, are also available. Long-term medical therapy with finasteride can reduce clinically significant endpoints such as acute urinary retention or surgery. According to the metaanalysis of six randomised clinical trial with finasteride, finasteride is most effective in men with large prostates. A more effective dual inhibitor of type 1 and 2 human 5 alpha-reductase may lower circulating DHT to a greater extent than finasteride and show advantages in the treatment of human benign prostatic hyperplasia and other disease states that depend on DHT. Conclusion: Clinical evaluation of potent dual Su-reductase inhibitors may help define the relative roles of human type 1 and 2 5 alpha-reductase in the pathophysiology of benign prostatic hyperplasia and other androgen-dependent diseases. Copyright (C) 2000 S. Karger AG, Basel.