Bartsch G, Rittmaster R S, Klocker H
Department of Urology, University of Innsbruck, Austria.
Eur Urol. 2000 Apr;37(4):367-80. doi: 10.1159/000020181.
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 dihydrotestosterone (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.
DHT is generated by reduction of testosterone. Two isoenzymes of 5alpha-reductase have been discovered. Type 1 is present in most tissues of the body where 5alpha-reductase is expressed and is the dominant form in sebaceous glands. Type2 5alpha-reductase is the dominant isoenzyme in genital tissues, including the prostate. Finasteride is a 5alpha-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 5alpha-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 5alpha-reductase. Suppression of both 5alpha-reductase isoenzymes with GI198745 result in greater and more consistent suppression of serum dihydrotestosterone than that observed with a selective inhibitor of type 2 5alpha-reductase. Physiological and clinical studies comparing dual 5alpha-reductase inhibitors, such as GI198745, with selective type 2, such as finasteride, will be needed to determine the clinical relevance of type 1 5alpha-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 human 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 meta-analysis 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 5alpha-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.
Clinical evaluation of potent dual 5alpha-reductase inhibitors may help define the relative roles of human type 1 and 2 5alpha-reductase in the pathophysiology of benign prostatic hyperplasia and other androgen-dependent diseases.
人类良性前列腺增生的发展显然需要睾丸雄激素和衰老共同作用。尽管雄激素作为人类良性前列腺增生病因的作用存在争议，但它们无疑至少起允许作用。主要的前列腺雄激素是二氢睾酮（DHT）。尽管在人类良性前列腺增生中DHT水平未升高，但随着年龄增长，尽管血浆睾酮水平下降，前列腺中的DHT水平仍保持在正常水平。
DHT由睾酮还原产生。已发现5α-还原酶的两种同工酶。1型存在于身体中表达5α-还原酶的大多数组织中，是皮脂腺中的主要形式。2型5α-还原酶是包括前列腺在内的生殖组织中的主要同工酶。非那雄胺是一种5α-还原酶抑制剂，已用于治疗良性前列腺增生和男性型秃发。在临床使用剂量下，其主要作用是通过抑制2型5α-还原酶，因为它对1型同工酶的亲和力低得多。非那雄胺可使血清中的DHT降低约70%，前列腺中的DHT降低多达85 - 90%。前列腺中剩余的DHT可能是1型5α-还原酶作用的结果。与2型5α-还原酶选择性抑制剂相比，用GI198745抑制两种5α-还原酶同工酶可使血清二氢睾酮得到更大且更一致的抑制。需要进行生理和临床研究，将GI198745等双重5α-还原酶抑制剂与非那雄胺等2型选择性抑制剂进行比较，以确定前列腺内1型5α-还原酶的临床相关性。已发表两项大型国际多中心III期试验，记录了非那雄胺治疗人类良性前列腺增生的安全性和有效性。综合这两项研究，可获得12个月的随机对照数据。也有来自部分选择继续药物治疗3年、4年或5年患者的这些数据的非对照扩展。长期使用非那雄胺进行药物治疗可减少急性尿潴留或手术等具有临床意义的终点事件。根据六项非那雄胺随机临床试验的荟萃分析，非那雄胺对前列腺大的男性最有效。一种更有效的1型和2型人5α-还原酶双重抑制剂可能比非那雄胺更大程度地降低循环中的DHT，并在治疗人类良性前列腺增生和其他依赖DHT的疾病状态方面显示出优势。
强效双重5α-还原酶抑制剂的临床评估可能有助于确定人类1型和2型5α-还原酶在良性前列腺增生和其他雄激素依赖性疾病病理生理学中的相对作用。
