臨床泌尿器科66巻7号

2012年06月発行

セミナー テストステロンを再考する・2

テストステロンと5α還元酵素

著者： 前田高宏¹ 菊地栄次¹ 大家基嗣¹

所属機関： ¹慶應義塾大学医学部泌尿器科

ページ範囲：P.495 - P.502

文献概要

要約　男性ホルモン（アンドロゲン）は，性の分化をはじめ，さまざまな生理作用を有する。体内で最も豊富なアンドロゲンであるテストステロンは5α還元酵素を介し，より生理活性の強いDHTに変換される。本稿では，5α還元酵素が先天的に部分欠損した，先天性5α還元酵素欠損症の病態について述べるとともに，本邦において近年使用が可能になった2種類の5α還元酵素阻害剤の日常臨床における役割およびその治療効果について概説する。

参考文献

1）Federman DD：The biology of human sex differences. N Engl J Med 354：1507-1514, 2006

2）Saartok T, Dahlberg E and Gustafsson JA：Relative binding affinity of anabolic-androgenic steroids：comparison of the binding to the androgen receptors in skeletal muscle and in prostate, as well as to sex hormone-binding globulin. Endocrinology 114：2100-2106, 1984

3）Mendonca BB, Domenice S, Arnhold IJ, et al：46, XY disorders of sex development（DSD）. Clin Endocrinol 70：173-187, 2009

4）Schneider JJ and Horstmann PM：Effects of incubating desoxycorticosterone with various rat tissues. J Biol Chem 191：327-338, 1951

5）Tomkins GM：The enzymatic reduction of delta 4-3-ketosteroids. J Biol Chem 225：13-24, 1957

6）Wilson JD：Recent studies on the mechanism of action of testosterone. N Engl J Med 287：1284-1291, 1972

7）Imperato-McGinley J, Guerrero L, Gautier T, et al：Steroid 5α reductase deficiency in man：an inherited form of male pseudohermaphroditism. Science 186：1213-1215, 1974

8）Russell DW and Wilson JD：Steroid 5α-reductase：two genes/two enzymes. Annu Rev Biochem 63：25-61, 1994

9）Uemura M, Tamura K, Chung S, et al：Novel 5α-steroid reductase（SRD5A3, type-3）is overexpressed in hormone refractory prostate cancer. Cancer Sci 99：81-86, 2008

10）Cantagrel V, Lefeber DJ, Ng BG, et al：SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell 142：203-217, 2010

11）Sasaki G, Nakagawa K, Hashiguchi A, et al：Giant seminoma in a patient with 5 alpha-reductase type 2 deficiency. J Urol 169：1080-1081, 2003

12）Sasaki G, Ogata T, Ishii T, et al：Micropenis and the 5alpha-reductase-2（SRD5A2）gene：mutation and V89L polymorphism analysis in 81 Japanese patients. J Clin Endocrinol Metab 88：3431-3436, 2003

13）Sinnecker GH, Hiort O, Dibbelt L, et al：Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency. Am J Med Genet 63：223-230, 1996

14）Vilain E, Sarafoglou K and Yehya N：Disorders of sex development. In：Pediatric Endocrinology and Inborn Errors of Metabolism. edited by Sarafoglou K, Hoffmann GF, Roth KS. McGraw-Hill, New York, pp 545-546, 2008

15）Houk CP, Hughes IA, Ahmed SF, et al：Summary of consensus statement on intersex disorders and their management. International Intersex Consensus Conference. Pediatrics 118：753-757, 2006

16）Sudduth SL and Koronkowski MJ：Finasteride：the first 5 alpha-reductase inhibitor. Pharmacotherapy 13：309-325, 1993

17）McConnell JD, Wilson JD, George FW, et al：Finasteride, an inhibitor of 5alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab 74：505-508, 1992

inhibitor of 5α-reductase isozyme enzymatic activity in the human prostate. J Urol 161：332-337, 1999

19）Azzouni F, Godoy A, Li Y, et al：The 5 alpha-reductase isozyme family：a review of basic biology and their role in human diseases. Adv Urol.［Epub Dec 25, 2011］

20）Clark RV, Hermann DJ, Cunningham GR, et al：Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5 alpha-reductase inhibitor. J Clin Endocrinol Metab 89：2179-2184, 2004

21）Andriole GL, Humphrey P, Ray P, et al：Effect of the dual 5α-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer. J Urol 172：915-919, 2004

22）Moore RJ, Gazak JM, Quebbeman JF, et al：Concentration of dihydrotestosterone and 3α-androstanediol in naturally occurring and androgen-induced prostatic hyperplasia in the dog. J Clin Invest 64：1003-1010, 1979

23）Wenderoth UK, George FW, and Wilson JD：The effect of a 5α-reductase inhibitor on androgen-mediated growth of the dog prostate. Endocrinology 113：569-573, 1983

24）McConnell JD, Roehrborn CG, Bautista OM, et al：The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 349：2387-2398, 2003

25）Roehrborn CG, Siami P, Barkin J, et al：The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia：4-year results from the combat study. Eur Urol 57：123-131, 2011

26）Essah PA, Wickham EP 3rd, Nunley JR, et al：Dermatology of androgen-related disorders. Clin Dermatol 24：289-298, 2006

27）Rathnayake D and Sinclair R：Male androgenetic alopecia. Expert Opin Pharmacother 11：1295-1304, 2010

28）Thiboutot D：Acne：hormonal concepts and therapy. Clin Dermatol 22：419-428, 2004

29）Moghetti P, Tosi F, Tosti A, et al：Comparison of spironolactone, flutamide, and finasteride efficacy in the treatment of hirsutism：a randomized, double blind, placebo-controlled. J Clin Endocrinol Metab 85：89-94, 2000

30）Drake L, Hordinsky M, Fiedler V, et al：The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. J Am Acad Dermatol 41：550-554, 1999

31）Olsen EA, Hordinsky M, Whiting D, et al：The importance of dual 5α-reductase inhibition in the treatment of male pattern hair loss：results of a randomized placebo controlled study of dutasteride versus finasteride. J Am Acad Dermatol 55：550-554, 1999

32）Thompson IM, Goodman PJ, Tangen CM, et al：The influence of finasteride on the development of prostate cancer. N Engl J Med 349：215-224, 2003

33）Andriole GL, Bostwick DG, Brawley OW, et al：Effect of dutasteride on the risk of prostate cancer. N Engl J Med 362：1192-1202, 2010

34）Theoret MR, Ning YM, Zhang JJ, et al：The risks and benefits of 5α-reductase inhibitors for prostate-cancer prevention. N Engl J Med 365：97-99, 2011

35）Fleshner NE, Lucia MS, Egerdie B, et al：Dutasteride in localised prostate cancer management：the REDEEM randomised, double-blind, placebo-controlled trial. Lancet. 2012 Jan 23.［Epub ahead of print］

36）Andriole G, Lieber M, Smith J, et al：Treatment with finasteride following radical prostatectomy for prostate cancer. Urology 45：491-497, 1995

37）Perrotti M, Jain R, Abriel LM, et al：Dutasteride monotherapy in men with serologic relapse following radical therapy for adenocarcinoma of the prostate：a pilot study. Urol Oncol. 2010 Aug 25.［Epub ahead of print］

38）Shah SK, Trump DL, Sartor O, et al：Phase Ⅱ study of Dutasteride for recurrent prostate cancer during androgen deprivation therapy. J Urol 181：621-626, 2009

39）Tay MH, Kaufman DS, Regan MM, et al：Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate. Ann Oncol 15：974-978, 2004

40）Taplin ME, Regan MM, Ko YJ, et al：Phase Ⅱ study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res 15：7099-7105, 2009

41）Roehrborn CG, Lee M, Meehan A, et al：Effects of finasteride on serum testosterone and body mass index in men with benign prostatic hyperplasia. Urology 62：894-899, 2003

42）Andriole G, Bruchovsky N, Chung LW, et al：Dihydrotestosterone and the prostate：the scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia. J Urol 172：1399-1403, 2004

43）Hong SK, Min GE, Ha SB, et al：Effect of the dual 5alpha-reductase inhibitor, dutasteride, on serum testosterone and body mass index in men with benign prostatic hyperplasia. BJU Int 105：970-974, 2010

44）Marks LS and Kaplan SA：Should testosterone replacement be given to men with large prostates? J Urol 182：2109-2111, 2009

45）Amory JK, Bush MA, Zhi H, et al：Oral testosterone with and without concomitant inhibition of 5α-reductase by dutasteride in hypogonadal men for 28 days. J Urol 185：626-632, 2011

46）Page ST, Hirano L, Gilchriest J, et al：Dutasteride reduces prostate size and prostate specific antigen in older hypogonadal men with benign prostatic hyperplasia undergoing testosterone replacement therapy. J Urol 186：191-197, 2011