The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases

Faris Azzouni, Alejandro Godoy, Yun Li, James Mohler, Faris Azzouni, Alejandro Godoy, Yun Li, James Mohler

Abstract

Despite the discovery of 5 alpha-reduction as an enzymatic step in steroid metabolism in 1951, and the discovery that dihydrotestosterone is more potent than testosterone in 1968, the significance of 5 alpha-reduced steroids in human diseases was not appreciated until the discovery of 5 alpha-reductase type 2 deficiency in 1974. Affected males are born with ambiguous external genitalia, despite normal internal genitalia. The prostate is hypoplastic, nonpalpable on rectal examination and approximately 1/10th the size of age-matched normal glands. Benign prostate hyperplasia or prostate cancer does not develop in these patients. At puberty, the external genitalia virilize partially, however, secondary sexual hair remains sparse and male pattern baldness and acne develop rarely. Several compounds have been developed to inhibit the 5 alpha-reductase isozymes and they play an important role in the prevention and treatment of many common diseases. This review describes the basic biochemical properties, functions, tissue distribution, chromosomal location, and clinical significance of the 5 alpha-reductase isozyme family.

Figures

Figure 1
Figure 1
Structure of various steroids.

References

    1. Imperato-McGinley J, Zhu YS. Androgens and male physiology the syndrome of 5α-reductase-2 deficiency. Molecular and Cellular Endocrinology. 2002;198(1-2):51–59.
    1. Siiteri PK, Wilson JD. Testosterone formation and metabolism during male sexual differentiation in the human embryo. Journal of Clinical Endocrinology and Metabolism. 1974;38(1):113–125.
    1. Cilotti A, Danza G, Serio M. Clinical application of 5α-reductase inhibitors. Journal of Endocrinological Investigation. 2001;24(3):199–203.
    1. Imperato McGinley J, Guerrero L, Gautier T, Peterson RE. Steroid 5α reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science. 1974;186(4170):1213–1215.
    1. Saartok T, Dahlberg E, 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. 1984;114(6):2100–2106.
    1. Beato M. Gene regulation by steroid hormones. Cell. 1989;56(3):335–344.
    1. Stiles AR, Russell DW. SRD5A3: a surprising role in glycosylation. Cell. 2010;142(2):196–198.
    1. Langlois VS, Zhang D, Cooke GM, Trudeau VL. Evolution of steroid-5α-reductases and comparison of their function with 5β-reductase. General and Comparative Endocrinology. 2010;166(3):489–497.
    1. Aggarwal S, Thareja S, Verma A, Bhardwaj TR, Kumar M. An overview on 5α-reductase inhibitors. Steroids. 2010;75(2):109–153.
    1. Eicheler W, Dreher M, Hoffmann R, Happle R, Aumuller G. Immunohistochemical evidence for differential distribution of 5α-reductase isoenzymes in human skin. British Journal of Dermatology. 1995;133(3):371–376.
    1. Aumüller G, Eicheler W, Renneberg H, Adermann K, Vilja P, Forssmann WG. Immunocytochemical evidence for differential subcellular localization of 5α-reductase isoenzymes in human tissues. Acta Anatomica. 1997;156(4):241–252.
    1. Bayne EK, Flanagan J, Einstein M, et al. Immunohistochemical localization of types 1 and 2 5α-reductase in human scalp. British Journal of Dermatology. 1999;141(3):481–491.
    1. Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW. Tissue distribution and ontogeny of steroid 5α-reductase isozyme expression. Journal of Clinical Investigation. 1993;92(2):903–910.
    1. Thomas LN, Douglas RC, Lazier CB, Too CKL, Rittmaster RS, Tindall DJ. Type 1 and type 2 5α-reductase expression in the development and progression of prostate cancer. European Urology. 2008;53(2):244–252.
    1. Söderström TG, Bjelfman C, Brekkan E, et al. Messenger ribonucleic acid levels of steroid 5α-reductase 2 in human prostate predict the enzyme activity. Journal of Clinical Endocrinology and Metabolism. 2001;86(2):855–858.
    1. Habib FK, Ross M, Bayne CW, et al. The localisation and expression of 5α-reductase types I and II mRNAs in human hyperplastic prostate and in prostate primary cultures. Journal of Endocrinology. 1998;156(3):509–517.
    1. Bonkhoff H, Stein U, Aumüller G, Remberger K. Differential expression of 5α-reductase isoenzymes in the human prostate and prostatic carcinomas. The Prostate. 1996;29(4):261–267.
    1. Shirakawa T, Okada H, Acharya B, et al. Messenger RNA levels and enzyme activities of 5 alpha-reductase types 1 and 2 in human benign prostatic hyperplasia (BPH) tissue. The Prostate. 2004;58(1):33–40.
    1. Titus MA, Gregory CW, Ford OH, Schell MJ, Maygarden SJ, Mohler JL. Steroid 5α-reductase isozymes I and II in recurrent prostate cancer. Clinical Cancer Research. 2005;11(12):4365–4371.
    1. Godoy A, Kawinski E, Li Y, et al. 5α-reductase type 3 expression in human benign and malignant tissues: a comparative analysis during prostate cancer progression. The Prostate. 2011;71(10):1033–1046.
    1. Yamana K, Labrie F, Luu-The V, et al. Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited finasteride and dutasteride. Hormone Molecular Biology and Clinical Investigation. 2010;2(3):293–299.
    1. Moss GP. Nomenclature of steroids (Recommendations 1989) Pure and Applied Chemistry. 1989;61(10):1783–1822.
    1. Dorfman RI, Forchielli E. Separation of delta 4-5 alpha-hydrogenases from rat liver homogenates. The Journal of Biological Chemistry. 1956;223(1):443–448.
    1. Schneider JJ, Horstmann PM. Effects of incubating desoxycorticosterone with various rat tissues. The Journal of Biological Chemistry. 1951;191(1):327–338.
    1. Tomkins GM. The enzymatic reduction of Δ4-3-ketosteroids. The Journal of Biological Chemistry. 1957;225(1):13–24.
    1. Saunders FJ. Some aspects of relation of structure of steroids to their prostate stimulating effects. In: Vollmer EP, editor. Biology of the Prostate and Related Tissue. Washington, DC, USA: U.S. Government Printing Office; 1963. pp. 139–159.
    1. Wilson JD. Recent studies on the mechanism of action of testosterone. The New England Journal of Medicine. 1972;287(25):1284–1291.
    1. Wilson JD, Lasnitzki I. Dihydrotestosterone formation in fetal tissues of the rabbit and rat. Endocrinology. 1971;89:659–668.
    1. Russell DW, Wilson JD. Steroid 5α-reductase: two genes/two enzymes. Annual Review of Biochemistry. 1994;63:25–61.
    1. Occhiato EG, Guarna A, Danza G, Serio M. Selective non-steroidal inhibitors of 5α-reductase type 1. Journal of Steroid Biochemistry and Molecular Biology. 2004;88(1):1–16.
    1. Milewich L, Gomez Sanchez C, Crowley G. Progesterone and 5α pregnane 3,20 dione in peripheral blood of normal young women. Daily measurements throughout the menstrual cycle. Journal of Clinical Endocrinology and Metabolism. 1977;45(4):617–622.
    1. Weinstein BI, Kandalaft N, Ritch R, et al. 5α-dihydrocortisol in human aqueous humor and metabolism of cortisol by human lenses in vitro. Investigative Ophthalmology and Visual Science. 1991;32(7):2130–2135.
    1. Kenyon CJ, Brem AS, McDermott MJ. Antinatriuretic and kaliuretic activities of the reduced derivatives of aldosterone. Endocrinology. 1983;112(5):1852–1856.
    1. Uemura M, Tamura K, Chung S, et al. Novel 5α-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer. Cancer Science. 2008;99(1):81–86.
    1. 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. 2010;142(2):203–217.
    1. Gordon AS, Zanjani ED, Levere RD, Kappas A. Stimulation of mammalian erythropoiesis by 5β-H steroid metabolites. Proceedings of the National Academy of Sciences of the United States of America. 1970;65(4):919–924.
    1. Kondo K-H, Kai M-H, Setoguchi Y, et al. Cloning and expression of cDNA of human Δ4-3-oxosteroid 5β-reductase and substrate specificity of the expressed enzyme. European Journal of Biochemistry. 1994;219(1-2):357–363.
    1. Moon YA, Horton JD. Identification of two mammalian reductases involved in the two-carbon fatty acyl elongation cascade. Journal of Biological Chemistry. 2003;278(9):7335–7343.
    1. .
    1. .
    1. .
    1. Ntais C, Polycarpou A, Tsatsoulis A. Molecular epidemiology of prostate cancer: androgens and polymorphisms in androgen-related genes. European Journal of Endocrinology. 2003;149(6):469–477.
    1. Cussenot O, Azzouzi AR, Nicolaiew N, et al. Low-activity V89L variant in SRD5A2 is associated with aggressive prostate cancer risk: an explanation for the adverse effects observed in chemoprevention trials using 5-alpha-reductase inhibitors. European Urology. 2007;52(4):1082–1089.
    1. Graupp M, Wehr E, Schweighofer N, Pieber TR, Obermayer-Pietsch B. Association of genetic variants in the two isoforms of 5α-reductase, SRD5A1 and SRD5A2, in lean patients with polycystic ovary syndrome. European Journal of Obstetrics Gynecology and Reproductive Biology. 2011;157(2):175–179.
    1. .
    1. Chen W, Zouboulis CC, Orfanos CE. The 5α-reductase system and its inhibitors. Recent development and its perspective in treating androgen-dependent skin disorders. Dermatology. 1996;193(3):177–184.
    1. Tian G. 17β-(N-tert-butylcarbamoyl)-4-aza-5α-androstan-1-en-3-one is an active site-directed slow time-dependent inhibitor of human steroid 5α-reductase. Biochemistry. 1994;33(8):2291–2296.
    1. McConnell JD, Wilson JD, George FW, Geller J, Pappas F, Stoner E. Finasteride, an inhibitor of 5α-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. Journal of Clinical Endocrinology and Metabolism. 1992;74(3):505–508.
    1. Span PN, Völler MCW, Smals AGH, et al. Selectivity of finasteride as an in vivo inhibitor of 5α-reductase isozyme enzymatic activity in the human prostate. Journal of Urology. 1999;161(1):332–337.
    1. Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor. Journal of Clinical Endocrinology and Metabolism. 2004;89(5):2179–2184.
    1. Andriole GL, Humphrey P, Ray P, et al. Effect of the dual 5α-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer. Journal of Urology. 2004;172(3):915–919.
    1. Gleave M, Qian J, Andreou C, et al. The effects of the dual 5α-reductase inhibitor dutasteride on localized prostate cancer—results from a 4-month pre-radical prostatectomy study. The Prostate. 2006;66(15):1674–1685.
    1. Cabeza M, Heuze I, Bratoeff E, Murillo E, Ramirez E, Lira A. New progesterone esters as 5α-reductase inhibitors. Chemical and Pharmaceutical Bulletin. 2001;49(9):1081–1084.
    1. Ellsworth K, Harris G. Expression of the type 1 and 2 steroid 5α-reductases in human fetal tissues. Biochemical and Biophysical Research Communications. 1995;215(2):774–780.
    1. Lunacek A, Schwentner C, Oswald J, et al. Fetal distribution of 5α-reductase 1 and 5α-reductase 2, and their input on human prostate development. Journal of Urology. 2007;178(2):716–721.
    1. .
    1. .
    1. .
    1. Thomas LN, Lazier CB, Gupta R, et al. Differential alterations in 5α-reductase type 1 and type 2 levels during development and progression of prostate cancer. The Prostate. 2005;63(3):231–239.
    1. Thomas LN, Douglas RC, Lazier CB, et al. Levels of 5α-reductase type 1 and type 2 are increased in localized High grade compared to low grade prostate cancer. Journal of Urology. 2008;179(1):147–151.
    1. Iehle C, Radvanyi F, Gil Diez de Medina S, et al. Differences in steroid 5alpha-reductase iso-enzymes expression between normal and pathological human prostate tissue. The Journal of Steroid Biochemistry and Molecular Biology. 1999;68:189–195.
    1. Zhu YS, Sun GH. 5α-reductase isozymes in the prostate. Journal of Medical Sciences. 2005;25(1):1–12.
    1. Roehrborn CG, Marks L, Harkaway R. Enlarged prostate: a landmark national survey of its prevalence and impact on US men and their partners. Prostate Cancer and Prostatic Diseases. 2006;9(1):30–34.
    1. Huggins C, Stevens R. The effect of castration on benign hypertrophy of the prostate in man. Journal of Urology. 1940;43:705–714.
    1. Moore RJ, Gazak JM, Quebbeman JF, Wilson JD. Concentration of dihydrotestosterone and 3α-androstanediol in naturally occurring and androgen-induced prostatic hyperplasia in the dog. Journal of Clinical Investigation. 1979;64(4):1003–1010.
    1. Wenderoth UK, George FW, Wilson JD. The effect of a 5α-reductase inhibitor on androgen-mediated growth of the dog prostate. Endocrinology. 1983;113(2):569–573.
    1. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. The New England Journal of Medicine. 2003;349(3):215–224.
    1. Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. The New England Journal of Medicine. 2010;362(13):1192–1202.
    1. Nickel J, Gilling P, Tammela T, et al. Comparison of dutasteride and finasteride for treating benign prostate hyperplasia: the enlarged prostate international comparator study (EPICS) BJU International. 2011;108(3):388–394.
    1. Andriole G, Lieber M, Smith J, et al. Treatment with finasteride following radical prostatectomy for prostate cancer. Urology. 1995;45(3):491–497.
    1. Perotti M, Jain R, Abriel L, et al. Dutasteride momotherapy in men with serologic relapse following radical therapy for adenocarcinoma of the prostate: a pilot study. Urologic Oncology: Seminars and Original Investigations. In press.
    1. Barqawi AB, Moul JW, Ziada A, Handel L, Crawford ED. Combination of low-dose flutamide and finasteride for PSA-only recurrent prostate cancer after primary therapy. Urology. 2003;62(5):872–876.
    1. Bañez LL, Blake GW, McLeod DG, Crawford ED, Moul JW. Combined low-dose flutamide plus finasteride vs low-dose flutamide monotherapy for recurrent prostate cancer: a comparative analysis of two phase II trials with a long-term follow-up. BJU International. 2009;104(3):310–314.
    1. Mohler JL, Gregory CW, Ford H, et al. The androgen axis in recurrent prostate cancer. Clinical Cancer Research. 2004;10(2):440–448.
    1. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clinical Cancer Research. 2005;11(13):4653–4657.
    1. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Research. 2006;66(5):2815–2825.
    1. Attard G, Reid AHM, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. Journal of Clinical Oncology. 2008;26(28):4563–4571.
    1. Mohler J, Titus M, Bai S, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Research. 2011;71(4):1486–1496.
    1. Locke JA, Guns ES, Lubik AA, et al. Androgen Levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Research. 2008;68(15):6407–6415.
    1. Ford OH, III, Gregory CW, Kim D, Smitherman AB, Mohler JL. Androgen receptor gene amplification and protein expression in recurrent prostate cancer. Journal of Urology. 2003;170(5):1817–1821.
    1. Gregory CW, Johnson RT, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Research. 2001;61(7):2892–2898.
    1. Agoulnik IU, Vaid A, Nakka M, et al. Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer. Cancer Research. 2006;66(21):10594–10602.
    1. Guo Z, Dai B, Jiang T, et al. Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell. 2006;10(4):309–319.
    1. Taplin ME, Bubley GJ, Ko YJ, et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Research. 1999;59(11):2511–2515.
    1. Scher HI, Anand A, Rathkopf D, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. The Lancet. 2010;375(9724):1437–1446.
    1. Shah SK, Trump DL, Sartor O, Tan W, Wilding GE, Mohler JL. Phase II study of dutasteride for recurrent prostate cancer during androgen deprivation therapy. Journal of Urology. 2009;181(2):621–626.
    1. Tay MH, Kaufman DS, Regan MM, et al. Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate. Annals of Oncology. 2004;15(6):974–978.
    1. Sartor O, Nakabayashi M, Taplin ME, et al. Activity of dutasteride plus ketoconazole in castration-refractory prostate cancer after progression on ketoconazole alone. Clinical Genitourinary Cancer. 2009;7(3):E90–E92.
    1. 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. Clinical Cancer Research. 2009;15(22):7099–7105.
    1. Lee AT, Zane LT. Dermatologic manifestations of polycystic ovary syndrome. American Journal of Clinical Dermatology. 2007;8(4):201–219.
    1. Falsetti L, Gambera A, Andrico S, et al. Acne and hirsutism in polycystic ovary syndrome: clinical, endocrine-metabolic and ultrasonographic differences. Gynecological Endocrinology. 2002;16(275):27–84.
    1. Somani N, Harrison S, Bergfeld WF. The clinical evaluation of hirsutism. Dermatologic Therapy. 2008;21(5):376–391.
    1. Essah PA, Wickham EP, Nunley JR, Nestler JE. Dermatology of androgen-related disorders. Clinics in Dermatology. 2006;24(4):289–298.
    1. Rathnayake D, Sinclair R. Male androgenetic alopecia. Expert Opinion on Pharmacotherapy. 2010;11(8):1295–1304.
    1. Thiboutot D. Acne: hormonal concepts and therapy. Clinics in Dermatology. 2004;22(5):419–428.
    1. Drake L, Hordinsky M, Fiedler V, et al. The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. Journal of the American Academy of Dermatology. 1999;41(4):550–554.
    1. 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. Journal of the American Academy of Dermatology. 2006;55(6):1014–1023.
    1. Kaufman KD, Olsen EA, Whiting D, et al. Finasteride in the treatment of men with androgenetic alopecia. Journal of the American Academy of Dermatology. 1998;39(4):578–589.
    1. Eun HC, Kwon OS, Yeon JH, et al. Efficacy, safety, and tolerability of dutasteride 0.5 mg once daily in male patients with male pattern hair loss: a randomized, double-blind, placebo-controlled, phase III study. Journal of the American Academy of Dermatology. 2010;63(2):252–258.
    1. Arca E, Acikgoz G, Tastan HB, et al. An open, randomized, comparative study of oral finasteride and 5% topical minoxidil in male androgenetic alopecia. Dermatology. 2004;209(2):117–125.
    1. Shum KW, Cullen DR, Messenger AG. Hair loss in women with hyperandrogenism: four cases responding to finasteride. Journal of the American Academy of Dermatology. 2002;47(5):733–739.
    1. Olszewska M, Rudnicka L. Effective treatment of female androgenic alopecia with dutasteride. Journal of Drugs in Dermatology. 2005;4(5):637–640.
    1. 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 trial. Journal of Clinical Endocrinology and Metabolism. 2000;85(1):89–94.
    1. Falsetti L, Gambera A, Legrenzi L, Iacobello C, Bugari G. Comparison of finasteride versus flutamide in the treatment of hirsutism. European Journal of Endocrinology. 1999;141(4):361–367.
    1. Schwartz JI, Tanaka WK, Wang DZ, et al. MK-386, an inhibitor of 5α-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen. Journal of Clinical Endocrinology and Metabolism. 1997;82(5):1373–1377.
    1. Leyden J, Bergfeld W, Drake L, et al. A systemic type I 5 α-reductase inhibitor is ineffective in the treatment of acne vulgaris. Journal of the American Academy of Dermatology. 2004;50(3):443–447.
    1. Carmina E, Lobo RA. A comparison of the relative efficacy of antiandrogens for the treatment of acne in hyperandrogenic women. Clinical Endocrinology. 2002;57(2):231–234.

Source: PubMed

3
구독하다