5α-reductases in human physiology: An unfolding story

Endocrine Practice

Volumn 18, Issue 6, 2012, Pages 965-975

  Traish, Abdulmaged M ^a  

^a BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3ALPHA HYDROXYSTEROID DEHYDROGENASE; ALDOSTERONE; CORTICOSTERONE; DEOXYCORTICOSTERONE; DOLICHOL PHOSPHATE; DOXAZOSIN; DUTASTERIDE; FINASTERIDE; PROGESTERONE; STEROID 5ALPHA REDUCTASE; STEROID 5ALPHA REDUCTASE 1; STEROID 5ALPHA REDUCTASE 2; STEROID 5ALPHA REDUCTASE INHIBITOR; TAMSULOSIN; TERAZOSIN; TESTOSTERONE;

ANXIETY; BLOOD BRAIN BARRIER; BONE MASS; CENTRAL NERVOUS SYSTEM; DOWN REGULATION; DRUG BINDING; DRUG HALF LIFE; DRUG TOLERABILITY; ENZYME DEGRADATION; ERECTILE DYSFUNCTION; EXON; GENE MUTATION; GRIP STRENGTH; HUMAN; INTRON; LASER THERMOTHERAPY; MALE TYPE ALOPECIA; MEMORY; MICROWAVE THERAPY; NEUROPROTECTION; NONHUMAN; ORGASM DISORDER; PHYTOTHERAPY; PROSTATE HYPERTROPHY; PROTEIN EXPRESSION; PROTEIN GLYCOSYLATION; REVIEW; SEX DIFFERENTIATION; SEXUAL DYSFUNCTION; SLEEP; STRESS; TISSUE DISTRIBUTION; TRANSURETHRAL NEEDLE ABLATION;

EID: 84871382108     PISSN: 1530891X     EISSN: 19342403     Source Type: Journal    
DOI: 10.4158/EP12108.RA     Document Type: Review

References (101)

1. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE. Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science. 1974; 186: 1213-1215.
2. Imperato-McGinley J. 5alpha-reductase-2 deficiency and complete androgen insensitivity: lessons from nature. Adv Exp Med Biol. 2002; 511: 121-131.
3. Imperato-McGinley J, Zhu YS. Androgens and male physiology the syndrome of 5alpha-reductase-2 deficiency. Mol Cell Endocrinol. 2002; 198: 51-59.
4. 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. 2003; 88: 3431-3436.
5. Sasaki G, Nakagawa K, Hashiguchi A, Hasegawa T, Ogata T, Murai M. Giant seminoma in a patient with 5 alpha-reductase type 2 deficiency. J Urol. 2003; 169: 1080-1081.
6. Katz MD, Kligman I, Cai LQ, et al. Paternity by intrauterine insemination with sperm from a man with 5alpha-reductase-2 deficiency. New Engl J Med. 1997; 336: 994-997.
7. Uemura M, Tamura K, Chung S, et al. Novel 5 alpha-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer. Cancer Sci. 2008; 99: 81-86.
8. 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: 23; 203-217.
9. Kasapkara CS, Tümer L, Ezgü FS, et al. SRD5A3-CDG: a patient with a novel mutation. Eur J Paediatr Neurol. January 10, 2012. [Epub ahead of print].
10. Denecke J, Kranz C. Hypoglycosylation due to dolichol metabolism defects. Biochim Biophys Acta. 2009; 1792: 888-895.
11. Gründahl JE, Guan Z, Rust S, et al. Life with too much polyprenol: polyprenol reductase deficiency. Mol Genet Metab. 2012; 105: 642-621.
12. Godoy A, Kawinski E, Li Y, et al. 5alpha-reductase type 3 expression in human benign and malignant tissues: a comparative analysis during prostate cancer progression. Prostate. 2011; 71: 1033-1046.
13. Stiles AR, Russell DW. SRD5A3: a surprising role in glycosylation. Cell. 2010; 142: 196-198.
14. Morava E, Wevers RA, Cantagrel V, et al. A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Brain. 2010; 133: 3210-3220.
15. Li J, Ding Z, Wang Z, et al. Androgen regulation of 5a-reductase isoenzymes in prostate cancer: implications for prostate cancer prevention. PLoS One. 2011; 6: e28840.
16. Azzouni F, Godoy A, Li Y, Mohler J. The 5 alpha-reductase isozyme family: a review of basic biology and their role in human diseases. Adv Urol. 2012; 2012: 530121.
17. Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994; 63: 25-61.
18. Poletti A, Coscarella A, Negri-Cesi P, Colciago A, Celotti F, Martini L. 5 alpha-reductase isozymes in the central nervous system. Steroids. 1998; 63: 246-251.
19. Poletti A, Martini L. Androgen-activating enzymes in the central nervous system. J Steroid Biochem Mol Biol. 1999; 69: 117-122.
20. Poletti A, Negri-Cesi P, Rabuffetti M, Colciago A, Celotti F, Martini L. Transient expression of the 5alpha-reductase type 2 isozyme in the rat brain in late fetal and early postnatal life. Endocrinology. 1998; 139: 2171-2178.
21. Iehlé C, Délos S, Guirou O, Tate R, Raynaud JP, Martin PM. Human prostatic steroid 5 alpha-reductase isoforms-a comparative study of selective inhibitors. J Steroid Biochem Mol Biol. 1995; 54: 273-279.
22. Langlois VS, Zhang D, Cooke GM, Trudeau VL. Evolution of steroid-5alpha-reductases and comparison of their function with 5beta-reductase. Gen Comp Endocrinol. 2010; 166: 489-497.
23. Thigpen AE, Davis DL, Milatovich A, et al. Molecular genetics of steroid 5 alpha-reductase 2 deficiency. J Clin Invest. 1992; 90: 799-809.
24. Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnel JD, Russell DW. Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J Clin Invest. 1993; 92: 903-910.
25. Patte-Mensah C, Penning TM, Mensah-Nyagan AG. Anatomical and cellular localization of neuroactive 5 alpha/3 alpha-reduced steroid-synthesizing enzymes in the spinal cord. J Comp Neurol. 2004; 477: 286-299.
26. Pozzi P, Bendotti C, Simeoni S, et al. Androgen 5-alpha-reductase type 2 is highly expressed and active in rat spinal cord motor neurons. J Neuroendocrinol. 2003; 15: 882-887.
27. Normington K, Russell DW. Tissue distribution and kinetic characteristics of rat steroid 5 alpha-reductase isozymes: evidence for distinct physiological functions. J Biol Chem. 1992; 267: 19548-19554.
28. Melcangi RC, Poletti A, Cavarretta I , et al. The 5alpha-reductase in the central nervous system: expression and modes of control. J Steroid Biochem Mol Biol. 1998; 65: 295-299.
29. Bramson HN, Hermann D, Batchelor KW, Lee FW, James MK, Frye SV. Unique preclinical characteristic of GG745, a potent dual inhibitor of 5AR. J Pharmacol Exp Ther. 1997; 282: 1496-1502.
30. Dubrovsky B. Neurosteroids, neuroactive steroids, and symptoms of affective disorders. Pharmacol Biochem Behav. 2006; 84: 644-655.
31. Marver D, Edelman IS. Dihydrocortisol: a potential mineralocorticoid. J Steroid Biochem. 1978; 9: 1-7.
32. Windahl SH, Andersson N, Börjesson AE, et al. Reduced bone mass and muscle strength in male 5a-reductase type 1 inactivated mice. PLoS One. 2011; 6: e21402.
33. Mahendroo MS, Porter A, Russell DW, Word RA. The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening. Mol Endocrinol. 1999; 13: 981-992.
34. Osborne DM, Frye CA. Estrogen increases latencies to seizures and levels of 5alpha-pregnan-3alpha-ol-20-one in hippocampus of wild-type, but not 5alpha-reductase knockout, mice. Epilepsy Behav. 2009; 16: 411-414.
35. Koonce CJ, Walf AA, Frye CA. Type 1 5a-reductase may be required for estrous cycle changes in affective behaviors of female mice. Behav Brain Res. 2012; 226: 376-380.
36. Frye CA, Walf AA, Rhodes ME, Harney JP. Progesterone enhances motor, anxiolytic, analgesic, and antidepressive behavior of wild-type mice, but not those deficient in type 1 5 alpha-reductase. Brain Res. 2004; 1004: 116-124.
37. Frye CA, Rhodes ME, Walf A, Harney JP. Testosterone enhances aggression of wild-type mice but not those deficient in type I 5alpha-reductase. Brain Res. 2002; 948: 165-170.
38. Frye CA, Rhodes ME, Walf AA, Harney JP. Testosterone reduces pentylenetetrazole-induced ictal activity of wildtype mice but not those deficient in type I 5alpha-reductase. Brain Res. 2001; 918: 182-186.
39. Mahendroo MS, Cala KM, Hess DL, Russell DW. Unexpected virilization in male mice lacking steroid 5 alpha-reductase enzymes. Endocrinology. 2001; 142: 4652-4662.
40. Mahendroo MS, Cala KM, Landrum DP, Russell DW. Fetal death in mice lacking 5alpha-reductase type 1 caused by estrogen excess. Mol Endocrinol. 1997; 11: 917-927.
41. Cheon CK. Practical approach to steroid 5alpha-reductase type 2 deficiency. Eur J Pediatr. 2011; 170: 1-8.
42. Maimoun L, Philibert P, Cammas B, et al. Phenotypical, biological, and molecular heterogeneity of 5a-reductase deficiency: an extensive international experience of 55 patients. J Clin Endocrinol Metab. 2011; 96: 296-307.
43. Prahalada S, Tarantal AF, Harris GS, et al. Effect of finasteride, a type 2 5-alpha reductase inhibitor, on fetal development in the rhesus monkey (Macaca mulatta). Teratology. 1997; 55: 119-131.
44. Levy MA, Brandt M, Sheedy KM, et al. Cloning, expression and functional characterization of type 1 and type 2 steroid 5 alpha-reductase from Cynomolgus monkey: comparisons with human and rat isoenzymes. J Steroid Biochem Mol Biol. 1995; 52: 307-319.
45. Baulieu EE. Neurosteroids: a novel function of the brain. Psychoneuroendocrinology. 1998; 23: 963-987.
46. Barbaccia ML, Roscetti G, Trabucchi M, et al. The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone concentrations. Br J Pharmacol. 1997; 120: 1582-1588.
47. Reddy DS, Rogawski MA. Stress-induced deoxycorticosterone-derived neurosteroids modulate GABA(A) receptor function and seizure susceptibility. J Neurosci. 2002; 22: 3795-3805.
48. Ghoumari AM, Ibanez C, El-Etr M, et al. Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J Neurochem. 2003; 86: 848-859.
49. Morrow AL, Suzdak PD, Paul SM. Steroid hormone metabolites potentiate GABA receptor-mediated chloride ion flux with nanomolar potency. Eur J Pharmacol. 1987; 142: 483-485.
50. Morrow AL. Recent developments in the significance and therapeutic relevance of neuroactive steroids-introduction to the special issue. Pharmacol Ther. 2007; 116: 1-6.
51. Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res. 2010; 186: 113-137.
52. Rupprecht R, Holsboer F. Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci. 1999; 22: 410-416.
53. Stoffel-Wagner B. Neurosteroid biosynthesis in the human brain and its clinical implications. Ann N Y Acad Sci. 2003; 1007: 64-78.
54. Stoffel-Wagner B. Neurosteroid metabolism in the human brain. Eur J Endocrinol. 2001; 145: 669-679.
55. Römer B, Pfeiffer N, Lewicka S, et al. Finasteride treatment inhibits adult hippocampal neurogenesis in male mice. Pharmacopsychiatry. 2010; 43: 174-178.
56. Sánchez P, Torres JM, Ortega E. Effects of dihydrotestosterone on brain mRNA levels of steroid 5alpha-reductase isozymes in early postnatal life of rat. Neurochem Res. 2005; 30: 577-581.
57. Torres JM, Ortega E. Differential regulation of steroid 5alpha-reductase isozymes expression by androgens in the adult rat brain. FASEB J. 2003; 17: 1428-1433.
58. Torres JM, Ortega E. Quantitation of mRNA levels of steroid 5alpha-reductase isozymes: a novel method that combines quantitative RT-PCR and capillary electrophoresis [published correction appears in Int J Biochem Cell Biol. 2004; 36: 2359-2361]. Int J Biochem Cell Biol. 2004; 36: 78-88.
59. Saalmann YB, Morgan IG, Calford MB. Neurosteriods involved in regulating inhibition in the inferior colliculus. J Neurophysiol. 2006; 96: 3064-3073.
60. Gormley GJ, Stoner E, Brusketwitz RC, et al (Finasteride Study Group). The effect of finasteride in men with benign prostatic hyperplasia: 1992. J Urol. 2002; 167(2 pt 2): 1102-1107.
61. Bartsch G, Rittmaster RS, Klocker H. Dihydro-testosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia. World J Urol. 2002; 19: 413-425.
62. Lephart ED. Age-related changes in brain and pituitary 5 alpha-reductase with finasteride (Proscar) treatment. Neurobiol Aging. 1995; 16: 647-650.
63. Andersson S, Berman DM, Jenkins EP, Russell DW. Deletion of 5 alpha-reductase 2 gene in male pseudohermaphroditism. Nature. 1991; 354: 159-161.
64. Jenkins EP, Andersson S, Imperato-McGinley J, Wilson JD, Russell DW. Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase. J Clin Invest. 1992; 89: 293-300.
65. Faller B, Farley D, Nick H. Finasteride: a slow-binding 5 alpha-reductase inhibitor. Biochemistry. 1993; 32: 5705-5710.
66. Bull HG, Garcia-Calvo M, Andersson S, et al. Mechanism-based inhibition of human steroid 5 alpha-reductase by finasteride: enzyme-catalyzed formation of NADP-dihydrofinasteride, a potent bisubstrate analog inhibitor. J Am Chem Soc. 1996; 118: 2359-2365.
67. Azzolina B, Ellsworth K, Andersson S, Geissler W, Bull HG, Harris GS. Inhibition of rat alpha-reductases by finasteride: evidence for isozyme differences in the mechanism of inhibition. J Steroid Biochem Mol Biol. 1997; 61: 55-64.
68. Tian G, Stuart JD, Moss ML, et al. 17alpha-(N-tert-butylcarbamoyl)-4-aza- 5 alpha-androstan-1-en-3-one is an active site-directed slow time-dependent inhibitor of human steroid 5 alpha-reductase 1. Biochemistry. 1994; 33: 2291-2296.
69. Desgrandchamps F, Droupy S, Irani J, Saussine C, Comenducci A. Effect of dutasteride on the symptoms of benign prostatic hyperplasia, and patient quality of life and discomfort, in clinical practice. BJU Int. 2006; 98: 83-88.
70. AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003): chapter 1; diagnosis and treatment recommendations. J Urol. 2003; 170(2 pt 1): 530-547.
71. Marberger MJ (PROWESS Study Group). Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind placebo-controlled, multicenter study. Urology. 1998; 51: 677-686.
72. Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efficacy and safety of a dual inhibitor of 5-alpha-reductases types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002; 60: 434-441.
73. McConnell JD, Brusketwitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med. 1998; 338: 557-563.
74. Debruyne F, Koch G, Boyle P, et al. Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study [with discussion]. Eur Urol. 2002; 41: 497-507.
75. Marks LS, Partin AW, Epstein JI, et al. Effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia. J Urol. 2000; 163: 1451-1456.
76. Steers WD. 5alpha-reductase activity in the prostate. Urology. 2001; 58(6 suppl 1): 17-24.
77. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003; 349: 215-224.
78. Andriole GL, Bostwick DG Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010; 362: 1192-1202.
79. Wessells H, Roy J, Bannow J, et al. Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia. Urology. 2003; 61: 579-584.
80. Traish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML. Adverse side effects of 5a-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients. J Sex Med. 2011; 8: 872-884.
81. Irwig MS, Kolukula S. Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med. 2011; 8: 1747-1753.
82. Pinsky MR, Gur S, Tracey AJ, Harbin A, Hellstrom WJ. The effects of chronic 5-alpha-reductase inhibitor (dutasteride) treatment on rat erectile function. J Sex Med. 2011; 8: 3066-3074.
83. Oztekin CV, Gur S, Abdulkadir NA, et al. Incomplete recovery of erectile function in rat after discontinuation of dual 5-alpha reductase inhibitor therapy. J Sex Med. 2012; 9: 1773-1781.
84. Römer B, Gass P. Finasteride-induced depression: new insights into possible pathomechanisms [published correction appears in J Cosmet Dermatol. 2011; 10: 85]. J Cosmet Dermatol. 2010; 9: 331-332.
85. Corradi LS, Campos SG, Santos FC, Vilamaior PS, Góes RM, Taboga SR. Long-term inhibition of 5-alpha reductase and aromatase changes the cellular and extracellular compartments in gerbil ventral prostate at different postnatal ages. Int J Exp Pathol. 2009; 90: 79-94.
86. Corradi LS, Góes RM, Carvalho HF, Taboga SR. Inhibition of 5-alpha-reductase activity induces stromal remodeling and smooth muscle de-differentiation in adult gerbil ventral prostate. Differentiation. 2004; 72: 198-208.
87. Kampitak T, Binkley K. Angioedema associated with dutasteride therapy. Ann Allergy Asthma Immunol. 2011; 107: 376-377.
88. Wong AC, Mak ST. Finasteride-associated cataract and intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2011; 37: 1351-1354.
89. Santo Domingo D, Stevenson ML, Auerbach J, Lerman J. Finasteride-induced pseudoporphyria. Arch Dermatol. 2011; 147: 747-748.
90. Tresch S, Cozzio A, Kamarashev J, et al. T cell-mediated acute localized exanthematous pustulosis caused by finasteride. J Allergy Clin Immunol. 2012; 129: 589-594.
91. Merck Sharp & Dohme Corp. Highlights of prescribing information. These highlights do not include all the information needed to use Propecia safely and effectively. See full prescribing information for Propecia. Warnings and precautions, increased risk of high-grade prostate cancer with 5alpha-reductase inhibitors (5.3) 06/2011. Highlights of prescribing information. http://www.merck.com/product/usa/pi-circulars/p/propecia/propecia- pi.pdf. Accessed for verification July 20, 2012.
92. Mellon SH. Neurosteroid regulation of central nervous system development. Pharmacol Ther. 2007; 116: 107-124.
93. Liao G, Cheung S, Galeano J, Ji AX, Qin Q, Bi X. Allopregnanolone treatment delays cholesterol accumulation and reduces autophagic/lysosomal dysfunction and inflammation in Npc1-/- mouse brain. Brain Res. 2009; 1270: 140-151.
94. Zampieri S, Mellon SH, Butters TD, et al. Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone. J Cell Mol Med. 2009; 13: 3786-3796.
95. Mellon SH, Gong W, Schonemann MD. Endogenous and synthetic neurosteroids in treatment of Niemann-Pick type C disease. Brain Res Rev. 2008; 57: 410-420.
96. Langmade SJ, Gale SE, Frolov A, et al. Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc Natl Acad Sci U S A. 2006; 103: 13807-13812.
97. Ahmad I, Lope-Piedrafita S, Bi X, et al. Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice. J Neurosci Res. 2005; 82: 811-821.
98. Mellon S, Gong W, Griffin LD. Niemann pick type C disease as a model for defects in neurosteroidogenesis. Endocr Res. 2004; 30: 727-735.
99. Burns MP, Duff K. Brain on steroids resists neurodegeneration. Nat Med. 2004; 10: 675-676.
100. Griffin LD, Gong W, Verot L, Mellon SH. Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat Med. 2004; 10: 704-711.
101. Ellsworth KP, Azzolina BA, Cimis G, Bull HG, Harris GS. Cloning, expression and characterization of rhesus macaque types 1 and 2 5alpha-reductase: evidence for mechanism-based inhibition by finasteride. J Steroid Biochem. Mol. Biol. 1998; 66: 271-279.