Skip to main content

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

Reviews in Endocrine and Metabolic Disorders volume 16, pages 177–198 (2015)Cite this article

Abstract

Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5α-reductase (5α-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5α-R inhibition and supplementation of 5α-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5α-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5α-R inhibitors, as well as their biological underpinnings.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Traish AM. 5alpha-reductases in human physiology: an unfolding story. Endocr Pract. 2012;18:965–75.

    PubMed  Article  Google Scholar 

  2. Paba S, Frau R, Godar SC, Devoto P, Marrosu F, Bortolato M. Steroid 5α-reductase as a novel therapeutic target for schizophrenia and other neuropsychiatric disorders. Curr Pharm Des. 2011;17:151–67.

    PubMed  Article  CAS  Google Scholar 

  3. 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;166:489–97.

    PubMed  Article  CAS  Google Scholar 

  4. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE. Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science. 1974;186:1213–5.

    PubMed  Article  CAS  Google Scholar 

  5. Imperato-McGinley J. 5alpha-reductase-2 deficiency and complete androgen insensitivity: lessons from nature. Adv Exp Med Biol. 2002;511:121–31.

    PubMed  Article  CAS  Google Scholar 

  6. Imperato-McGinley J, Zhu YS. Androgens and male physiology the syndrome of 5alpha-reductase-2 deficiency. Mol Cell Endocrinol. 2002;198:51–9.

    PubMed  Article  CAS  Google Scholar 

  7. Sasaki G, Ogata T, Ishii T, Kosaki K, Sato S, Homma K, et al. Micropenis and the 5alpha-reductase-2 (SRD5A2) gene: mutation and V89L polymorphism analysis in 81 Japanese patients. J Clin Endocrinol Metab. 2003;88:3431–6.

    PubMed  Article  CAS  Google Scholar 

  8. 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;169:1080–1.

    PubMed  Article  Google Scholar 

  9. Katz MD, Kligman I, Cai LQ, Zhu YS, Fratianni CM, Zervoudakis I, et al. Paternity by intrauterine insemination with sperm from a man with 5alpha-reductase-2 deficiency. N Engl J Med. 1997;336:994–7.

    PubMed  Article  CAS  Google Scholar 

  10. Russell DW, Wilson JD. Steroid 5α-reductase: Two genes/Two enzymes. Annu Rev Biochem. 1994;63:25–61.

    PubMed  Article  CAS  Google Scholar 

  11. Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, et al. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 2010;142:203–17.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. Kasapkara CS, Tümer L, Ezgü FS, Hasanoğlu A, Race V, Matthijs G, et al. SRD5A3-CDG: a patient with a novel mutation. Eur J Paediatr Neurol. 2012;16:554–6.

    PubMed  Article  CAS  Google Scholar 

  13. Gründahl JE, Guan Z, Rust S, Reunert J, Müller B, Du Chesne I, et al. Life with too much polyprenol: polyprenol reductase deficiency. Mol Genet Metab. 2012;105:642–51.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. Morava E, Wevers RA, Cantagrel V, Hoefsloot LH, Al-Gazali L, Schoots J, et al. A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Brain. 2010;133:3210–20.

    PubMed  Article  Google Scholar 

  15. Çalışkan M, Chong JX, Uricchio L, Anderson R, Chen P, Sougnez C, et al. Exome sequencing reveals a novel mutation for autosomal recessive non-syndromic mental retardation in the TECR gene on chromosome 19p13. Hum Mol Genet. 2011;20:1285–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. Bramson HN, Hermann D, Batchelor KW, Lee FW, James MK, Frye SV. Unique preclinical characteristic of GG745, a potent dual inhibitor of 5α-Rs. J Pharmacol Exp Ther. 1997;282:1496–502.

    PubMed  CAS  Google Scholar 

  17. Marver D, Edelman IS. Dihydrocortisol: a potential mineralocorticoid. J Steroid Biochem. 1978;9:1.

    PubMed  Article  CAS  Google Scholar 

  18. Dubrovsky B. Neurosteroids, neuroactive steroids, and symptoms of affective disorders. Pharmacol Biochem Behav. 2006;84:644–55.

    PubMed  Article  CAS  Google Scholar 

  19. Kang HJ, Imperato-McGinley J, Zhu YS, Rosenwaks Z. The effect of 5α-reductase-2 deficiency on human fertility. Fertil Steril. 2014;101:310–6.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. Blouin K, Veilleux A, Luu-The V, Tchernof A. Androgen metabolism in adipose tissue: recent advances. Mol Cell Endocrinol. 2009;301:97–103.

    PubMed  Article  CAS  Google Scholar 

  21. Yarrow JF, Beggs LA, Conover CF, McCoy SC, Beck DT, Borst SE. Influence of androgens on circulating adiponectin in male and female rodents. PLoS One. 2012;7, e47315.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 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.

    PubMed  PubMed Central  Article  Google Scholar 

  23. Traish AM, Guay AT, Zitzmann M. 5α-Reductase inhibitors alter steroid metabolism and may contribute to insulin resistance, diabetes, metabolic syndrome and vascular disease: a medical hypothesis. Horm Mol Biol Clin Invest. 2014;20:73–80.

    CAS  Google Scholar 

  24. Walker BR, Stewart PM, Shackleton CH, Padfield PL, Edwards CR. Deficient inactivation of cortisol by 11 beta-hydroxysteroid dehydrogenase in essential hypertension. Clin Endocrinol. 1993;39:221–7.

    Article  CAS  Google Scholar 

  25. Hellman L, Nakada F, Zumoff B, Fukushima D, Bradlow HL, Gallagher TF. Renal capture and oxidation of cortisol in man. J Clin Endocrinol Metab. 1971;33:52–62.

    PubMed  Article  CAS  Google Scholar 

  26. Bamberger CM, Schulte HM, Chrousos GP. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev. 1996;17:245–61.

    PubMed  Article  CAS  Google Scholar 

  27. DeRijk R, Schaaf M, de Kloet E. Glucocorticoid receptor variants: clinical implications. J Steroid Biochem Mol Biol. 2002;81:103–22.

    PubMed  Article  CAS  Google Scholar 

  28. Melcangi RC, Garcia-Segura LM, Mensah-Nyagan AG. Neuroactive steroids: state of the art and new perspectives. Cell Mol Life Sci. 2008;65:777–97.

    PubMed  Article  CAS  Google Scholar 

  29. Melcangi RC, Panzica G, Garcia-Segura LM. Neuroactive steroids: focus on human brain. Neuroscience. 2011;191:1–5.

    PubMed  Article  CAS  Google Scholar 

  30. Melcangi RC, Giatti S, Pesaresi M, Calabrese D, Mitro N, Caruso D, et al. Role of neuroactive steroids in the peripheral nervous system. Front Endocrinol (Lausanne). 2011;2:104.

    Google Scholar 

  31. Melcangi RC, Panzica GC. Allopregnanolone: state of the art. Prog Neurobiol. 2014;113:1–5.

    PubMed  Article  CAS  Google Scholar 

  32. Melcangi RC, Panzica GC. Neuroactive steroids and the nervous system: further observations on an incomplete tricky puzzle. J Neuroendocrinol. 2013;25:957–63.

    PubMed  Article  CAS  Google Scholar 

  33. Panzica GC, Balthazart J, Frye CA, Garcia-Segura LM, Herbison AE, Mensah-Nyagan AG, et al. Milestones on Steroids and the Nervous System: 10 years of basic and translational research. J Neuroendocrinol. 2012;24:1–15.

    PubMed  Article  CAS  Google Scholar 

  34. Pelletier G. Steroidogenic enzymes in the brain: morphological aspects. Prog Brain Res. 2010;181:193–207.

    PubMed  Article  CAS  Google Scholar 

  35. Lephart ED, Lund TD, Horvath TL. Brain androgen and progesterone metabolizing enzymes: biosynthesis, distribution and function. Brain Res Brain Res Rev. 2001;37:25–37.

    PubMed  Article  CAS  Google Scholar 

  36. Jin Y, Penning TM. Steroid 5alpha-reductases and 3alpha-hydroxysteroid dehydrogenases: key enzymes in androgen metabolism. Best Pract Res Clin Endocrinol Metab. 2001;15:79–94.

    PubMed  Article  CAS  Google Scholar 

  37. Garcia-Segura LM, Veiga S, Sierra A, Melcangi RC, Azcoitia I. Aromatase: a neuroprotective enzyme. Prog Neurobiol. 2003;71:31–41.

    PubMed  Article  CAS  Google Scholar 

  38. Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA. Neurosteroid modulation of GABAA receptors. Prog Neurobiol. 2003;71:67–80.

    PubMed  Article  CAS  Google Scholar 

  39. Belelli D, Lambert JJ. Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci. 2005;6:565–75.

    PubMed  Article  CAS  Google Scholar 

  40. Intlekofer KA, Petersen SL. Distribution of mRNAs encoding classical progestin receptor, progesterone membrane components 1 and 2, serpine mRNA binding protein 1, and progestin and ADIPOQ receptor family members 7 and 8 in rat forebrain. Neuroscience. 2011;13(172):55–65.

    Article  CAS  Google Scholar 

  41. Thomas P, Pang Y. Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells. Neuroendocrinology. 2012;96:162–71.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. Cooke PS, Nanjappa MK, Yang Z, Wang KK. Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms. Front Neurosci. 2013;7:108.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. Handa RJ, Pak TR, Kudwa AE, Lund TD, Hinds L. An alternate pathway for androgen regulation of brain function: activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5alpha-androstane-3beta,17beta-diol. Horm Behav. 2008;53:741–52.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. Foradori CD, Weiser MJ, Handa RJ. Non-genomic actions of androgens. Front Neuroendocrinol. 2008;29:169–81.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. Negri-Cesi P, Colciago A, Celotti F, Motta M. Sexual differentiation of the brain: role of testosterone and its active metabolites. J Endocrinol Investig. 2004;27:120–7.

    CAS  Google Scholar 

  46. Frye CA. Some rewarding effects of androgens may be mediated by actions of its 5alpha-reduced metabolite 3alpha-androstanediol. Pharmacol Biochem Behav. 2007;86:354–67.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. Handa RJ, Kudwa AE, Donner NC, McGivern RF, Brown R. Central 5-alpha reduction of testosterone is required for testosterone’s inhibition of the hypothalamo-pituitary-adrenal axis response to restraint stress in adult male rats. Brain Res. 2013;1529:74–82.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. Denecke J, Kranz C. Hypoglycosylation due to dolichol metabolism defects. Biochim Biophys Acta. 2009;1792:888–95.

    PubMed  Article  CAS  Google Scholar 

  49. Stiles AR, Russell DW. SRD5A3: a surprising role in glycosylation. Cell. 2010;23(142):196–8.

    Article  CAS  Google Scholar 

  50. Wong AC, Mak ST. Finasteride-associated cataract and intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2011;37:1351–4.

    PubMed  Article  Google Scholar 

  51. Rasmusson GH, Reynolds GF, Steinberg NG, Walton E, Patel GF, Liang T, et al. Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding. J Med Chem. 1986;29:2298–315.

    PubMed  Article  CAS  Google Scholar 

  52. Goldsmith LA, Fitzpatrick TB. Fitzpatrick’s dermatology in general medicine. 8th ed. New York: McGraw-Hill Professional; 2012.

    Google Scholar 

  53. Bull HG, Garcia-Calvo M, Andersson S, Baginsky WF, Chan HK, Ellsworth DE, et al. Mechanism-Based Inhibition of Human Steroid 5α-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP−Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor. J Am Chem Soc. 1996;118:2359–65.

    Article  CAS  Google Scholar 

  54. Frye SV, Bramson HN, Hermann DJ, Lee FW, Sinhababu AK, Tian G. Discovery and development of GG745, a potent inhibitor of both isozymes of 5 alpha-reductase. Pharm Biotechnol. 1998;11:393–422.

    PubMed  Article  CAS  Google Scholar 

  55. Bakshi RK, Patel GF, Rasmusson GH, Baginsky WF, Cimis G, Ellsworth K, et al. 4,7 beta-Dimethyl-4-azacholestan-3-one (MK-386) and related 4-azasteroids as selective inhibitors of human type 1 5 alpha-reductase. J Med Chem. 1994;37:3871–4.

    PubMed  Article  CAS  Google Scholar 

  56. Ellsworth K, Azzolina B, Baginsky W, Bull H, Chang B, Cimis G, et al. MK386: a potent, selective inhibitor of the human type 1 5alpha-reductase. J Steroid Biochem Mol Biol. 1996;58:377–84.

    PubMed  Article  CAS  Google Scholar 

  57. Aggarwal S, Thareja S, Verma A, Bhardwaj TR, Kumar M. An overview on 5alpha-reductase inhibitors. Steroids. 2010;75:109–53.

    PubMed  Article  CAS  Google Scholar 

  58. Nickel JC, Fradet Y, Boake RC, Pommerville PJ, Perreault JP, Afridi SK, et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). PROscar Safety Plus Efficacy Canadian Two year Study. CMAJ. 1996;155:1251–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  59. McConnell JD, Brusketwitz R, Walsh P, Andriole G, Lieber M, Holtgrewe L, 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;338:557–63.

    PubMed  Article  CAS  Google Scholar 

  60. Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002;60:434–41.

    PubMed  Article  Google Scholar 

  61. Debruyne F, Barkin J, van Erps P, Reis M, Tammela TL, Roehrborn C. Efficacy and safety of long-term treatment with the dual 5 alpha-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol. 2004;46:488–94.

    PubMed  Article  CAS  Google Scholar 

  62. Wu C, Kapoor A. Dutasteride for the treatment of benign prostatic hyperplasia. Expert Opin Pharmacother. 2013;14:1399–408.

    PubMed  Article  CAS  Google Scholar 

  63. Bechis SK, Otsetov AG, Ge R, Olumi AF. Personalized medicine for management of benign prostatic hyperplasia. J Urol. 2014;192:16–23.

    PubMed  PubMed Central  Article  Google Scholar 

  64. Kaufman KD, Olsen EA, Whiting D, Savin R, DeVillez R, Bergfeld W, et al. Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group. J Am Acad Dermatol. 1998;39:578–89.

    PubMed  Article  CAS  Google Scholar 

  65. Castello R, Tosi F, Perrone F, Negri C, Muggeo M, Moghetti P. Outcome of long-term treatment with 5 alpha-reductase inhibitor finasteride in idiopaathic hirsutism: clinical and hormonal effecs during a 1-year course of therapy and 1-year follow-up. Fertil Steril. 1996;66:734–40.

  66. Moghetti P, Castello R, Magnani CM, Tosi F, Negri C, Armanini D, et al. Clinical and hormonal effects of the 5 alpha-reductase inhibitor finasteride in idiopathic hirsutism. J Clin Endocrinol Metab. 1994;79:1115–21.

    PubMed  CAS  Google Scholar 

  67. Moghetti P, Tosi F, Tosti A, Negri C, Misciali C, Perrone F, et al. Comparison of spironolactone, flutamide, and finasteride efficacy in the treatment of hirsutism: a randomized, double blind, placebo-controlled trial. J Clin Endocrinol Metab. 2000;85:89–94.

    PubMed  CAS  Google Scholar 

  68. Muroni A, Paba S, Puligheddu M, Marrosu F, Bortolato M. A preliminary study of finasteride in Tourette syndrome. Mov Disord. 2011;26:2146–7.

    PubMed  Article  Google Scholar 

  69. Bortolato M, Frau R, Godar SC, Mosher LJ, Paba S, Marrosu F, et al. The implication of neuroactive steroids in Tourette’s syndrome pathogenesis: a role for 5α-reductase? J Neuroendocrinol. 2013;25:1196–208.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. Bortolato M, Cannas A, Solla P, Bini V, Puligheddu M, Marrosu F. Finasteride attenuates pathological gambling in patients with Parkinson disease. J Clin Psychopharmacol. 2012;32:424–5.

    PubMed  Article  Google Scholar 

  71. Bortolato M, Frau R, Orrù M, Bourov Y, Marrosu F, Mereu G, et al. Antipsychotic-like properties of 5-alpha-reductase inhibitors. Neuropsychopharmacology. 2008;33:3146–56.

    PubMed  Article  CAS  Google Scholar 

  72. Devoto P, Frau R, Bini V, Pillolla G, Saba P, Flore G, et al. Inhibition of 5α-reductase in the nucleus accumbens counters sensorimotor gating deficits induced by dopaminergic activation. Psychoneuroendocrinology. 2012;37:1630–45.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. Ikemoto S, Panksepp J. The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res Brain Res Rev. 1999;31:6–41.

    PubMed  Article  CAS  Google Scholar 

  74. Salamone JD, Correa M. Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine. Behav Brain Res. 2002;137:3–25.

    PubMed  Article  CAS  Google Scholar 

  75. Stoner E. The clinical development of a 5 alpha-reductase inhibitor, finasteride. J Steroid Biochem Mol Biol. 1990;37:375–8.

    PubMed  Article  CAS  Google Scholar 

  76. De Schepper PJ, Imperato-McGinley J, Van Hecken A, De Lepeleire I, Buntinx A, Carlin J, et al. Hormonal effects, tolerability, and preliminary kinetics in men of MK-906, a 5 alpha-reductase inhibitor. Steroids. 1991;56:469–71.

    PubMed  Article  Google Scholar 

  77. McConnell JD, Roehrborn CG, Bautista OM, Andriole Jr GL, Dixon CM, Kusek JW, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003;349:2387–98.

    PubMed  Article  CAS  Google Scholar 

  78. Lowe FC, McConnell JD, Hudson PB, Romas NA, Boake R, Lieber M, et al. Long-term 6-year experience with finasteride in patients with benign prostatic hyperplasia. Urology. 2003;61:791–6.

    PubMed  Article  Google Scholar 

  79. Andriole GL, Guess HA, Epstein JI, Wise H, Kadmon D, Crawford ED, Hudson P, Jackson CL, Romas NA, Patterson L, cook TJ, Waldstreicher J. Treatment with finasteride perserves usefulness of prostate specific antigen in the dection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial. PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Urology. 1998;52:195–201.

  80. Naslund MJ, Miner M. A review of the clinical efficacy and safety of 5alpha-reductase inhibitors for the enlarged prostate. Clin Ther. 2007;29:17–25.

    PubMed  Article  CAS  Google Scholar 

  81. Yim E, Nole KL, Tosti A. 5α-Reductase inhibitors in androgenetic alopecia. Curr Opin Endocrinol Diabetes Obes. 2014;21:493–8.

    PubMed  Article  CAS  Google Scholar 

  82. Falto-Aizpurua L, Choudhary S, Tosti A. Emerging treatments in alopecia. Expert Opin Emerg Drugs. 2014;19:545–56.

    PubMed  Article  CAS  Google Scholar 

  83. Food and Drug Administration. Oncologic Drugs Advisory Committee - 2010 Meeting Materials, Oncologic Drugs Advisory Committee. 2010

  84. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215–24.

    PubMed  Article  CAS  Google Scholar 

  85. Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362:1192–202.

    PubMed  Article  CAS  Google Scholar 

  86. Wessells H, Roy J, Bannow J, Grayhack J, Matsumoto AM, Tenover L, et al. Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia. Urology. 2003;61:579–84.

    PubMed  Article  Google Scholar 

  87. Gupta AK, Charrette A. The efficacy and safety of 5alpha-reductase inhibitors in androgenetic alopecia: a network meta-analysis and benefit-risk assessment of finasteride and dutasteride. J Dermatol Treat. 2014;25:156–61.

    Article  CAS  Google Scholar 

  88. Mella JM, Perret MC, Manzotti M, Catalano HN, Guyatt G. Efficacy and safety of finasteride therapy for androgenetic alopecia: a systematic review. Arch Dermatol. 2010;146:1141–50.

    PubMed  Article  Google Scholar 

  89. Belknap SM, Aslam I, Kiguradze T, Temps WH, Yarnold PR, Cashy J, et al. Adverse event reporting in clinical trials of finasteride for androgenic alopecia: a meta-analysis. JAMA Dermatol. 2015;151:600–6.

  90. Moore TJ. Finasteride and the uncertainties of establishing harms. JAMA Dermatol. 2015;151:586–6.

  91. Roehrborn CG, Perez IO, Roos EP, Calomfirescu N, Brotherton B, Wang F, et al. Efficacy and safety of a fixed-dose combination of dutasteride and tamsulosin treatment (Duodart™) compared with watchful waiting with initiation of tamsulosin therapy if symptoms do not improve, both provided with lifestyle advice, in the management of treatment-naïve men with moderately symptomatic benign prostatic hyperplasia: 2-Year CONDUCT study results. BJU Int. 2015. doi:10.1111/bju.13033.

  92. Traish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML. Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients. J Sex Med. 2011;8:872–84.

    PubMed  Article  CAS  Google Scholar 

  93. Irwig MS, Kolukula S. Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med. 2011;8:1747–53.

    PubMed  Article  Google Scholar 

  94. 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;8:3066–74.

    PubMed  Article  CAS  Google Scholar 

  95. Oztekin CV, Gur S, Abdulkadir NA, Lokman U, Akdemir AO, Cetinkaya M, et al. Incomplete recovery of erectile function in rat after discontinuation of dual 5-alpha reductase inhibitor therapy. J Sex Med. 2012;9:1773–81.

    PubMed  Article  CAS  Google Scholar 

  96. MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med. 2004;350:367–78.

    PubMed  Article  CAS  Google Scholar 

  97. Bradshaw WG, Baum MJ, Awh CC. Attenuation by a 5 alpha-reductase inhibitor of the activational effect of testosterone propionate on penile erections in castrated male rats. Endocrinology. 1981;109:1047–51.

    PubMed  Article  CAS  Google Scholar 

  98. Gray GD, Smith ER, Davidson JM. Hormonal regulation of penile erection in castrated male rats. Physiol Behav. 1980;24:463–8.

    PubMed  Article  CAS  Google Scholar 

  99. Hart BL. Effects of testosterone propionate and dihydrotestosterone on penile morphology and sexual reflexes of spinal male rats. Horm Behav. 1973;4:239–46.

    PubMed  Article  CAS  Google Scholar 

  100. Hart BL. Activation of sexual reflexes of male rats by dihydrotestosterone but not estrogen. Physiol Behav. 1979;23:107–9.

    PubMed  Article  CAS  Google Scholar 

  101. Mantzoros CS, Georgiadis EI, Trichopoulos D. Contribution of dihydrotestosterone to male sexual behaviour. BMJ. 1995;310:1289–91.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. Saksena SK, Lau IF, Chang MC. The inhibition of the conversion of testosterone into 5alpha-dihydrotestosterone in the reproductive organs of the male rat. Steroids. 1976;27:751–7.

    PubMed  Article  CAS  Google Scholar 

  103. Baum MJ. A comparison of the effects of methyltrienolone (R 1881) and 5 alpha-dihydrotestosterone on sexual behavior of castrated male rats. Horm Behav. 1979;13:165–74.

    PubMed  Article  CAS  Google Scholar 

  104. Lugg JA, Rajfer J, Gonzalez-Cadavid NF. Dihydrotestosterone is the active androgen in the maintenance of nitric oxide-mediated penile erection in the rat. Endocrinology. 1995;136:1495–501.

    PubMed  CAS  Google Scholar 

  105. Bialy M, Sachs BD. Androgen implants in medial amygdala briefly maintain noncontact erection in castrated male rats. Horm Behav. 2002;42:345–55.

    PubMed  Article  CAS  Google Scholar 

  106. Manzo J, Cruz MR, Hernandez ME, Pacheco P, Sachs BD. Regulation of noncontact erection in rats by gonadal steroids. Horm Behav. 1999;35:264–70.

    PubMed  Article  CAS  Google Scholar 

  107. Seo SI, Kim SW, Paick JS. The effects of androgen on penile reflex, erectile response to electrical stimulation and penile NOS activity in the rat. Asian J Androl. 1999;1:169–74.

    PubMed  CAS  Google Scholar 

  108. Zhang MG, Wang XJ, Shen ZJ, Gao PJ. Long-term oral administration of 5alpha-reductase inhibitor attenuates erectile function by inhibiting autophagy and promoting apoptosis of smooth muscle cells in corpus cavernosum of aged rats. Urology. 2013;82:743.

    PubMed  Google Scholar 

  109. Traish AM, Park K, Dhir V, Kim NN, Moreland RB, Goldstein I. Effects of castration and androgen replacement on erectile function in a rabbit model. Endocrinology. 1999;140:1861–8.

    PubMed  CAS  Google Scholar 

  110. Tenover JL, Pagano GA, Morton AS, Liss CL, Byrnes CA. Efficacy and tolerability of finasteride in symptomatic benign prostatic hyperplasia: a primary care study. Primary Care Investigator Study Group. Clin Ther. 1997;19:243–58.

    PubMed  Article  CAS  Google Scholar 

  111. Hudson PB, Boake R, Trachtenberg J, Romas NA, Rosenblatt S, Narayan P, et al. Efficacy of finasteride is maintained in patients with benign prostatic hyperplasia treated for 5 years. The North American Finasteride Study Group. Urology. 1999;53:690–5.

    PubMed  Article  CAS  Google Scholar 

  112. Bruskewitz R, Girman CJ, Fowler J, Rigby OF, Sullivan M, Bracken RB, et al. Effect of finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia. PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Urology. 1999;54:670–8.

    PubMed  Article  CAS  Google Scholar 

  113. Wilton L, Pearce G, Edet E, Freemantle S, Stephens MD, Mann RD. The safety of finasteride used in benign prostatic hypertrophy: a non-interventional observational cohort study in 14,772 patients. Br J Urol. 1996;78:379–84.

    PubMed  Article  CAS  Google Scholar 

  114. AUA guideline on management of benign prostatic hyperplasia. Chapter 1: diagnosis and treatment recommendations. J Urol. 2003;170:530–47.

    Article  Google Scholar 

  115. Edwards JE, Moore RA. Finasteride in the treatment of clinical benign prostatic hyperplasia: a systematic review of randomised trials. BMC Urol. 2002;2:14.

    PubMed  PubMed Central  Article  Google Scholar 

  116. Roehrborn CG, Siami P, Barkin J, Damiao R, Major-Walker K, Morrill B, et al. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol. 2008;179:616–21.

    PubMed  Article  CAS  Google Scholar 

  117. Siami P, Roehrborn CG, Barkin J, Damiao R, Wyczolkowski M, Duggan A, et al. Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: the CombAT (Combination of Avodart and Tamsulosin) trial rationale and study design. Control Clin Trials. 2007;28:770–9.

    Article  CAS  Google Scholar 

  118. 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;98:83–8.

    PubMed  Article  CAS  Google Scholar 

  119. Canguven O, Burnett AL. The effect of 5 alpha-reductase inhibitors on erectile function. J Androl. 2008;29:514–23.

    PubMed  Article  CAS  Google Scholar 

  120. Kaplan SA, Chung DE, Lee RK, Scofield S, Te AE. A 5-year retrospective analysis of 5alpha-reductase inhibitors in men with benign prostatic hyperplasia: finasteride has comparable urinary symptom efficacy and prostate volume reduction, but less sexual side effects and breast complications than dutasteride. Int J Clin Pract. 2012;66:1052–5.

    PubMed  Article  CAS  Google Scholar 

  121. Chi BH, Kim SC. Changes in sexual function in benign prostatic hyperplasia patients taking dutasteride: 1-year follow-up results. Korean J Urol. 2011;52:632–6.

    PubMed  PubMed Central  Article  Google Scholar 

  122. Fwu CW, Eggers PW, Kirkali Z, McVary KT, Burrows PK, Kusek JW. Change in sexual function in men with lower urinary tract symptoms (LUTS)/ benign prostatic hyperplasia (BPH) associated with long-term treatment with doxazosin, finasteride, and combined therapy. J Urol. 2014;191:1828–34.

  123. Irwig MS. Persistent sexual and non-sexual adverse effects of finasteride in younger men. Sex Med Rev. 2014;2:24–35.

    Article  Google Scholar 

  124. Irwig MS. Androgen levels and semen parameters among former users of Finasteride with persistent sexual adverse effects. JAMA Dermatol. 2014;150:1361–3.

    PubMed  Article  Google Scholar 

  125. Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012;73:1220–3.

    PubMed  Article  CAS  Google Scholar 

  126. Singh MK, Avram M. Persistent sexual dysfunction and depression in finasteride users for male pattern hair loss: a serious concern or red herring? J Clin Aesthet Dermatol. 2014;7:51–5.

    PubMed  PubMed Central  Google Scholar 

  127. Mahony MC, Swanlund DJ, Billeter M, Roberts KP, Pryor JL. Regional distribution of 5 alpha-reductase type 1 and type 2 mRNA along the human epididymis. Fertil Steril. 1998;69:1116–21.

    PubMed  Article  CAS  Google Scholar 

  128. Di Loreto C, La Marra F, Mazzon G, Belgrano E, Trombetta C, Cauci S. Immunohistochemical evaluation of androgen receptor and nerve structure density inhuman prepuce from patients with persistent sexual side effects after finasteride use for androgenetic alopecia. PLoS One. 2014;9, e100237.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  129. Traish AM, Haider KS, Doros G, Haider A. Finasteride, not tamsulosin, increases severity of erectile dysfunction and decreases testosterone levels in men with benign prostatic hyperplasia. Horm Mol Biol Clin Investig. 2015. doi:10.1515/hmbci-2015-0015.

    PubMed  Google Scholar 

  130. Mondaini N, Gontero P, Giubilei G, Lombardi G, Cai T, Gavazzi A, et al. Finasteride 5 mg and sexual side effects: how many of these are related to a nocebo phenomenon? J Sex Med. 2007;4:1708–12.

    PubMed  Article  Google Scholar 

  131. Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol. 2009;55:310–20.

    PubMed  Article  Google Scholar 

  132. Traish AM, Morgentaler A. Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth. Br J Cancer. 2009;101:1949–56.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. Morgentaler A. Goodbye androgen hypothesis, hello saturation model. Eur Urol. 2012;62:765–7.

    PubMed  Article  Google Scholar 

  134. Muller RL, Gerber L, Moreira DM, Andriole G, Castro-Santamaria R, Freedland SJ. Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial. Eur Urol. 2012;62:757–64.

    PubMed  Article  CAS  Google Scholar 

  135. Theoret MR, Ning YM, Zhang JJ, Justice R, Keegan P, Pazdur R. The risks and benefits of 5alpha-reductase inhibitors for prostate-cancer prevention. N Engl J Med. 2011;365:97–9.

    PubMed  Article  CAS  Google Scholar 

  136. Walsh PC. Three considerations before advising 5-alpha-reductase inhibitors for chemoprevention. J Clin Oncol. 2009;27, e22.

    PubMed  Article  Google Scholar 

  137. Walsh PC. Chemoprevention of prostate cancer. N Engl J Med. 2010;362:1237–8.

    PubMed  Article  CAS  Google Scholar 

  138. Thompson Jr IM, Goodman PJ, Tangen CM, Parnes HL, Minasian LM, Godley PA, et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med. 2013;369:603–10.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. Ehdaie B, Touijer KA. 5-alpha Reductase inhibitors in prostate cancer: from clinical trials to clinical practice. Eur Urol. 2013;63:788–9.

    PubMed  Article  Google Scholar 

  140. Hoffman RM, Roberts RG, Barry MJ. Battling prostate cancer with 5-alpha-reductase inhibitors: a pyrrhic victory? J Gen Intern Med. 2011;26:798–801.

    PubMed  PubMed Central  Article  Google Scholar 

  141. Andriole GL, Kirby R. Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia. Eur Urol. 2003;44:82–8.

    PubMed  Article  CAS  Google Scholar 

  142. Roehrborn CG, Andriole GL, Wilson TH, Castro R, Rittmaster RS. Effect of dutasteride on prostate biopsy rates and the diagnosis of prostate cancer in men with lower urinary tract symptoms and enlarged prostates in the Combination of Avodart and Tamsulosin trial. Eur Urol. 2011;59:244–9.

    PubMed  Article  CAS  Google Scholar 

  143. Justman S. What’s wrong with chemoprevention of prostate cancer? Am J Bioeth. 2011;11:21–5.

    PubMed  Article  Google Scholar 

  144. Tomlinson JW, Finney J, Gay C, Hughes BA, Hughes SV, Stewart PM. Impaired glucose tolerance and insulin resistance are associated with increased adipose 11 -hydroxysteroid dehydrogenase type 1 expression and elevated hepatic 5 -reductase activity. Diabetes. 2008;57:2652–60.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  145. Ferris HA, Kahn CR. New mechanisms of glucocorticoid-induced insulin resistance: make no bones about it. J Clin Invest. 2012;122:3854–7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  146. Barat P, Livingstone DEW, Elferink CMC, McDonnell CR, Walker BR, Andrew R. Effects of Gonadectomy on glucocorticoid metabolism in obese Zucker rats. Endocrinology. 2007;148:4836–43.

    PubMed  Article  CAS  Google Scholar 

  147. Morgan SA, Gathercole LL, Simonet C, Hassan-Smith ZK, Bujalska I, Guest P, et al. Regulation of lipid metabolism by glucocorticoids and 11â-HSD1 in skeletal muscle. Endocrinology. 2013;154:2374–84.

    PubMed  Article  CAS  Google Scholar 

  148. Solas M, Gerenu G, Gil-Bea FJ, Ramírez MJ. Mineralocorticoid receptor activation induces insulin resistance through c-Jun N-terminal kinases in response to chronic corticosterone: cognitive implications. J Neuroendocrinol. 2013;25:350–6.

    PubMed  Article  CAS  Google Scholar 

  149. Upreti R, Hughes KA, Livingstone DE, Gray CD, Minns FC, Macfarlane DP, et al. 5α-reductase type 1 modulates insulin sensitivity in men. J Clin Endocrinol Metab. 2014;99:E1397–406.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  150. Hanley AJ, Karter AJ, Williams K, Festa A, D’Agostino Jr RB, Wagenknecht LE, et al. Prediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study. Circulation. 2005;112:3713–21.

    PubMed  Article  Google Scholar 

  151. Livingstone DE, Barat P, Di Rollo EM, Rees GA, Weldin BA, Rog-Zielinska EA, et al. 5α-Reductase type 1 deficiency or inhibition predisposes to insulin resistance, hepatic steatosis and liver fibrosis in rodents. Diabetes. 2015;64:447-58.

  152. Livingstone DE, Di Rollo EM, Yang C, Codrington LE, Mathews JA, Kara M, et al. Relative adrenal insufficiency in mice deficient in 5α-reductase 1. J Endocrinol. 2014;222:257–66.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  153. Lin WL, Hsieh YW, Lin CL, Sung FC, Wu CH, Kao CH. A population-based nested case–control study: the use of 5-alpha-reductase inhibitors and the increased risk of osteoporosis diagnosis in patients with benign prostate hyperplasia. Clin Endocrinol (Oxf). 2015;82:503–8.

  154. Windahl SH, Andersson N, Börjesson AE, Swanson C, Svensson J, Movérare-Skrtic S, et al. Reduced bone mass and muscle strength in male 5α-reductase type 1 inactivated mice. PLoS One. 2011;6, e21402.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  155. Altomare G, Capella GL. Depression circumstantially related to the administration of finasteride for androgenetic alopecia. J Dermatol. 2002;29:665–9.

    PubMed  Article  Google Scholar 

  156. Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A. Finasteride induced depression: a prospective study. BMC Clin Pharmacol. 2006;6:7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  157. Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, et al. Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc Natl Acad Sci U S A. 2001;98:2849–54.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  158. Guidotti A, Dong E, Matsumoto K, Pinna G, Rasmusson AM, Costa E. The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5alpha-dihydroprogesterone in psychiatric disorders. Brain Res Brain Res Rev. 2001;37:110–5.

    PubMed  Article  CAS  Google Scholar 

  159. Bali A, Jaggi AS. Multifunctional aspects of allopregnanolone in stress and related disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:64–78.

    PubMed  Article  CAS  Google Scholar 

  160. Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, et al. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci U S A. 1998;95:3239–44.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  161. Strohle A, Romeo E, Hermann B, Pasini A, Spalletta G, di Michele F, et al. Concentrations of 3 alpha-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery. Biol Psychiatry. 1999;45:274–7.

    PubMed  Article  CAS  Google Scholar 

  162. Griffin LD, Mellon SH. Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci U S A. 1999;96:13512–7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  163. Romeo E, Strohle A, Spalletta G, di Michele F, Hermann B, Holsboer F, et al. Effects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry. 1998;155:910–3.

    PubMed  Article  CAS  Google Scholar 

  164. Uzunova V, Sampson L, Uzunov DP. Relevance of endogenous 3alpha-reduced neurosteroids to depression and antidepressant action. Psychopharmacology (Berl). 2006;186:351–61.

    Article  CAS  Google Scholar 

  165. Padberg F, di Michele F, Zwanzger P, Romeo E, Bernardi G, Schule C, et al. Plasma concentrations of neuroactive steroids before and after repetitive transcranial magnetic stimulation (rTMS) in major depression. Neuropsychopharmacology. 2002;27:874–8.

    PubMed  Article  CAS  Google Scholar 

  166. Baghai TC, di Michele F, Schule C, Eser D, Zwanzger P, Pasini A, et al. Plasma concentrations of neuroactive steroids before and after electroconvulsive therapy in major depression. Neuropsychopharmacology. 2005;30:1181–6.

    PubMed  Article  CAS  Google Scholar 

  167. Mensah-Nyagan AG, Kibaly C, Schaeffer V, Venard C, Meyer L, Patte-Mensah C. Endogenous steroid production in the spinal cord and potential involvement in neuropathic pain modulation. J Steroid Biochem Mol Biol. 2008;109:286–93.

    PubMed  Article  CAS  Google Scholar 

  168. Patte-Mensah C, Kibaly C, Boudard D, Schaeffer V, Béglé A, Saredi S, et al. Mensah-Nyagan AG Neurogenic pain and steroid synthesis in the spinal cord. J Mol Neurosci. 2006;28:17–31.

    PubMed  Article  CAS  Google Scholar 

  169. Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG. Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain. Prog Neurobiol. 2014;113:70–8.

    PubMed  Article  CAS  Google Scholar 

  170. Calabrese D, Giatti S, Romano S, Porretta-Serapiglia C, Bianchi R, Milanese M, et al. Diabetic neuropathic pain: a role for testosterone metabolites. J Endocrinol. 2014;7(221):1–13.

    Article  CAS  Google Scholar 

  171. Melcangi RC, Giatti S, Calabrese D, et al. Levels and actions of progesterone and its metabolites in the nervous system during physiological and pathological conditions. Prog Neurobiol. 2014;113:56–69.

    PubMed  Article  CAS  Google Scholar 

  172. He J, Evans CO, Hoffman SW, Oyesiku NM, Stein DG. Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury. Exp Neurol. 2004;189:404–12.

    PubMed  Article  CAS  Google Scholar 

  173. VanLandingham JW, Cutler SM, Virmani S, Hoffman SW, Covey DF, Krishnan K, et al. The enantiomer of progesterone acts as a molecular neuroprotectant after traumatic brain injury. Neuropharmacology. 2006;51:1078–85.

    PubMed  Article  CAS  Google Scholar 

  174. Ishrat T, Sayeed I, Atif F, Hua F, Stein DG. Progesterone and allopregnanolone attenuate blood-brin barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases. Exp Neurol. 2010;226:183–90.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  175. Morali G, Montes P, Gonzalez-Burgos I, Velazquez-Zamora DA, Cervantes M. Cytoarchitectural characteristics of hippocampal CA1 pyramidal neurons of rats, four months after global cerebral ischemia and progesterone treatment. Restor Neurol Neurosci. 2012;30:1–8.

    PubMed  CAS  Google Scholar 

  176. Sayeed I, Guo Q, Hoffman SW, Stein DG. Allopregnanolone, a progesterone metabolite, is more effective than progesterone in reducing cortical infarct volume after transient middle cerebral artery occlusion. Ann Emerg Med. 2006;47:381–9.

    PubMed  Article  Google Scholar 

  177. Yawno T, Yan EB, Walker DW, Hirst JJ. Inhibition of neurosteroid synthesis increases asphyxia-induced brain injury in the late gestation fetal sheep. Neuroscience. 2007;146:1726–33.

    PubMed  Article  CAS  Google Scholar 

  178. Ciriza I, Azcoitia I, Garcia-Segura LM. Reduced progesterone metabolites protect rat hippocampal neurones from kainic acid excitotoxicity in vivo. J Neuroendocrinol. 2004;16:58–63.

    PubMed  Article  CAS  Google Scholar 

  179. Ishihara Y, Kawami T, Ishida A, Yamazaki T. Allopregnanolone-mediated protective effects of progesterone on tributyltin-induced neuronal injury in rat hippocampal slices. J Steroid Biochem Mol Biol. 2013;135:1–6.

    PubMed  Article  CAS  Google Scholar 

  180. Romer B, Pfeiffer N, Lewicka S, Ben-Abdallah N, Vogt MA, Deuschle M, et al. Finasteride treatment inhibits adult hippocampal neurogenesis in male mice. Pharmacopsychiatry. 2010;43:174–8.

    PubMed  Article  CAS  Google Scholar 

  181. Mellon SH. Neurosteroid regulation of central nervous system development. Pharmacol Ther. 2007;116:107–24.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  182. Irwin RW, Brinton RD. Allopregnanolone as regenerative therapeutic for Alzheimer’s disease: translational development and clinical promise. Prog Neurobiol. 2014;113:40–55.

    PubMed  Article  CAS  Google Scholar 

  183. Caruso D, Scurati S, Maschi O, et al. Evaluation of neuroactive steroid levels by liquid chromatography-tandem mass spectrometry in central and peripheral nervous system: effect of diabetes. Neurochem Int. 2008;52:560–8.

    PubMed  Article  CAS  Google Scholar 

  184. Caruso D, Scurati S, Roglio I, Nobbio L, Schenone A, Melcangi RC. Neuroactive Steroid Levels in a transgenic rat model of CMT1A Neuropathy. J Mol Neurosci. 2008;34:249–53.

    PubMed  Article  CAS  Google Scholar 

  185. Caruso D, D’Intino G, Giatti S, et al. Sex-dimorphic changes in neuroactive steroid levels after chronic experimental autoimmune encephalomyelitis. J Neurochem. 2010;114:921–32.

    PubMed  Article  CAS  Google Scholar 

  186. Caruso D, Barron AM, Brown MA, et al. Age-related changes in neuroactive steroid levels in 3xTg-AD mice. Neurobiol Aging. 2013;34:1080–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  187. Giatti S, D’Intino G, Maschi O, et al. Acute experimental autoimmune encephalomyelitis induces sex dimorphic changes in neuroactive steroid levels. Neurochem Int. 2010;56:118–27.

    PubMed  Article  CAS  Google Scholar 

  188. Giatti S, Boraso M, Abbiati F, et al. Multimodal analysis in acute and chronic experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol. 2013;8:238–50.

    PubMed  Article  Google Scholar 

  189. Labombarda F, Pianos A, Liere P, Eychenne B, Gonzalez S, Cambourg A, et al. Injury elicited increase in spinal cord neurosteroid content analyzed by gas chromatography mass spectrometry. Endocrinology. 2006;147:1847–59.

    PubMed  Article  CAS  Google Scholar 

  190. Meffre D, Pianos A, Liere P, Eychenne B, Cambourg A, Schumacher M, et al. Steroid profiling in brain and plasma of male and pseudopregnant female rats after traumatic brain injury: analysis by gas chromatography/mass spectrometry. Endocrinology. 2007;148:2505–17.

    PubMed  Article  CAS  Google Scholar 

  191. Melcangi RC, Caruso D, Levandis G, Abbiati F, Armentero MT, Blandini F. Modifications of neuroactive steroid levels in an experimental model of nigrostriatal degeneration: potential relevance to the pathophysiology of parkinson’s disease. J Mol Neurosci. 2012;46:177–83.

    PubMed  Article  CAS  Google Scholar 

  192. Melcangi RC, Garcia-Segura LM. Sex-specific therapeutic strategies based on neuroactive steroids: In search for innovative tools for neuroprotection. Horm Behav. 2010;57:2–11.

    Article  CAS  Google Scholar 

  193. Pesaresi M, Maschi O, Giatti S, Garcia-Segura LM, Caruso D, Melcangi RC. Sex differences in neuroactive steroid levels in the nervous system of diabetic and non-diabetic rats. Horm Behav. 2010;57:46–55.

    PubMed  Article  CAS  Google Scholar 

  194. Naylor JC, Kilts JD, Hulette CM, Steffens DC, Blazer DG, Ervin JF, et al. Allopregnanolone levels are reduced in temporal cortex in patients with Alzheimer’s disease compared to cognitively intact control subjects. Biochim Biophys Acta. 2010;1801:951–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  195. Hirst JJ, Kelleher MA, Walker DW, Palliser HK. Neuroactive steroids in pregnancy: key regulatory and protective roles in the foetal brain. J Steroid Biochem Mol Biol. 2014;139:144–53.

    PubMed  Article  CAS  Google Scholar 

  196. Fwu CW, Eggers PW, Kirkali Z, McVary KT, Burrows PK, Kusek JW. Change in sexual function in men with lower urinary tract symptoms/benign prostatic hyperplasia associated with long-term treatment with doxazosin, finasteride and combined therapy. J Urol. 2014;191:1828–34.

    PubMed  Article  CAS  Google Scholar 

  197. Stanczyk FZ, Azen CG, Pike MC. Effect of finasteride on serum levels of androstenedione, testosterone and their 5α-reduced metabolites in men at risk for prostate cancer. J Steroid Biochem Mol Biol. 2013;138:10–6.

    PubMed  Article  CAS  Google Scholar 

  198. Dusková M, Hill M, Hanus M, Matousková M, Stárka L. Finasteride treatment and neuroactive steroid formation. Prague Med Rep. 2009;110:222–30.

    PubMed  Google Scholar 

  199. Caruso D, Abbiati F, Giatti S, et al. Patients treated for male pattern hair with finasteride show, after discontinuation of the drug, altered levels of neuroactive steroids in cerebrospinal fluid and plasma. J Steroid Biochem Mol Biol. 2015;146:74–9.

    PubMed  Article  CAS  Google Scholar 

  200. Fowke JH, Howard L, Andriole GL, Freedland SJ. Alcohol intake increases high-grade prostate cancer risk among men taking dutasteride in the REDUCE trial. Eur Urol. 2014;66:1133–8.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  201. Juang PS, Peng S, Allehmazedeh K, Shah A, Coviello AD, Herbst KL. Testosterone with dutasteride, but not anastrazole, improves insulin sensitivity in young obese men: a randomized controlled trial. J Sex Med. 2014;11:563–73.

    PubMed  Article  CAS  Google Scholar 

  202. Bhasin S, Travison TG, Storer TW, Lakshman K, Kaushik M, Mazer NA, et al. Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial. JAMA. 2012;307:931–9.

    PubMed  Article  CAS  Google Scholar 

  203. Glina S, Roehrborn CG, Esen A, Plekhanov A, Sorsaburu S, Henneges C, et al. Sexual function in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: results of a 6-month, randomized, double-blind, placebo-controlled study of tadalafil coadministered with finasteride. J Sex Med. 2015;12:129-38.

  204. Kirschbaum C, Pirke KM, Hellhammer DH. The ‘Trier Social Stress Test’--a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28:76–81.

    PubMed  Article  CAS  Google Scholar 

  205. Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J. Psychiatric genetics: search for phenotypes. Trends Neurosci. 1998;21:102–5.

    PubMed  Article  CAS  Google Scholar 

  206. Traish AM, Mulgaonkar A, Giordano N. The dark side of 5α-reductase inhibitors’ therapy: sexual dysfunction, high Gleason grade prostate cancer and depression. Korean J Urol. 2014;55:367–79.

    PubMed  PubMed Central  Article  Google Scholar 

  207. Gubelin Harcha W, Barboza Martínez J, Tsai TF, Katsuoka K, Kawashima M, Tsuboi R, et al. A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia. J Am Acad Dermatol. 2014;70:489–98.

    PubMed  Article  CAS  Google Scholar 

  208. Ali AK, Heran BS, Etminan M. Persistent sexual dysfunction and suicidal ideation in young men treated with low-dose Finasteride: a Pharmacovigilance study. Pharmacotherapy. 2015. doi:10.1002/phar.1612.

    PubMed  Google Scholar 

Download references

Funding

This study was not funded by any agency or industry. It is a collaborative effort among several scientists and clinicians.

Conflict of interest

Drs. Traish, Zitzmann and Garcia-Segura declare they have no conflict of interest. Drs. Melcangi and Bortolato have received research grants from the Post-Finasteride Syndrome Foundation.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Department of Urology, Boston University School of Medicine, 715 Albany Street, A502, Boston, MA, 02118, USA

    Abdulmaged M. Traish

  2. Department of Pharmacological and Biomolecular Sciences- Center of Excellence on Neurodegenerative Diseases, Iniversità degli Studi di Milano, Milan, Italy

    Roberto Cosimo Melcangi

  3. Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA

    Marco Bortolato

  4. Instituto Cajal, C.S.I.C, E-28002, Madrid, Spain

    Luis M. Garcia-Segura

  5. Centre for Reproductive Medicine and Andrology, University Clinics Muenster, Domagkstrasse 11, D-48149, Muenster, Germany

    Michael Zitzmann

Authors
  1. Abdulmaged M. Traish
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberto Cosimo Melcangi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Bortolato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luis M. Garcia-Segura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Zitzmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abdulmaged M. Traish.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Traish, A.M., Melcangi, R.C., Bortolato, M. et al. Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?. Rev Endocr Metab Disord 16, 177–198 (2015). https://doi.org/10.1007/s11154-015-9319-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-015-9319-y

Keywords

  • 5α-Reductases
  • Finasteride
  • Dutasteride
  • Sexual dysfunction
  • Adverse effects
  • Neurosteroids
  • Benign prostate hyperplasia