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.
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References
Traish AM. 5alpha-reductases in human physiology: an unfolding story. Endocr Pract. 2012;18:965–75.
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.
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.
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.
Imperato-McGinley J. 5alpha-reductase-2 deficiency and complete androgen insensitivity: lessons from nature. Adv Exp Med Biol. 2002;511:121–31.
Imperato-McGinley J, Zhu YS. Androgens and male physiology the syndrome of 5alpha-reductase-2 deficiency. Mol Cell Endocrinol. 2002;198:51–9.
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.
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.
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.
Russell DW, Wilson JD. Steroid 5α-reductase: Two genes/Two enzymes. Annu Rev Biochem. 1994;63:25–61.
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.
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.
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.
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.
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.
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.
Marver D, Edelman IS. Dihydrocortisol: a potential mineralocorticoid. J Steroid Biochem. 1978;9:1.
Dubrovsky B. Neurosteroids, neuroactive steroids, and symptoms of affective disorders. Pharmacol Biochem Behav. 2006;84:644–55.
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.
Blouin K, Veilleux A, Luu-The V, Tchernof A. Androgen metabolism in adipose tissue: recent advances. Mol Cell Endocrinol. 2009;301:97–103.
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.
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.
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.
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.
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.
Bamberger CM, Schulte HM, Chrousos GP. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev. 1996;17:245–61.
DeRijk R, Schaaf M, de Kloet E. Glucocorticoid receptor variants: clinical implications. J Steroid Biochem Mol Biol. 2002;81:103–22.
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.
Melcangi RC, Panzica G, Garcia-Segura LM. Neuroactive steroids: focus on human brain. Neuroscience. 2011;191:1–5.
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.
Melcangi RC, Panzica GC. Allopregnanolone: state of the art. Prog Neurobiol. 2014;113:1–5.
Melcangi RC, Panzica GC. Neuroactive steroids and the nervous system: further observations on an incomplete tricky puzzle. J Neuroendocrinol. 2013;25:957–63.
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.
Pelletier G. Steroidogenic enzymes in the brain: morphological aspects. Prog Brain Res. 2010;181:193–207.
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.
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.
Garcia-Segura LM, Veiga S, Sierra A, Melcangi RC, Azcoitia I. Aromatase: a neuroprotective enzyme. Prog Neurobiol. 2003;71:31–41.
Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA. Neurosteroid modulation of GABAA receptors. Prog Neurobiol. 2003;71:67–80.
Belelli D, Lambert JJ. Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci. 2005;6:565–75.
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.
Thomas P, Pang Y. Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells. Neuroendocrinology. 2012;96:162–71.
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.
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.
Foradori CD, Weiser MJ, Handa RJ. Non-genomic actions of androgens. Front Neuroendocrinol. 2008;29:169–81.
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.
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.
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.
Denecke J, Kranz C. Hypoglycosylation due to dolichol metabolism defects. Biochim Biophys Acta. 2009;1792:888–95.
Stiles AR, Russell DW. SRD5A3: a surprising role in glycosylation. Cell. 2010;23(142):196–8.
Wong AC, Mak ST. Finasteride-associated cataract and intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2011;37:1351–4.
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.
Goldsmith LA, Fitzpatrick TB. Fitzpatrick’s dermatology in general medicine. 8th ed. New York: McGraw-Hill Professional; 2012.
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.
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.
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.
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.
Aggarwal S, Thareja S, Verma A, Bhardwaj TR, Kumar M. An overview on 5alpha-reductase inhibitors. Steroids. 2010;75:109–53.
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.
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.
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.
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.
Wu C, Kapoor A. Dutasteride for the treatment of benign prostatic hyperplasia. Expert Opin Pharmacother. 2013;14:1399–408.
Bechis SK, Otsetov AG, Ge R, Olumi AF. Personalized medicine for management of benign prostatic hyperplasia. J Urol. 2014;192:16–23.
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.
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.
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.
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.
Muroni A, Paba S, Puligheddu M, Marrosu F, Bortolato M. A preliminary study of finasteride in Tourette syndrome. Mov Disord. 2011;26:2146–7.
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.
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.
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.
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.
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.
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.
Stoner E. The clinical development of a 5 alpha-reductase inhibitor, finasteride. J Steroid Biochem Mol Biol. 1990;37:375–8.
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.
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.
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.
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.
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.
Yim E, Nole KL, Tosti A. 5α-Reductase inhibitors in androgenetic alopecia. Curr Opin Endocrinol Diabetes Obes. 2014;21:493–8.
Falto-Aizpurua L, Choudhary S, Tosti A. Emerging treatments in alopecia. Expert Opin Emerg Drugs. 2014;19:545–56.
Food and Drug Administration. Oncologic Drugs Advisory Committee - 2010 Meeting Materials, Oncologic Drugs Advisory Committee. 2010
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.
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.
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.
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.
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.
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.
Moore TJ. Finasteride and the uncertainties of establishing harms. JAMA Dermatol. 2015;151:586–6.
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.
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.
Irwig MS, Kolukula S. Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med. 2011;8:1747–53.
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.
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.
MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med. 2004;350:367–78.
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.
Gray GD, Smith ER, Davidson JM. Hormonal regulation of penile erection in castrated male rats. Physiol Behav. 1980;24:463–8.
Hart BL. Effects of testosterone propionate and dihydrotestosterone on penile morphology and sexual reflexes of spinal male rats. Horm Behav. 1973;4:239–46.
Hart BL. Activation of sexual reflexes of male rats by dihydrotestosterone but not estrogen. Physiol Behav. 1979;23:107–9.
Mantzoros CS, Georgiadis EI, Trichopoulos D. Contribution of dihydrotestosterone to male sexual behaviour. BMJ. 1995;310:1289–91.
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.
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.
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.
Bialy M, Sachs BD. Androgen implants in medial amygdala briefly maintain noncontact erection in castrated male rats. Horm Behav. 2002;42:345–55.
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.
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.
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.
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.
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.
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.
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.
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.
AUA guideline on management of benign prostatic hyperplasia. Chapter 1: diagnosis and treatment recommendations. J Urol. 2003;170:530–47.
Edwards JE, Moore RA. Finasteride in the treatment of clinical benign prostatic hyperplasia: a systematic review of randomised trials. BMC Urol. 2002;2:14.
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.
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.
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.
Canguven O, Burnett AL. The effect of 5 alpha-reductase inhibitors on erectile function. J Androl. 2008;29:514–23.
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.
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.
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.
Irwig MS. Persistent sexual and non-sexual adverse effects of finasteride in younger men. Sex Med Rev. 2014;2:24–35.
Irwig MS. Androgen levels and semen parameters among former users of Finasteride with persistent sexual adverse effects. JAMA Dermatol. 2014;150:1361–3.
Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012;73:1220–3.
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.
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.
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.
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.
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.
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.
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.
Morgentaler A. Goodbye androgen hypothesis, hello saturation model. Eur Urol. 2012;62:765–7.
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.
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.
Walsh PC. Three considerations before advising 5-alpha-reductase inhibitors for chemoprevention. J Clin Oncol. 2009;27, e22.
Walsh PC. Chemoprevention of prostate cancer. N Engl J Med. 2010;362:1237–8.
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.
Ehdaie B, Touijer KA. 5-alpha Reductase inhibitors in prostate cancer: from clinical trials to clinical practice. Eur Urol. 2013;63:788–9.
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.
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.
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.
Justman S. What’s wrong with chemoprevention of prostate cancer? Am J Bioeth. 2011;11:21–5.
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.
Ferris HA, Kahn CR. New mechanisms of glucocorticoid-induced insulin resistance: make no bones about it. J Clin Invest. 2012;122:3854–7.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Altomare G, Capella GL. Depression circumstantially related to the administration of finasteride for androgenetic alopecia. J Dermatol. 2002;29:665–9.
Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A. Finasteride induced depression: a prospective study. BMC Clin Pharmacol. 2006;6:7.
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.
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.
Bali A, Jaggi AS. Multifunctional aspects of allopregnanolone in stress and related disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:64–78.
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.
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.
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.
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.
Uzunova V, Sampson L, Uzunov DP. Relevance of endogenous 3alpha-reduced neurosteroids to depression and antidepressant action. Psychopharmacology (Berl). 2006;186:351–61.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Mellon SH. Neurosteroid regulation of central nervous system development. Pharmacol Ther. 2007;116:107–24.
Irwin RW, Brinton RD. Allopregnanolone as regenerative therapeutic for Alzheimer’s disease: translational development and clinical promise. Prog Neurobiol. 2014;113:40–55.
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.
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.
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.
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.
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.
Giatti S, Boraso M, Abbiati F, et al. Multimodal analysis in acute and chronic experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol. 2013;8:238–50.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Dusková M, Hill M, Hanus M, Matousková M, Stárka L. Finasteride treatment and neuroactive steroid formation. Prague Med Rep. 2009;110:222–30.
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.
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.
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.
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.
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.
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.
Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J. Psychiatric genetics: search for phenotypes. Trends Neurosci. 1998;21:102–5.
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.
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.
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.
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.
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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
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DOI: https://doi.org/10.1007/s11154-015-9319-y