Skip to main content

Advertisement

SpringerLink
Log in

The Post-finasteride Syndrome: Clinical Manifestation of Drug-Induced Epigenetics Due to Endocrine Disruption

  • Medical Comorbidities (A Goldstein, M Miner, and S Parish, Section Editors)
  • Published:
Current Sexual Health Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Post-finasteride syndrome (PFS) is a disorder characterized by a set of clinical symptoms experienced during use or after drug discontinuation. This cluster of symptoms encompasses overall sexual dysfunction (SD), erectile dysfunction (ED), loss of libido, depression, suicidal ideation, anxiety, panic attacks, insomnia, and cognitive dysfunction. To date, there is lack of comprehensive understanding of the biochemical and pathophysiological mechanisms responsible for the adverse effects of finasteride. More importantly, there is lack of knowledge and effective clinical tools for treatments of this condition, resulting in outright dismissal of complaints by individuals afflicted with this syndrome. Psychological symptoms and cognitive dysfunction of PFS are far more serious and difficult to treat than sexual dysfunction symptoms and may lead young men to contemplate, attempt, or even commit suicide. Therefore, an urgent need exists to fill the knowledge gap in physiology, pathophysiology, and clinical management of patients with PFS.

Recent Findings

Finasteride treatment impairs biosynthesis and function of neurosteroids, which are critical regulators of central (CNS) as well as peripheral nervous system functions and modulate a host of neurotransmitter receptors, such as gamma amino butyric acid receptors. Thus, finasteride-induced neuroendocrine disruption of biosynthesis of critical signaling molecules results in pathophysiological states, which contribute to inhibition of biochemical pathways responsible for a host of physiological functions, ranging from sexual activity, mood, and cognition. In addition, finasteride-induced epigenetic changes in gene expression, including upregulation of androgen receptors (AR), increased histone acetylation, and methylation results in undesirable biological outcomes such as impairment of dopaminergic signaling and modulation of other neurotransmitter receptors, may be the underlying mechanism causing persistent or permanent adverse effects, manifested in anxiety, depression, and suicidal ideation.

Summary

The medical community has an obligation not to turn a blind eye on this rare yet debilitating condition in young men. Patients with this condition should not be stereotyped or stigmatized by untrained and unprepared clinicians, due to lack of awareness and knowledge pertaining to this new and rare syndrome. Greater awareness and education is needed among the medical and scientific communities in order to develop better approaches for managing men with PFS. It is paramount that steps are taken to develop better understanding of the underlying mechanisms contributing to the onset and progression of PFS and to promote educational and training programs to increase awareness and improve management of this condition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem. 1994;63:25–61.

    Article  PubMed  CAS  Google Scholar 

  2. Baulieu EE. Neurosteroids: a novel function of the brain. Psychoneuroendocrinology. 1998;23:963–87.

    Article  PubMed  CAS  Google Scholar 

  3. Melcangi RC, Giatti S, Garcia-Segura LM. Levels and actions of neuroactive steroids in the nervous system under physiological and pathological conditions: sex-specific features. Neurosci Biobehav Rev. 2016;67:25–40.

    Article  PubMed  CAS  Google Scholar 

  4. 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.

    Article  PubMed  CAS  Google Scholar 

  5. 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 

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

    Article  PubMed  CAS  Google Scholar 

  7. 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 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. Melcangi RC, Giatti S, Calabrese D, Pesaresi M, Cermenati G, Mitro N, 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. Faller B, Farley D, Nick H. Finasteride: a slow-binding 5 alpha-reductase inhibitor. Biochemistry. 1993;32:5705–10.

    Article  PubMed  CAS  Google Scholar 

  14. •• 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 bi-substrate analog inhibitor. J Am Chem Soc. 1996;118:2359–65. This is a key study on the kinetics of drug-enzyme interactions that explained the near irreversible nature of the enzyme adduct complex formed by binding of finasteride to the enzyme

    Article  CAS  Google Scholar 

  15. Morrison JF, Walsh CT. The behavior and significance of slow-binding enzyme inhibitors. Adv Enzymol. 1988;61:201–301.

    PubMed  CAS  Google Scholar 

  16. •• Frankel S. Study of the Food and Drug Administration files on Propecia: dosages, side effects, and recommendations. Arch Dermatol. 1999;135:257–8. This study demonstrated that the enzyme is inhibited at a dose of approximately 0.2 mg of finasteride; therefore, a 1- or 5-mg dose is expected to provide similar effects.

    Article  PubMed  CAS  Google Scholar 

  17. Suzuki R, Satoh H, Ohtani H, Hori S, Sawada Y. Saturable binding of finasteride to steroid 5 alpha-reductase as determinant of nonlinear pharmacokinetics. Drug Metab Pharmacokinet. 2010;25:208–13.

    Article  PubMed  CAS  Google Scholar 

  18. Traish AM, Melcangi RC, Bortolato M, Garcia-Segura LM, Zitzmann M. Adverse effects of 5α-reductase inhibitors: what do we know, don’t know, and need to know? Rev Endocr Metab Disord. 2015;16:177–98.

    Article  PubMed  CAS  Google Scholar 

  19. 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 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Morrow AL. Recent developments in the significance and therapeutic relevance of neuroactive steroids—introduction to the special issue. Pharmacol Ther. 2007;116:1–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. •• Giatti S, Diviccaro S, Panzica G, Melcangi RC. Post-finasteride syndrome and post-SSRI sexual dysfunction: two sides of the same coin? Endocrine. 2018; https://doi.org/10.1007/s12020-018-1593-5. This review provides strong evidence to the potential underlying finasteride-induced neuropathological mechanisms contributing to sexual dysfunction

  24. •• Melcangi RC, Santi D, Spezzano R, Grimoldi M, Tabacchi T, Fusco ML, Diviccaro S, Giatti S, Carrà G, Caruso D, Simoni M, Cavaletti G. Neuroactive steroid levels and psychiatric and andrological features in post-finasteride patients. J Steroid Biochem Mol Biol. 2017 ;171:229–235. This study provides evidence to the potential underlying finasteride-induced reduction in neuroactive steroids and how this may impact psychological and sexual function.

  25. • Caruso D, Abbiati F, Giatti S, Romano S, Fusco L, Cavaletti G, Melcangi RC. 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; 146:74–79. This study provides evidence to the potential underlying finasteride-induced reduction in neuroactive steroids and how this may impact psychological and sexual function.

  26. Melcangi RC, Caruso D, Abbiati F, Giatti S, Calabrese D, Piazza F, et al. Neuroactive steroid levels are modified in cerebrospinal fluid and plasma of post-finasteride patients showing persistent sexual side effects and anxious/depressive symptomatology. J Sex Med. 2013;10:2598–603.

    Article  PubMed  CAS  Google Scholar 

  27. • Bechis SK, Otsetov AG, Ge R, Olumi AF. Personalized medicine for management of benign prostatic hyperplasia. J Urol. 2014;192:16–23. This study highlights that approximately 30% of patients with BPH do not express 5alpha reductase type 2 in the prostate.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Niu Y, Ge R, Hu L, Diaz C, Wang Z, Wu CL, et al. Reduced levels of 5α-reductase 2 in adult prostate tissue and implications for BPH therapy. Prostate. 2011;71:1317–24.

    PubMed  CAS  Google Scholar 

  29. Whitelaw NC, Whitelaw E. How lifetimes shape epigenotype within and across generations. Hum Mol Genet. 2006;15:R131–7.

    Article  PubMed  CAS  Google Scholar 

  30. Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature. 2007;447:433–40.

    Article  PubMed  CAS  Google Scholar 

  31. Palotas M, Palotas A, Puskas LG, Kitajka K, Pakaski M, Janka Z, et al. Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram. Int J Neuropsychopharmacol. 2004;7:401–13.

    Article  PubMed  CAS  Google Scholar 

  32. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci. 2006;9:519–25.

    Article  PubMed  CAS  Google Scholar 

  33. Panzer C, Wise S, Fantini G, Kang D, Munarriz R, Guay A, et al. Impact of oral contraceptives on sex hormone-binding globulin and androgen levels: a retrospective study in women with sexual dysfunction. J Sex Med. 2006;3:104–13.

    Article  PubMed  CAS  Google Scholar 

  34. Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, et al. Antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology. 2006;31:47–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. de Jong TR, Snaphaan LJ, Pattij T, Veening JG, Waldinger MD, Cools AR, et al. Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats. Eur Neuropsychopharmacol. 2006;16:39–48.

    Article  PubMed  CAS  Google Scholar 

  36. Csoka AB, Bahrick A, Mehtonen OP. Persistent sexual dysfunction after discontinuation of selective serotonin reuptake inhibitors. J Sex Med. 2008;5:227–33.

    Article  PubMed  CAS  Google Scholar 

  37. Pradhan S, Bacolla A, Wells RD, Roberts RJ. Recombinant human DNA (cytosine-5) methyltransferase. I. Expression, purification, and comparison of de novo and maintenance methylation. J Biol Chem. 1999;274:33002–10.

    Article  PubMed  CAS  Google Scholar 

  38. • Vottero A, Minari R, Viani I, Tassi F, Bonatti F, Neri TM, et al. Evidence for epigenetic abnormalities of the androgen receptor gene in foreskin from children with hypospadias. J Clin Endocrinol Metab. 2011;96:E1953–62. This study provided evidence that epigenetic changes in the androgen receptor are real in children with hypospadias and suggests that epigenetic changes can play a role as a result of inhibition of DHT formation

    Article  PubMed  CAS  Google Scholar 

  39. Cecchin E, De Mattia E, Mazzon G, Cauci S, Trombetta C, Toffoli G. A pharmacogenetic survey of androgen receptor (CAG)n and (GGN)n polymorphisms in patients experiencing long term side effects after finasteride discontinuation. Int J Biol Markers. 2014;29:e310–6.

    Article  PubMed  CAS  Google Scholar 

  40. Cauci S, Chiriacò G, Cecchin E, Toffoli G, Xodo S, Stinco G, et al. Androgen receptor (AR) gene (CAG)n and (GGN)n length polymorphisms and symptoms in young males with long-lasting adverse effects after finasteride use against androgenic alopecia. Sex Med. 2017;5:e61–71.

    Article  PubMed  Google Scholar 

  41. Bauman TM, Sehgal PD, Johnson KA, Pier T, Bruskewitz RC, Ricke WA, et al. Finasteride treatment alters tissue specific androgen receptor expression in prostate tissues. Prostate. 2014;74:923–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Schug TT, Janesick A, Blumberg B, Heindel JJ. Endocrine disrupting chemicals and disease susceptibility. J Steroid Biochem Mol Biol. 2011;127:204–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Traish A. Effects of endocrine-disrupting chemicals on penile tissue development, histoarchitecture and erectile physiology. In: Bioenvironmental issues affecting men’s reproductive and sexual health. Eds Sikka SC and Hellstrom WJG. Academic Press. 2018 pp 401–416.

  45. Kavlock RJ, Daston GP, Derosa C, Fenner-Crisp P, Gray LE, Kaattari S, et al. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. Environ Health Perspect. 1996;104(Suppl 4):715–40.

    Article  PubMed  PubMed Central  Google Scholar 

  46. MRC institute for Environment and Health. European workshop on the impact of endocrine disrupters on human health and wildlife. Brussels: European Commission; 1997.

    Google Scholar 

  47. Duarte-Guterman P, Langlois VS, Hodgkinson K, Pauli BD, Cooke GM, Wade MG, et al. The aromatase inhibitor fadrozole and the 5α-reductase inhibitor finasteride affect gonadal differentiation and gene expression in the frog Silurana tropicalis. Sex Dev. 2010;3:333–41.

    Article  CAS  Google Scholar 

  48. Urbatzka R, Watermann B, Lutz I, Kloas W. Exposure of Xenopus laevis tadpoles to finasteride, an inhibitor of 5-alpha reductase activity, impairs spermatogenesis and alters hypophyseal feedback mechanisms. J Mol Endocrinol. 2009;43:209–19.

    Article  PubMed  CAS  Google Scholar 

  49. Christiansen S, Scholze M, Axelstad M, Boberg J, Kortenkamp A, Hass U. Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat. Int J Androl. 2008;31:241–8.

    Article  PubMed  CAS  Google Scholar 

  50. Christiansen S, Scholze M, Dalgaard M, Vinggaard AM, Axelstad M, Kortenkamp A, et al. Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. Environ Health Perspect. 2009;117:1839–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Kiguradze T, Temps WH, Yarnold PR, Cashy J, Brannigan RE, Nardone B, et al. Persistent erectile dysfunction in men exposed to the 5α-reductase inhibitors, finasteride, or dutasteride. PeerJ. 2017;5:e3020.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Giatti S, Foglio B, Romano S, Pesaresi M, Panzica G, Garcia-Segura LM, et al. Effects of subchronic finasteride treatment and withdrawal on neuroactive steroid levels and their receptors in the male rat brain. Neuroendocrinology. 2016;103:746–57.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  56. 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.

    Article  PubMed  CAS  Google Scholar 

  57. 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.

    Article  PubMed  CAS  Google Scholar 

  58. 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.

    Article  PubMed  CAS  Google Scholar 

  59. Mantzoros CS, Georgiadis EI, Trichopoulos D. Contribution of dihydrotestosterone to male sexual behaviour. Br Med J. 1995;310:1289–91.

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  61. 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.

    Article  PubMed  CAS  Google Scholar 

  62. 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 

  63. •• 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. This study illustrated that chronic inhibition of 5alpha reductase in the rat penis with dutasteride produced erectile dysfunction

    Article  PubMed  CAS  Google Scholar 

  64. •• Oztekin CV, Gur S, Abdulkadir NA, et al. Incomplete recovery of erectile function in rat after discontinuation of dual 5-alpha reductase inhibitor therapy. J Sex Med. 2012;9:1773–81. This study illustrated that chronic inhibition of 5alpha reductase in the rat penis with dutasteride produced persistent erectile dysfunction which is not reversible by a wash out period

    Article  PubMed  CAS  Google Scholar 

  65. •• 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):e9–15. This study illustrated that chronic inhibition of 5alpha reductase in the rat penis with finasteride produced erectile dysfunction and loss of smooth muscle and reduction in endothelial nitric oxide synthase expression

    Google Scholar 

  66. Lu YL, Kuang L, Zhu H, Wu H, Wang XF, Pang YP, et al. Changes in aortic endothelium ultrastructure in male rats following castration, replacement with testosterone and administration of 5alpha-reductase inhibitor. Asian J Androl. 2007;9:843–7.

    Article  PubMed  CAS  Google Scholar 

  67. Rogers RS, Graziottin TM, Lin CS, Kan YW, Lue TF. Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno-associated virus-mediated VEGF gene therapy prevent and reverse venogenic erectile dysfunction in rats. Int J Impot Res. 2003;15:26–37.

    Article  PubMed  CAS  Google Scholar 

  68. Traish AM, Munarriz R, O’Connell L, Choi S, Kim SW, Kim NN, et al. Effects of medical or surgical castration on erectile function in an animal model. J Androl. 2003;24:381–7.

    Article  PubMed  Google Scholar 

  69. Traish AM, Toselli P, Jeong SJ, Kim NN. Adipocyte accumulation in penile corpus cavernosum of the orchiectomized rabbit: a potential mechanism for veno-occlusive dysfunction in androgen deficiency. J Androl. 2005;26:242–8.

    Article  PubMed  Google Scholar 

  70. Kacker R, Morgentaler A, Traish A. Medical hypothesis: loss of the endocrine function of the prostate is important to the pathophysiology of postprostatectomy erectile dysfunction. J Sex Med. 2014;11:1898–902.

    Article  PubMed  CAS  Google Scholar 

  71. Liao S, Liang T, Fang S, Castañeda E, Shao TC. Steroid structure and androgenic activity. Specificities involved in the receptor binding and nuclear retention of various androgens. J Biol Chem. 1973;248:6154–62.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  73. 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 PROSPECTstudy). PROscar Safety Plus Efficacy Canadian Two-year Study. CMAJ. 1996;155:1251–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  74. 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.

    Article  PubMed  CAS  Google Scholar 

  75. 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.

    Article  PubMed  CAS  Google Scholar 

  76. 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.

    Article  PubMed  CAS  Google Scholar 

  77. 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.

    Article  PubMed  CAS  Google Scholar 

  78. Kaufman KD, Olsen EA, Whiting D. Finasteride in the treatment of men with androgenetic alopecia. J Am Acad Dermatol. 1998;39:578–89.

    Article  PubMed  CAS  Google Scholar 

  79. 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.

    Article  PubMed  CAS  Google Scholar 

  80. 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.

    Article  PubMed  Google Scholar 

  81. Marberger MJ, PROWESS Study Group. Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind placebo-controlled, multicenter study. Urology. 1998;51:677–86.

    Article  PubMed  CAS  Google Scholar 

  82. Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S. Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab. 2004;89:2179–84.

    Article  PubMed  CAS  Google Scholar 

  83. 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.

    Article  PubMed  Google Scholar 

  84. 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.

    Article  PubMed  Google Scholar 

  85. Roehrborn CG, Siami P, Barkin J, Damião 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.

    Article  PubMed  CAS  Google Scholar 

  86. 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 

  87. 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.

    Article  PubMed  CAS  Google Scholar 

  88. 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.

    Article  PubMed  CAS  Google Scholar 

  89. Uygur MC, Arik AI, Altuğ U, Erol D. Effects of the 5 alpha-reductase inhibitor finasteride on serum levels of gonadal, adrenal, and hypophyseal hormones and its clinical significance: a prospective clinical study. Steroids. 1998;63:208–13.

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  91. 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.

    Article  PubMed  CAS  Google Scholar 

  92. • 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. This study showed that the sexual adverse effects were not resolved in more than 50% of all patients

    Article  PubMed  Google Scholar 

  93. 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.

    Article  PubMed  CAS  Google Scholar 

  94. McConnell JD, Roehrborn CG, Bautista OM, Andriole 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.

    Article  PubMed  CAS  Google Scholar 

  95. Kaplan SA, Holtgrewe HL, Bruskewitz R, Saltzman B, Mobley D, Narayan P, et al. Comparison of the efficacy and safety of finasteride in older versus younger men with benign prostatic hyperplasia. Urology. 2001;57(6):1073–7.

    Article  PubMed  CAS  Google Scholar 

  96. • 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. This study showed that the sexual adverse effects persist with continued treatment

    Article  PubMed  CAS  Google Scholar 

  97. Fwu C-W, Eggers PW, Kaplan SA, Kirkali Z, Lee JY, Kusek JW. Long-term effects of doxazosin, finasteride and combination therapy on quality of life in men with benign prostatic hyperplasia. J Urol. 2013;190:187–93.

    Article  PubMed  CAS  Google Scholar 

  98. Gur S, Kadowitz PJ, Hellstrom WJ. Effects of 5-alpha reductase inhibitors on erectile function, sexual desire and ejaculation. Expert Opin Drug Saf. 2013;12:81–90.

    Article  PubMed  CAS  Google Scholar 

  99. •• 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. HormMol Biol Clin Investig. 2015;23:85–96. This study demonstrated that finasteride-induced sexual adverse effects did not diminish with continued treatment, contrary to previous claims

    CAS  Google Scholar 

  100. Amory JK, Anawalt BD, Matsumoto AM, Page ST. The effect of 5α-reductase inhibition with dutasteride and finasteride on bone mineral density, serum lipoproteins, hemoglobin, prostate specific antigen, and sexual functions in healthy young men J Urol 2008;179: 2333–2338.

  101. Amory JK, Wang C, Swerdloff RS, Anawalt BD, Matsumoto AM, Bremner WJ, et al. The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men. J Clin Endocrinol Metab. 2007;92:1659–65.

    Article  PubMed  CAS  Google Scholar 

  102. Debruyne F, Barkin J, van Erps P, Reis M, Tammela TL, Roehrborn C, et al. 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.

    Article  PubMed  CAS  Google Scholar 

  103. Na Y, Ye Z, Zhang S, Chinese Dutasteride Phase III Trial (ARIA108898) Study Group. Efficacy and safety of dutasteride in Chinese adults with symptomatic benign prostatic hyperplasia: a randomized, double-blind, parallel-group, placebo-controlled study with an open-label extension. Clin Drug Investig. 2012;32:29–39.

    Article  CAS  PubMed  Google Scholar 

  104. 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 co-administered with finasteride. J Sex Med. 2015;12:129–38.

    Article  PubMed  CAS  Google Scholar 

  105. Choi GS, Kim JH, Oh SY, Park JM, Hong JS, Lee YS, et al. Safety and tolerability of the dual 5-alpha reductase inhibitor dutasteride in the treatment of androgenetic alopecia. Ann Dermatol. 2016;28:444–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Tsunemi Y, Irisawa R, Yoshiie H, Brotherton B, Ito H, Tsuboi R, et al. Long-term safety and efficacy of dutasteride in the treatment of male patients with androgenetic alopecia. J Dermatol. 2016;43:1051–8.

    Article  PubMed  CAS  Google Scholar 

  107. Guo M, Heran B, Flannigan R, Kezouh A, Etminan M. Persistent sexual dysfunction with finasteride 1 mg taken for hair loss. Pharmacotherapy. 2016;36:1180–4.

    Article  PubMed  CAS  Google Scholar 

  108. 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.

    Article  PubMed  CAS  Google Scholar 

  109. 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 

  110. 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.

    Article  PubMed  Google Scholar 

  111. Liu L, Zhao S, Li F, Li E, Kang R, Luo L, et al. Effect of 5α-reductase inhibitors on sexual function: a meta-analysis and systematic review of randomized controlled trials. J Sex Med. 2016;13(9):1297–310.

    Article  PubMed  Google Scholar 

  112. Ganzer CA, Jacobs AR, Iqbal F. Persistent sexual, emotional, and cognitive impairment post-finasteride: a survey of men reporting symptoms. Am J Mens Health. 2015;9:222–8.

    Article  PubMed  Google Scholar 

  113. Ganzer CA, Jacobs AR. Emotional consequences of finasteride: fool’s gold. Am J Mens Health 2016.

  114. Traish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML. Adverse side effects of 5alpha-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients. J Sex Med 2011; 8:872–884. 9.

  115. Irwig MS. Persistent sexual side effects of finasteride: could they be permanent? J Sex Med. 2012;9:2927–32.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  117. Irwig MS. Decreased alcohol consumption among former male users of finasteride with persistent sexual side effects: a preliminary report. Alcohol Clin Exp Res. 2013;37:1823–6.

    Article  PubMed  CAS  Google Scholar 

  118. Irwig MS. Androgen levels and semen parameters among former users of finasteride with persistent sexual adverse effects. J Am Med Assoc Dermatol. 2014;150:1361–3.

    Google Scholar 

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

    Article  PubMed  Google Scholar 

  120. Irwig MS. Safety concerns regarding 5α reductase inhibitors for the treatment of androgenetic alopecia. Curr Opin Endocrinol Diabetes Obes. 2015;22:248–53.

    Article  PubMed  CAS  Google Scholar 

  121. •• Basaria S, Jasuja R, Huang G, Wharton W, Pan H, Pencina K, et al. Characteristics of men who report persistent sexual symptoms after finasteride use for hair loss. J Clin Endocrinol Metab. 2016;101:4669–80. This study showed that men with post-finasteride syndrome exhibited abnormal functional MRI

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. 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;35:687–95.

    Article  PubMed  CAS  Google Scholar 

  123. Chiriacò G, Cauci S, Mazzon G, Trombetta C. An observational retrospective evaluation of 79 young men with long-term adverse effects after use of finasteride against androgenetic alopecia. Andrology. 2016;4:245–50.

    Article  PubMed  CAS  Google Scholar 

  124. Butcher M, Baas W, Lwin A, Holland B, Herberts M, Clemons J, et al. Post-finasteride syndrome: real or imagined. J Urol. 2016;195(4S, Supplement):e1139.

    Article  Google Scholar 

  125. Fertig R, Shapiro J, Bergfeld W, Tosti A. Investigation of the plausibility of 5-alpha-reductase inhibitor syndrome. Skin Appendage Disord. 2017;2:3–4.

    Google Scholar 

  126. •• Corona G, Tirabassi G, Santi D, Maseroli E, Gacci M, Dicuio M, et al. Sexual dysfunction in subjects treated with inhibitors of 5α-reductase for benign prostatic hyperplasia: a comprehensive review and meta-analysis. Andrology. 2017;5:671–8. This meta-analysis showed that finasteride contributes to sexual dysfunction

    Article  PubMed  CAS  Google Scholar 

  127. Favilla V, Russo GI, Privitera S, Castelli T, Giardina R, Calogero AE, et al. Impact of combination therapy 5-alpha reductase inhibitors (5-ARI) plus alpha-blockers (AB) on erectile dysfunction and decrease of libido in patients with LUTS/BPH: a systematic review with meta-analysis. Aging Male. 2016 Sep;19(3):175–81.

    Article  PubMed  CAS  Google Scholar 

  128. Golder S, Loke YK, Wright K, Norman G. Reporting of adverse events in published and unpublished studies of health care interventions: a systematic review. PLoS Med. 2016;13:e1002127.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Römer B, Gass P. Finasteride-induced depression: new insights into possible pathomechanisms. J Cosmet Dermatol. 2010;9:331–2.

    Article  PubMed  Google Scholar 

  132. Welk B, McArthur E, Ordon M, Anderson KK, Hayward J, Dixon S. Association of suicidality and depression with 5α-reductase inhibitors. JAMA Intern Med. 2017;177:683–91.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Welk B, McArthur E, Ordon M, Dirk J, Dixon S, Garg AX. Risk of rhabdomyolysis from 5-α reductase inhibitors. Pharmacoepidemiol Drug Saf. 2018;27:351–5.

    Article  PubMed  CAS  Google Scholar 

  134. Welk B, McArthur E, Ordon M, Morrow SA, Hayward J, Dixon S. The risk of dementia with the use of 5 alpha reductase inhibitors. J Neurol Sci. 2017;379:109–11.

    Article  PubMed  CAS  Google Scholar 

  135. Propecia Adverse Drug Reactions. VigiAccess Uppsala Monitoring Centre. WHO Collaborating Centre for International Drug Monitoring, accessed August 16, 2017. Available from: http://www.vigiaccess.org/

  136. Gupta NK, McVary KT. Re: Risk of erectile dysfunction associated with use of 5α-reductase inhibitors for benign prostatic hyperplasia or alopecia: population based studies using the clinical practice research datalink. Eur Urol. 2017;72:317–8.

    Article  PubMed  CAS  Google Scholar 

  137. Walf AA, Sumida K, Frye CA. Inhibiting 5alpha-reductase in the amygdala attenuates antianxiety and antidepressive behavior of naturally receptive and hormone-primed ovariectomized rats. Psychopharmacology. 2006;186:302–11.

    Article  PubMed  CAS  Google Scholar 

  138. 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.

    Article  PubMed  CAS  Google Scholar 

  139. Traish AM, Goldstein I, Kim NN. Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol. 2007;52:54–70.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Traish AM, Guay AT. Are androgens critical for penile erections in humans? Examining the clinical and preclinical evidence. J Sex Med. 2006;3:382–404.

    Article  PubMed  CAS  Google Scholar 

  141. Zhang XH, Filippi S, Morelli A, Vignozzi L, Luconi M, Donati S, et al. Testosterone restores diabetes-induced erectile dysfunction and sildenafil responsiveness in two distinct animal models of chemical diabetes. J Sex Med. 2006;3:253–64.

    Article  PubMed  CAS  Google Scholar 

  142. Peters CA, Walsh PC. The effect of nafarelin acetate, a luteinizing-hormone-releasing hormone agonist, on benign prostatic hyperplasia. N Engl J Med 1987; 317:599–604.

  143. Zorumski CF, Paul SM, Izumi Y, Covey DF, Mennerick S. Neurosteroids, stress and depression: potential therapeutic opportunities. Neurosci Biobehav Rev. 2013;37:109–22.

    Article  PubMed  CAS  Google Scholar 

  144. Hsieh JT, Chen SC, Yu HJ, Chang HC. Finasteride upregulates expression of androgen receptor in hyperplastic prostate and LNCaP cells: implications for chemoprevention of prostate cancer. Prostate. 2011;71:1115–21.

    Article  PubMed  CAS  Google Scholar 

  145. Soggiu A, Piras C, Greco V, Devoto P, Urbani A, Calzetta L, et al. Exploring the neural mechanisms of finasteride: a proteomic analysis in the nucleus accumbens. Psychoneuroendocrinology. 2016;74:387–96.

    Article  PubMed  CAS  Google Scholar 

  146. Frau R, Mosher LJ, Bini V, Pillolla G, Pes R, Saba P, et al. The neurosteroidogenic enzyme 5alpha-reductase modulates the role of D1 dopamine receptors in rat sensorimotor gating. Psychoneuroendocrinology. 2016;63:59–67.

    Article  PubMed  CAS  Google Scholar 

  147. 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urology, Boston University School of Medicine, Boston, MA, 02118, USA

    Abdulmaged M. Traish

Authors
  1. Abdulmaged M. Traish
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abdulmaged M. Traish.

Ethics declarations

Conflict of Interest

Abdulmaged M Traish reports personal fees from Johnson and Becker Law firm, outside the submitted work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Medical Comorbidities

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Traish, A.M. The Post-finasteride Syndrome: Clinical Manifestation of Drug-Induced Epigenetics Due to Endocrine Disruption. Curr Sex Health Rep 10, 88–103 (2018). https://doi.org/10.1007/s11930-018-0161-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11930-018-0161-6

Keywords

Search

Navigation