5-ARIs can be used in the treatment ofhirsutism in women.[1] The usefulness of 5-ARIs for the potential treatment ofacne is uncertain.[4] 5-ARIs are sometimes used as antiandrogens infeminizing hormone therapy fortransgender women to help reduce body hair growth and scalp hair loss.[2]
They have also been explored in the treatment and prevention ofprostate cancer. While the 5-ARIfinasteride reduces the cancer risk by about a third, it also increases the fraction of aggressive forms of prostate cancer. Overall, there does not seem to be a survival benefit for prostate cancer patients under finasteride.[5]
Finasteride (brand names Proscar, Propecia) inhibits the function of two of the isoenzymes (types 2 and 3) of 5α-reductase.[6][7] It decreases circulating DHT levels by up to about 70%.[8]Dutasteride (brand name Avodart) inhibits all three 5α-reductase isoenzymes and can decrease DHT levels by 95%.[9][10] It can also reduce DHT levels in the prostate by 97 to 99% in men with prostate cancer.[11][12]Epristeride (brand names Aipuliete, Chuanliu) is marketed inChina for the treatment of benign prostatic hyperplasia.[13][14][15] However, it can only decrease circulating DHT levels by about 25 to 54%.[16]Alfatradiol (brand names Ell-Cranell Alpha, Pantostin) is a topical 5-ARI used to treat pattern hair loss inEurope.[17][18]
5-ARIs are generallywell tolerated in both men and women and produce fewside effects.[19][20] However, they have been found to have some risks in studies with men, including slightly increased risks of decreasedlibido,erectile dysfunction,ejaculatory dysfunction,infertility,breast tenderness,gynecomastia,depression,anxiety,self-harm, anddementia.[20][21][22] In addition, although 5-ARIs decrease the overall risk of developingprostate cancer, they have been found to increase the risk of developing certain rare but high-grade forms of prostate cancer.[19] As a result, the FDA has notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-ARI class of drugs has been revised to include new safety information about the increased risk of being diagnosed with these rare but more serious forms of prostate cancer.[23] Finasteride has also been associated withintraoperative floppy iris syndrome andcataract formation.[24][25] Depressive symptoms and suicidality have been reported.[26]
Sexual dysfunction, includingerectile dysfunction,loss of libido, andreduced ejaculate, may occur in 3.4 to 15.8% of men treated with finasteride or dutasteride.[19][27] This is linked to lowerquality of life and can cause stress in relationships.[28] There is also an association with lowered sexual desire.[29] It has been reported that in a subset of men, these adverse sexual side effects may persist even after discontinuation of finasteride or dutasteride.[29]
A 2017population-based,matched-cohort study of 93,197 men aged 66 years and older with BPH found that finasteride and dutasteride were associated with a significantly increased risk of depression (HRTooltip Hazard ratio, 1.94; 95%CITooltip Confidence interval, 1.73–2.16) andself-harm (HR, 1.88; 95% CI, 1.34–2.64) during the first 18 months of treatment, but were not associated with an increased risk ofsuicide (HR, 0.88; 95% CI, 0.53–1.45).[31][32][33][21] After the initial 18 months of therapy, the risk of self-harm was no longer heightened, whereas the elevation in risk of depression lessened but remained marginally increased (HR, 1.22; 95% CI, 1.08–1.37).[31][32][21] The absolute increase in the rate of depression was 247 per 100,000 patient-years and of self-harm was 17 per 100,000 patient-years.[21][34] As such, on the basis of these findings, it has been stated that cases of depression in patients that are attributable to 5-ARIs will be encountered on occasion, while cases of self-harm attributable to 5-ARIs will be encountered very rarely.[34] There were no differences in the rates of depression, self-harm, and suicide between finasteride and dutasteride, suggesting that the specific 5-ARI used does not influence the risks.[33][21][34] The absolute risks of self-harm and depression with 5-ARIs remain low (0.14% and 2.0%, respectively).[35]
The pharmacology of 5α-reductase inhibition is complex, but involves the binding ofNADPH to the enzyme followed by the substrate. Specific substrates includetestosterone,progesterone,androstenedione,epitestosterone,cortisol,aldosterone, anddeoxycorticosterone. The entire physiologic effect of their reduction is unknown, but likely related to their excretion or is itself physiologic.[4] 5α-Reductase reduces the steroid Δ4,5 double bond in testosterone to its more active form DHT. Thus, inhibition results in decreased amounts of DHT. Because of this, slight elevations in testosterone and estradiol levels occur.[36] The 5α-reductase reaction is a rate-limiting step in the testosterone reduction and involves the binding ofNADPH to the enzyme followed by the substrate.[4][37]
In BPH, DHT acts as a potent cellular androgen and promotesprostate growth; therefore, DHT blockers inhibit and alleviate symptoms of BPH. In alopecia, male and female-pattern baldness is an effect of androgenic receptor activation, so reducing levels of DHT also reduces hair loss.
Finasteride was the first 5-ARI to be introduced for medical use.[43] It was marketed for the treatment of BPH in 1992 and was subsequently approved for the treatment of pattern hair loss in 1997.[43] Epristeride was the second 5-ARI to be introduced and was marketed for the treatment of BPH inChina in 2000.[14] Dutasteride was approved for the treatment of BPH in 2001 and was subsequently approved for pattern hair loss inSouth Korea in 2009 and inJapan in 2015.[44][45] Thepatent protection on finasteride and dutasteride has expired and both drugs are available asgeneric medications.[46][47]
^abUlrike Blume-Peytavi; David A. Whiting; Ralph M. Trüeb (26 June 2008).Hair Growth and Disorders. Springer Science & Business Media. pp. 368–370.ISBN978-3-540-46911-7.Archived from the original on 9 November 2023. Retrieved29 October 2016.
^abWesp LM, Deutsch MB (2017). "Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons".Psychiatr. Clin. North Am.40 (1):99–111.doi:10.1016/j.psc.2016.10.006.PMID28159148.
^Yamana K, Labrie F, Luu-The V (January 2010). "Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride".Hormone Molecular Biology and Clinical Investigation.2 (3):293–9.doi:10.1515/hmbci.2010.035.PMID25961201.S2CID28841145.
^Yamana K.; Labrie F.; Luu-The V.; et al. (2010). "Human type 3 5α- reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited finasteride and dutasteride".Hormone Molecular Biology and Clinical Investigation.2 (3):293–299.doi:10.1515/hmbci.2010.035.PMID25961201.S2CID28841145.
^McConnell J. D.; Wilson J. D.; George F. W.; Geller J.; Pappas F.; Stoner E. (1992). "Finasteride, an inhibitor of 5α-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia".Journal of Clinical Endocrinology and Metabolism.74 (3):505–508.doi:10.1210/jcem.74.3.1371291.PMID1371291.
^Clark R. V.; Hermann D. J.; Cunningham G. R.; Wilson T. H.; Morrill B. B.; Hobbs S. (2004). "Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor".Journal of Clinical Endocrinology and Metabolism.89 (5):2179–2184.doi:10.1210/jc.2003-030330.PMID15126539.
^G. L. Andriole, P. Humphrey, P. Ray et al., "Effect of the dual 5α-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer,"
^Berger, Artur; Wachter, Helmut, eds. (1998).Hunnius Pharmazeutisches Wörterbuch (in German) (8th ed.). Walter de Gruyter Verlag. p. 486.ISBN978-3-11-015793-2.
^Mutschler, Ernst; Gerd Geisslinger; Heyo K. Kroemer; Monika Schäfer-Korting (2001).Arzneimittelwirkungen (in German) (8th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 453.ISBN978-3-8047-1763-3.
^Welk, Blayne; McArthur, Eric; Ordon, Michael; Morrow, Sarah A.; Hayward, Jade; Dixon, Stephanie (2017). "The risk of dementia with the use of 5 alpha reductase inhibitors".Journal of the Neurological Sciences.379:109–111.doi:10.1016/j.jns.2017.05.064.ISSN0022-510X.PMID28716218.S2CID4765640.
^Wong, A. C. M.; Mak, S. T. (2011). "Finasteride-associated cataract and intraoperative floppy-iris syndrome".Journal of Cataract & Refractive Surgery.37 (7):1351–1354.doi:10.1016/j.jcrs.2011.04.013.PMID21555201.
^Issa, S. A.; Dagres, E. (2007). "Intraoperative floppy-iris syndrome and finasteride intake".Journal of Cataract & Refractive Surgery.33 (12):2142–2143.doi:10.1016/j.jcrs.2007.07.025.PMID18053919.
^Liu, L; Zhao, S; Li, F; Li, E; Kang, R; Luo, L; Luo, J; Wan, S; Zhao, Z (September 2016). "Effect of 5α-Reductase Inhibitors on Sexual Function: A Meta-Analysis and Systematic Review of Randomized Controlled Trials".The Journal of Sexual Medicine.13 (9):1297–310.doi:10.1016/j.jsxm.2016.07.006.PMID27475241.
^Gur, S; Kadowitz, PJ; Hellstrom, WJ (January 2013). "Effects of 5-alpha reductase inhibitors on erectile function, sexual desire and ejaculation".Expert Opinion on Drug Safety.12 (1):81–90.doi:10.1517/14740338.2013.742885.PMID23173718.S2CID11624116.
^abTraish, AM; Hassani, J; Guay, AT; Zitzmann, M; Hansen, ML (March 2011). "Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients".The Journal of Sexual Medicine.8 (3):872–84.doi:10.1111/j.1743-6109.2010.02157.x.PMID21176115.
^abTraish, Abdulmaged M. (2018). "The Post-finasteride Syndrome: Clinical Manifestation of Drug-Induced Epigenetics Due to Endocrine Disruption".Current Sexual Health Reports.10 (3):88–103.doi:10.1007/s11930-018-0161-6.ISSN1548-3584.S2CID81560714.
^Weinstein BI, Kandalaft N, Ritch R, Camras CB, Morris DJ, Latif SA, Vecsei P, Vittek J, Gordon GG, Southren AL (June 1991). "5 alpha-dihydrocortisol in human aqueous humor and metabolism of cortisol by human lenses in vitro".Invest. Ophthalmol. Vis. Sci.32 (7):2130–5.PMID2055703.
^Kenyon CJ, Brem AS, McDermott MJ, Deconti GA, Latif SA, Morris DJ (May 1983). "Antinatriuretic and kaliuretic activities of the reduced derivatives of aldosterone".Endocrinology.112 (5):1852–6.doi:10.1210/endo-112-5-1852.PMID6403339.
^William Llewellyn (2011).Anabolics. Molecular Nutrition Llc. pp. 968–, 971–.ISBN978-0-9828280-1-4.Archived from the original on 2023-01-12. Retrieved2017-12-24.
^Wang LG, Mencher SK, McCarron JP, Ferrari AC (2004). "The biological basis for the use of an anti-androgen and a 5-alpha-reductase inhibitor in the treatment of recurrent prostate cancer: Case report and review".Oncology Reports.11 (6):1325–9.doi:10.3892/or.11.6.1325.PMID15138573.
^Merrick GS, Butler WM, Wallner KE, Galbreath RW, Allen ZA, Kurko B (2006). "Efficacy of neoadjuvant bicalutamide and dutasteride as a cytoreductive regimen before prostate brachytherapy".Urology.68 (1):116–20.doi:10.1016/j.urology.2006.01.061.PMID16844453.
^Sartor O, Gomella LG, Gagnier P, Melich K, Dann R (2009). "Dutasteride and bicalutamide in patients with hormone-refractory prostate cancer: the Therapy Assessed by Rising PSA (TARP) study rationale and design".The Canadian Journal of Urology.16 (5):4806–12.PMID19796455.
^Chu FM, Sartor O, Gomella L, Rudo T, Somerville MC, Hereghty B, Manyak MJ (2015). "A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate-resistant prostate cancer".European Journal of Cancer.51 (12):1555–69.doi:10.1016/j.ejca.2015.04.028.PMID26048455.
^Gaudet M, Vigneault É, Foster W, Meyer F, Martin AG (2016). "Randomized non-inferiority trial of Bicalutamide and Dutasteride versus LHRH agonists for prostate volume reduction prior to I-125 permanent implant brachytherapy for prostate cancer".Radiotherapy and Oncology.118 (1):141–7.doi:10.1016/j.radonc.2015.11.022.PMID26702991.
