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 - Tập 8 Số 3 - Trang 872-884 - 2011
Abdulmaged M. Traish1, John Hassani1, André T. Guay2, Michael Zitzmann3, Michael Hansén4
1Departments of Biochemistry and of Urology, Boston University School of Medicine, Boston, MA, USA
2Center for Sexual Function/Endocrinology, Lahey Clinic Northshore, Peabody, MA, USA
3Centre for Reproductive Medicine and Andrology/Clinical Andrology Domagkstrasse 11 University Clinics Muenster, Germany
4Department of OB/GYN, Stavanger University Hospital, Stavanger, Norway

Tóm tắt

ABSTRACT Introduction

5α-reductase inhibitors (5α-RIs), finasteride and dutasteride, have been approved for treatment of lower urinary tract symptoms, due to benign prostatic hyperplasia, with marked clinical efficacy. Finasteride is also approved for treatment of hair loss (androgenetic alopecia). Although the adverse side effects of these agents are thought to be minimal, the magnitude of adverse effects on sexual function, gynecomastia, depression, and quality of life remains ill-defined.

Aim

The goal of this review is to discuss 5α-RIs therapy, the potential persistent side effects, and the possible mechanisms responsible for these undesirable effects.

Methods

We examined data reported in various clinical studies from the available literature concerning the side effects of finasteride and dutasteride.

Main Outcome Measures

Data reported in the literature were reviewed and discussed.

Results

Prolonged adverse effects on sexual function such as erectile dysfunction and diminished libido are reported by a subset of men, raising the possibility of a causal relationship.

Conclusions

We suggest discussion with patients on the potential sexual side effects of 5α-RIs before commencing therapy. Alternative therapies may be considered in the discussion, especially when treating androgenetic alopecia.

Từ khóa


Tài liệu tham khảo

McConnell, 1998, 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, 338, 557, 10.1056/NEJM199802263380901

Roehrborn, 2002, Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (Dutasteride) in men with benign prostatic hyperplasia, Urology, 60, 434, 10.1016/S0090-4295(02)01905-2

Otberg, 2007, Androgenetic alopecia, Endocrinol Metab Clin North Am, 36, 379, 10.1016/j.ecl.2007.03.004

Marks, 1999, Long-term effects of finasteride on prostate tissue composition, Urology, 53, 574, 10.1016/S0090-4295(98)00567-6

Debruyne, 2004, Efficacy and safety of long-term treatment with 5-alpha-reductase inhibitor of dutasteride in men with symptomatic benign prostatic hyperplasia, Eur Urol, 46, 488, 10.1016/j.eururo.2004.05.008

Andriole, 2010, Effect of Dutasteride on the risk of prostate cancer, N Engl J Med, 362, 1192, 10.1056/NEJMoa0908127

Walsh, 2010, Chemoprevention of prostate cancer, N Engl J Med, 362, 1237, 10.1056/NEJMe1001045

Qiu, 2010, Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development, Endocrinology, 151, 3307, 10.1210/en.2009-1268

Russell, 1994, Steroid 5α-reductase: Two genes/Two enzymes, Annu Rev Biochem, 63, 25, 10.1146/annurev.bi.63.070194.000325

Bramson, 1997, Unique preclinical characteristic of GG745, a potent dual inhibitor of 5AR, J Pharmacol Exp Ther, 282, 1496

Dubrovsky, 2006, Neurosteroids, neuroactive steroids, and symptoms of affective disorders, Pharmacol Biochem Behav, 84, 644, 10.1016/j.pbb.2006.06.016

Baulieu, 1998, Neurosteroids: A novel function of the brain, Psychoneuroendocrino, 23, 963, 10.1016/S0306-4530(98)00071-7

Tsuruo, 2005, Topography and function of androgen-metabolizing enzymes in the central nervous system, Anat Sci Int, 80, 1, 10.1111/j.1447-073x.2005.00098.x

Bartsch, 2002, Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia, World J Urol, 19, 413, 10.1007/s00345-002-0248-5

Gormley, 1992, The effect of finasteride in men with benign prostatic hyperplasia, J Urol, 167, 1102, 10.1016/S0022-5347(02)80349-4

Lepart, 1995, Age-related changes in brain and pituitary 5alpha-reductase with finasteride(proscar) treatment, Neurobiol Aging, 16, 647, 10.1016/0197-4580(95)98115-5

Andersson, 1991, Deletion of 5α-reductase 2 gene in male pseudohermaphroditism, Nature, 354, 159, 10.1038/354159a0

Jenkins, 1992, Genetic and pharmacological evidence for more than one human steroid 5α-reductase, J Clin Invest, 89, 293, 10.1172/JCI115574

Iehle, 1995, Human prostatic steroid 5α-reductase isoforms-a comparative study of selective inhibitors, J Steroid Biochem Molec Biol, 54, 273, 10.1016/0960-0760(95)00134-L

Bull, 1996, 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, 118, 2359, 10.1021/ja953069t

Drury, 2009, Inhibition of human steroid 5β-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex, J Biol Chem, 285, 19786, 10.1074/jbc.C109.016931

Huskey, 1995, Identification of human cytochrome p450 isozymes responsible for the in vitro oxidative metabolism of finasteride, Drug Metab Dispos, 23, 1126

Stuart, 2001, Pharmacokinetic parameters and mechanisms of inhibition of rat type 1 and 2 steroid 5α-reductases: Determinants for different in vivo activities of GI198745 and finasteride in the rat, Biochem Pharmacol, 62, 933, 10.1016/S0006-2952(01)00728-6

Makridakis, 2005, Pharmacogenetic analysis of human steroid 5α reductase type II: Comparison of finasteride and dutasteride, J Mol Endocrinol, 34, 617, 10.1677/jme.1.01725

Wessells, 2003, Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia, Urology, 61, 579, 10.1016/S0090-4295(02)02401-9

Erdemir, 2008, 5-alpha reductase inhibitors and erectile dysfunction: The connection, J Sex Med, 5, 2917, 10.1111/j.1743-6109.2008.01001.x

Kaufman, 1998, Finasteride in the treatment of men with androgenetic alopecia, J Am Acad Dermatol, 39, 578, 10.1016/S0190-9622(98)70007-6

Leyden, 1999, Finasteride in the treatment of men with frontal male pattern hair loss, J Am Acad Dermatol, 40, 930, 10.1016/S0190-9622(99)70081-2

Whiting, 2003, Male Pattern Hair Loss Study Group. Efficacy and tolerability of finasteride 1 mg in men aged 41 to 60 years with male pattern hair loss, Eur J Dermatol, 13, 150

Byrnes, 1995, Efficacy, tolerability, and effect on health-related quality of life of Finasteride versus placebo in men with symptomatic benign prostatic hyperplasia: A community-based study, Clin Ther, 17, 956, 10.1016/0149-2918(95)80073-5

Clark, 2004, Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by Dutasteride, a dual 5α-reductase inhibitor, J Clin Endocrinol Metab, 89, 2179, 10.1210/jc.2003-030330

Hudson, 1999, Efficacy of Finasteride is maintained in patients with benign prostatic hyperplasia treated for 5 years. The north American Finasteride study, Urology, 53, 690, 10.1016/S0090-4295(98)00666-9

Kirby, 2003, Efficacy and tolerability of Doxazosin and Finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia, Urology, 61, 119, 10.1016/S0090-4295(02)02114-3

Lepor, 1996, The efficacy of Terazosin, Finasteride, or both in benign prostatic hyperplasia, N Engl J Med, 335, 533, 10.1056/NEJM199608223350801

Lowe, 2003, Long-term 6-year experience with Finasteride in patients with benign prostatic hyperplasia, Urology, 61, 791, 10.1016/S0090-4295(02)02548-7

Marberger, 1998, Long-term effects of Finasteride in patients with benign prostatic hyperplasia: A double-blind placebo-controlled, multicenter study, Urology, 51, 677, 10.1016/S0090-4295(98)00094-6

McConnell, 2003, The long-term effect of Doxazosin, Finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia, N Engl J Med, 349, 2387, 10.1056/NEJMoa030656

Tenover, 1997, Efficacy and tolerability of Finasteride in symptomatic benign prostatic hyperplasia: A primary care study, Clin Ther, 19, 243, 10.1016/S0149-2918(97)80113-0

Amory, 2007, The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men, J Clin Endocrinol Metab, 92, 1659, 10.1210/jc.2006-2203

Thompson, 2003, The influence of finasteride on the development of prostate cancer, N Engl J Med, 349, 214, 10.1056/NEJMoa030660

Roehrborn, 2008, 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, 179, 616, 10.1016/j.juro.2007.09.084

Amory, 2008, 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, 179, 2333, 10.1016/j.juro.2008.01.145

Marberger, 2006, Relationship among serum testosterone, sexual function, and response to treatment in men receiving Dutasteride for benign prostatic hyperplasia, J Clin Endocrinol Metab, 91, 1323, 10.1210/jc.2005-1947

Siami, 2007, 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, Contemp Clin Trials, 28, 770, 10.1016/j.cct.2007.07.008

Desgrandchamps, 2006, Effect of dutasteride on the symptoms of benign prostatic hyperplasia, and patient quality of life and discomfort, in clinical practice, BJU Int, 98, 83, 10.1111/j.1464-410X.2006.06241.x

2003, AUA guidelines on management of benign prostatic hyperplasia. Chapter 1: Diagnosis and treatment recommendations, J Urol, 170, 530, 10.1097/01.ju.0000078083.38675.79

Mondaini, 2007, Finasteride 5 mg and sexual side effects: How many of these are related to a nocebo phenomenon?, J Sex Med, 4, 1708, 10.1111/j.1743-6109.2007.00563.x

Canguven, 2008, The effect of 5α-reductase inhibitors on erectile function, J Androl, 29, 514, 10.2164/jandrol.108.005025

Bruskewitz, 1999, Effect of Finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia, Urology, 54, 670, 10.1016/S0090-4295(99)00209-5

Wilton, 1996, The safety of Finasteride used in benign prostatic hypertrophy: A non-interventional observational cohort study in 14,772 patients, BJU Int, 78, 379, 10.1046/j.1464-410X.1996.00091.x

Watson, 2004, Eliciting preferences for drug treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia, J Urol, 172, 2321, 10.1097/01.ju.0000140957.31325.7f

Traish, 2007, Testosterone and erectile function: From basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction, Eur Urol, 52, 54, 10.1016/j.eururo.2007.02.034

Traish, 2006, Are androgens critical for penile erections in humans? Examining the clinical and preclinical evidence, J Sex Med, 3, 382, 10.1111/j.1743-6109.2006.00245.x

Traish, 2009, The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction, J Androl, 30, 10, 10.2164/jandrol.108.005215

Yassin, 2006, Testosterone undecanoate restores erectile function in a subset of patients with venous leakage: A series of case reports, J Sex Med, 3, 727, 10.1111/j.1743-6109.2006.00267.x

Carruthers, 2008, The paradox dividing testosterone deficiency symptoms and androgen assays: A closer look at the cellular and molecular mechanisms of androgen action, J Sex Med, 5, 998, 10.1111/j.1743-6109.2007.00721.x

Mantzoros, 1995, Contribution of dihydrotestosterone to male sexual behaviour, BMJ, 310, 1289, 10.1136/bmj.310.6990.1289

Penson, 1997, Adrenal control of erectile function and nitric oxide synthase in the rat penis, Endocrinology, 138, 3925, 10.1210/endo.138.9.5402

Garban, 1995, Restoration of normal adult penile erectile response in aged rats by long-term treatment with androgens, Biol Reprod, 53, 1365, 10.1095/biolreprod53.6.1365

Park, 1999, Effects of androgens on the expression of nitric oxide synthase mRNAs in rat corpus cavernosum, BJU Int, 83, 327, 10.1046/j.1464-410x.1999.00913.x

Manzo, 1999, Regulation of noncontact erection in rats by gonadal steroids, Horm Behav, 35, 264, 10.1006/hbeh.1999.1519

Bialy, 2002, Androgen implants in medial amygdala briefly maintain noncontact erection in castrated male rats, Horm Behav, 42, 345, 10.1006/hbeh.2002.1821

Sachs, 1995, Placing erection in context: The reflexogenic-psychogenic dichotomy reconsidered, Neurosci Biobehav Rev, 19, 211, 10.1016/0149-7634(94)00063-7

Lugg, 1995, Dihydrotestosterone is the active androgen in the maintenance of nitric oxide-mediated penile erection in the rat, Endocrinology, 136, 1495, 10.1210/endo.136.4.7534702

Seo, 1999, The effects of androgen on penile reflex, erectile response to electrical stimulation and penile NOS acitivty in the rat, Asian J Androl, 1, 169

Kunelius, 2002, The effects of transdermal dihydrotestosterone in the aging male: A prospective, randomized, double blind study, J Clin Endocrinol Metab, 87, 1467, 10.1210/jcem.87.4.8138

Green, 1996, Gynecomastia and breast cancer during Finasteride therapy, N Engl J Med, 335, 823, 10.1056/NEJM199609123351116

Vaughan, 2007, Exogenous testosterone alone or with finasteride does not improve measurements of cognition in healthy older men with low serum testosterone, J Androl, 28, 875, 10.2164/jandrol.107.002931

Thomas, 1992, Breast cancer in men: Risk factors with hormonal implications, Am J Epidemiol, 135, 734, 10.1093/oxfordjournals.aje.a116360

Barrett-Connor, 1999, Bioavailable testosterone and depressed mood in older men: The Rancho Bernardo Study, J Clin Endocrinol Metab, 84, 573, 10.1210/jcem.84.2.5495

Seidman, 2003, The aging male: Androgens, erectile dysfunction, and depression, J Clin Psychiatry, 64, 31

Rizvi, 2010, The relationship between testosterone and sexual function in depressed and healthy men, J Sex Med, 7, 816, 10.1111/j.1743-6109.2009.01504.x

Shores, 2005, Low testosterone levels predict incident depressive illness in older men: Effects of age and medical morbidity, J Clin Psychiatry, 66, 7, 10.4088/JCP.v66n0102

McIntyre, 2006, Calculated bioavailable testosterone levels and depression in middle-aged men, Psychoneuroendocrinology, 31, 1029, 10.1016/j.psyneuen.2006.06.005

Almeida, 2008, Low free testosterone concentration as a potentially treatable cause of depressive symptoms in older men, Arch Gen Psychiatry, 65, 283, 10.1001/archgenpsychiatry.2007.33

Hintikka, 2009, Hypogonadism, decreased sexual desire, and long-term depression in middle aged men, J Sex Med, 6, 2049, 10.1111/j.1743-6109.2009.01299.x

Almeida, 2004, One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men, Psychoneuroendocrinology, 29, 1071, 10.1016/j.psyneuen.2003.11.002

Giltay, 2010, Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome, J Sex Med, 7, 2572, 10.1111/j.1743-6109.2010.01859.x

Finn, 2004, Interaction of chronic ethanol exposure and finasteride: Sex and strain differences, Pharmacol Biochem Behav, 78, 435, 10.1016/j.pbb.2004.04.016

Purdy, 1991, Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain, Proc Natl Acad Sci USA, 88, 4553, 10.1073/pnas.88.10.4553

Rupprecht, 1999, Neuroactive steroids: Mechanisms of action and neuropsychopharmacological perspectives, Trends Neurosci, 22, 410, 10.1016/S0166-2236(99)01399-5

Amikishieva, 2007, GABA in regulation of communicative activity and sexual motivation of male mice with different psychoemotional status, Bull Exp Biol Med, 143, 225, 10.1007/s10517-007-0057-3

Henderson, 2007, Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function, Neuropharmacology, 52, 1439, 10.1016/j.neuropharm.2007.01.022

Ghoumari, 2003, Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum, J Neurochem, 86, 848, 10.1046/j.1471-4159.2003.01881.x

Griffin, 2004, Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone, Nat Med, 10, 704, 10.1038/nm1073

Ahmad, 2005, Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of niemann-pick C mice, J Neurosci Res, 82, 811, 10.1002/jnr.20685

King, 2008, Emerging roles for neurosteroids in sexual behavior and function, J Androl, 29, 524, 10.2164/jandrol.108.005660

Stoffel-Wagner, 2003, Neurosteroid biosynthesis in the human brain and its clinical implications., Ann NY Acad Sci, 1007, 64, 10.1196/annals.1286.007

VanDoren, 2000, Neuroactive steroid 3α-hydroxy-5α-pregnan-20-one modulates electrophysiological and behavioral actions of ethanol, J Neurosci, 20, 1982, 10.1523/JNEUROSCI.20-05-01982.2000

Dayanithi, 1996, Rise in intracellular calcium via a nongenomic effect of allopregnanolone in fetal rat hypothalamic neurons, J Neurosci, 16, 130, 10.1523/JNEUROSCI.16-01-00130.1996

Poisbeau, 1997, Modulation of GABAA receptor-mediated IPSCs by neuroactive steroid in a rat hypothalamic-hypophyseal coculture model, J Physiol-London, 500, 475, 10.1113/jphysiol.1997.sp022034

Poletti, 1998, 5α-reductase isozymes in the central nervous system, Steroids, 63, 246, 10.1016/S0039-128X(98)00018-X

Wetzel, 1999, Bidirectional effects of the neuroactive steroid tetrahydrocorticosterone on GABA-activated Cl- currents in cultured rat hypothalamic neurons, Br J Pharmacol, 127, 863, 10.1038/sj.bjp.0702597

Womack, 2006, Inhibition of alpha-tetrahydrodeoxycorticosterone(THDOC) of pre-sympathetic parvocellular neurones in the paraventricular nucleus of rat hypothalamus, Br J Pharmacol, 149, 600, 10.1038/sj.bjp.0706911

Jain, 2005, Reversal of caffeine-induced anxiety by neurosteroid 3α-hydroxy-5α-pregnane-20-one in rats, Neuropharmacology, 48, 627, 10.1016/j.neuropharm.2004.11.016

Ugale, 2007, Neurosteroid allopregnanolone mediates anxiolytic effect of etifoxine in rats, Brain Res, 1184, 193, 10.1016/j.brainres.2007.09.041

Khisti, 2000, Antidepressent-like effect of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in mice forced swim test, Pharmacol Biochem Behav, 67, 137, 10.1016/S0091-3057(00)00300-2

Dong, 2001, Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation, Proc Natl Acad Sci USA, 98, 2849, 10.1073/pnas.051628598

Finn, 2006, A new look at the 5alpha-reductase inhibitor finasteride, CNS Drug Rev, 12, 53, 10.1111/j.1527-3458.2006.00053.x

Uzunova, 2006, Relevance of endogenous 3α-reduced neurosteroids to depression and antidepressant action, Psychopharmacology, 186, 351, 10.1007/s00213-005-0201-6

Uzunova, 1998, Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine, Proc Natl Acad Sci USA, 95, 3239, 10.1073/pnas.95.6.3239

Kennedy, 2009, Sexual dysfunction, depression, and the impact of antidepressants, J Clin Psychopharmacol, 29, 157, 10.1097/JCP.0b013e31819c76e9

Altomare, 2002, Depression circumstantially related to the administration of finasteride for androgenetic alopecia, J Dermatol, 29, 665, 10.1111/j.1346-8138.2002.tb00200.x

Rahimi-Ardabili, 2006, Finasteride induced depression: A prospective study, BMC Clin Pharmacol, 6, 7, 10.1186/1472-6904-6-7

Balon, 2008, Survey of treatment practices for sexual dysfunction(s) associated with anti-depressants, J Sex Marital Ther, 34, 353, 10.1080/00926230802096390

Meston, 2000, The neurobiology of sexual function, Arch Gen Psychiatry, 57, 1012, 10.1001/archpsyc.57.11.1012

Dazzi, 2002, Progesterone enhances ethanol-induced modulation of mesocrotical dopamine neurons: Antagonism by finasteride, J Neurochem, 83, 1103, 10.1046/j.1471-4159.2002.01218.x

Rouge-Pont, 2002, The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens, Eur J Neurosci, 16, 169, 10.1046/j.1460-9568.2002.02084.x

Charalampopoulos, 2005, Dehydroepiandrosterone sulfate and allopregnanolone directly stimulate catecholamine production via induction of tyrosine hydroxylase and secretion by affecting actin polymerization, Endocrinology, 146, 3309, 10.1210/en.2005-0263

Bishnoi, 2008, Progesterone attenuates neuroleptic-induced orofacial dyskinesia via the activity of its metabolite, allopregnanolone, a positive GABAA modulating neurosteroid, Prog Neuro-Psychoph, 32, 451, 10.1016/j.pnpbp.2007.09.017

Bortolato, 2008, Antipsychotic-like properties of 5-α-reductase inhibitors, Neuropsychopharmacol, 33, 3146, 10.1038/npp.2008.39

Van Broekhoven, 2003, Neurosteroids in depression: A review, Psychopharmacology (Berl), 165, 97, 10.1007/s00213-002-1257-1

Romeo, 1998, Effects of antidepressant treatment on neuroactive steroids in major depression, Am J Psychiatry, 155, 910, 10.1176/ajp.155.7.910

Römer, 2010, Finasteride treatment inhibits adult hippocampal neurogenesis in male mice, Pharmacopsychiatry, 43, 174, 10.1055/s-0030-1249095

Dusková, 2009, Finasteride treatment and neuroactive steroid formation, Prague Med Rep, 110, 222

Walf, 2006, Inhibiting 5alpha-reductase in the amygdala attenuates antianxiety and antidepressive behavior of naturally receptive and hormone-primed ovariectomized rats, Psychopharmacology (Berl), 186, 302, 10.1007/s00213-005-0100-x

Cohen, 2010, Do 5-alpha reductase inhibitors influence the severity of brain injury in men after a stroke?, Med Hypotheses, 74, 956, 10.1016/j.mehy.2009.07.010

Sayeed, 2006, Allopregnanolone, a progesterone metabolite, is more effective than progesterone in reducing cortical infarct volume after transient middle cerebral artery occlusion, Ann Emerg Med, 47, 381, 10.1016/j.annemergmed.2005.12.011

Andersen, 1995, Can Finasteride reverse the process of benign prostatic hyperplasia? A two-year placebo-controlled study, Urology, 46, 631, 10.1016/S0090-4295(99)80291-X

Nickel, 1996, Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: Results of a 2-year randomized controlled trial (the PROSPECT study), Can Med Assoc J, 155, 1251

Roehrborn, 2004, Efficacy and safety of dutasteride in the four-year treatment of men with benign prostatic hyperplasia, Urology, 63, 709, 10.1016/j.urology.2004.01.001

2009, MHRA drug safety advice: Finasteride and potential risk of male breast cancer, Drug Safety Update December, 3, 3