Side Effects of 5‐Alpha Reductase Inhibitors: A Comprehensive Review

24

Side Effects of 5-Alpha Reductase Inhibitors: A Comprehensive Review Landon Trost, MD,* Theodore R. Saitz, BS,† and Wayne J.G. Hellstrom, MD, FACS† *Mayo Clinic, Rochester, MN, USA; †Department of Urology, Section of Andrology, Tulane University School of Medicine, New Orleans, LA, USA DOI: 10.1002/smrj.3

ABSTRACT

Introduction. 5a-reductase inhibitors (5ARI) include finasteride and dutasteride, and are commonly prescribed in the treatment of benign prostatic hyperplasia and androgenic alopecia. 5ARIs are associated with several known adverse effects (AEs), with varying reported prevalence rates. Aim. The aim was to review and summarize findings from published literature detailing AEs associated with 5ARI use. A secondary aim was to review potential mechanisms of action, which may account for these observed and reported AEs. Methods. A PubMed search was conducted on articles published from 1992 to 2012, which reported AEs with 5ARIs. Priority was given to randomized, placebo-controlled trials. Studies investigating potential mechanisms of action for 5ARIs were included for review. Main Outcome Measures. AE data reported from available trials were summarized and reviewed. Results. Reported AEs with 5ARIs include sexual dysfunction, infertility, mood disorders, gynecomastia, high-grade prostate cancer, breast cancer, and cardiovascular morbidity/risk factors, although their true association, prevalence, causality, and clinical significance remain unclear. A pooled summary of all randomized, placebo-controlled trials evaluating 5ARIs (N = 62,827) revealed slightly increased rates over placebo for decreased libido (1.5%), erectile dysfunction (ED) (1.6%), ejaculatory dysfunction (EjD) (3.4%), and gynecomastia (1.3%). The limited data available on the impact of 5ARIs on mood disorders demonstrate statistically significant (although clinically minimal) differences in rates of depression and/or anxiety. Similarly, there are limited reports of reversible, diminished fertility among susceptible individuals. Post-marketing surveillance reports have questioned the actual prevalence of AEs associated with 5ARI use and suggest the possibility of persistent symptoms after drug discontinuation. Welldesigned studies evaluating these reports are needed. Conclusions. 5ARIs are associated with slightly increased rates of decreased libido, ED, EjD, gynecomastia, depression, and/or anxiety. Further studies directed at identifying prevalence rates and persistence of symptoms beyond drug discontinuation are required to assess causality. Trost L, Saitz TR, and Hellstrom WJG. Side effects of 5-alpha reductase inhibitors: A comprehensive review. Sex Med Rev 2013;1:24–41. Key Words. Prostate; Finasteride; Dutasteride; Adverse Events; Sexual Dysfunction

Introduction

a-reductase inhibitors (5ARI) competitively inhibit the enzyme 5a-reductase (5AR), and include finasteride (Propecia 1 mg and Proscar 5 mg, Merck, New Jersey, USA) and dutasteride (Avodart 0.5 mg and Jalyn [dutasteride 0.5 mg and tamsulosin 0.4 mg], GlaxoSmithKline, London, UK). 5AR is responsible for conversion of several hormones as a rate-limiting step throughout multiple organ systems and tissues [1,2]. Cur-

5

Sex Med Rev 2013;1:24–41

rently, three subtypes of 5AR have been identified, with 5AR-1 and 5AR-2 being the most studied [3,4]. 5AR-1 has been identified in the central and peripheral nervous systems, including midbrain, pons, spinal cord, corpus callosum, anterior commissure, optic chiasm, as well as in the skin, liver, and to a lesser degree in the prostate. 5AR-2 is present in the liver, epididymis, prostate, seminal vesicles, penis, urethra, and testes [5–10]. 5AR-3 has been localized to multiple tissues and organ systems, with the highest expression © 2013 International Society for Sexual Medicine

25

5ARI Side Effects exhibited in the skin, kidney, liver, skeletal muscle, myometrium, and pancreas, and moderate expression in the testes, brain, breast, colon, and stomach [4,11]. Indications for Use

Due to abundant 5ARI activity in the prostate and skin, 5ARIs have been investigated predominantly for their effects on benign prostatic hyperplasia (BPH)-associated lower urinary tract symptoms (LUTS) and for the treatment of androgenic alopecia (AGA). Several trials of 5ARIs in men with BPH have demonstrated beneficial effects, including a reduction of prostatic volume, improved International Prostate Symptom Scores, improved urinary flow rates, decreased risk for acute urinary retention, and reduced need for BPH-related surgery [12–15]. Finasteride has further been shown to significantly improve and maintain hair counts in men with AGA [16–18]. Beyond the treatment of BPH-related LUTS and AGA, 5ARIs have been investigated for a role in the prevention of prostate cancer, particularly given the observation that congenital absence of 5AR eliminates the risk of subsequent prostate cancer development [19]. The outcomes and adverse effects (AE) relating to prostate cancer will be more thoroughly discussed later in this communication. In addition to the beneficial effects listed above, 5ARIs may be associated with AEs, including sexual dysfunction (SD), infertility, cognitive/ psychological dysfunction, gynecomastia, breast cancer, high-grade prostate cancer (HGPC), and cardiovascular risk factors/comorbidities. More recently, post-marketing surveys and publications have questioned whether the true prevalence and persistence of AEs following drug discontinuation have been underreported. These reports have subsequently led to regulatory labeling changes [20–25]. To evaluate the prevalence of AEs associated with 5ARI use, a PubMed search was conducted of all publications reporting AEs with finasteride and/or dutasteride from 1992 to 2012. Priority was given to randomized, controlled trials (RCT), with a pooled summary of effects performed for commonly reported AEs, including SD and gynecomastia. Less frequently reported AEs were reviewed based on available literature. Additionally, the current review provides limited discussion on potential mechanisms, which may account for the AEs observed.

Mechanism of Action

5ARIs functionally inhibit the 5AR enzyme, with finasteride predominantly inhibiting 5AR-2, and dutasteride inhibiting both 5AR-1 and 5AR-2 isozymes [3]. Finasteride crosses the blood brain barrier and impairs 5b-reductases, which function in hepatic synthesis and metabolism [26]. 5ARIs reduce plasma dihydrotestosterone (DHT) by 70–80% (finasteride) to >90% (dutasteride) and result in initial compensatory increases in T levels [13,15,27–30]. 5AR is responsible for physiologic conversion of multiple hormones of testicular and adrenal origin, including testosterone (T) to DHT, progesterone to 5a-dihydroprogesterone (5a-DHP), and deoxycorticosterone to 5a-dihydrodeoxycorticosterone (5a-DHDOC). Each of these products is enzymatically modified by 3a-hydroxysteroid dehydrogenase (3AHSD) to convert DHT to 3a,5a androstane 17b-diol (3a-diol), 5a-DHP to 3a,5a-tetrahydroprogesterone (3a,5a-THP or allopregnanolone), and 5a-DHDOC to 3a,5atetrahydrodeoxycorticosterone (3a,5a-THDOC). See Figure 1 for graphical depiction of drug conversions, enzymes, and sites of action. These latter three products are categorized as neurosteroids, due to their role in neurological processes, with 5AR preferentially catalyzing a reaction with progesterone vs. T or androstenedione [6].

AEs

SD 5ARIs have a recognized, consistent association with sexual AEs, including decreased libido, erectile dysfunction (ED), and ejaculatory dysfunction (EjD). Among 27 RCTs reviewing the use of 5ARIs, reported ranges of decreased libido, ED, and EjD vary widely: drug: libido (0–65.4%), ED (0–67.4%), and EjD (0–60.4%); placebo: libido (0–59.6%), ED (0–61.5%), and EjD (0–47.3%) [12,13,15–18,31–51]. These widely discrepant results for both drug and placebo reflect differences in patient populations and study methodology. All cited studies obtained AE information through patient self-reporting and investigator review, with no prospective, placebo-controlled studies using targeted questionnaires, such as the International Index of Erectile Function (IIEF) or Male Sexual Health Questionnaire (MSHQ), among others. See Tables 1 and 2 for the summary of RCTs of 5ARIs reporting sexual AEs. Sex Med Rev 2013;1:24–41

26

Trost et al.

Testosterone

5α-DHT

•Via estradiol - Breast (gynecomasa, Ca)

•Skin (AGA) •Prostate (BPH, Ca) •Liver / Kidney •Penis (ED, EjD)

5AR

3α-diol 3AHSD

Progesterone •CNS (myelinaon)

•CNS Receptors (cognive, psychological, libido)

3α,5α-THP 5AR

5α-DHP

3AHSD

(allopregnanolone) •CNS Receptors (cognive, psychological, libido)

3α,5α-THDOC Deoxycorcosterone

5AR

5α-DHDOC

3AHSD

•CNS Receptors (cognive, psychological, libido)

AGA=Androgenic alopecia; DHT=Dihydrotestosterone; 3α-diol=3α,5α-Androstane 17β-diol; DHP=Dihydroprogesterone; THP=Tetrahydroprogesterone; DHDOC=Dihydrodeoxycorcosterone; THDOC=Tetrahydrodeoxycorcosterone; 5AR=5αReductase; 3AHSD=3α-Hydroxysteroid Dehydrogenase; CNS=Central Nervous System; BPH=Benign Prostac Hyperplasia; ED=Erecle Dysfuncon; Ca=Cancer; EjD=Ejaculatory Dysfuncon

Pooled Analysis of SD In an attempt to reconcile and consolidate reported findings, a pooled summary was performed of available RCTs reporting sexual AEs. Studies lacking a placebo group were not included in the analysis. Results demonstrated a total of 62,827 patients reviewed (drug—32,666; placebo —29,603), with the percentage of patients experiencing decreased libido, ED, and EjD being (drug/placebo) 21.5%/20.5%, 24.0%/22.4%, and 18.9%/15.5%, respectively. The difference between treatment and placebo groups for each AE was therefore 1.0%, 1.6%, and 3.4%, respectively. See Table 3 for a summary of pooled results of RCTs reporting AEs with 5ARI use. When results were stratified based on patient population (AGA, BPH, or prostate cancer), differences between drug/placebo for libido, ED, and EjD were as follows: AGA = 0.8%, 1.1%, 0.8%; BPH = 1.5%, 2.3%, 1.5%; and prostate cancer = 4.6%, 5.1%, 9.5%. Although the discrepancy of results between populations is not fully understood, it is likely related to a known increased prevalence of SD with BPH and prostate cancer [52–54]. Similarly, stratification by age (ⱕ55 years and ⱖ40 years) results in different rates of libido, ED, and EjD for drug-placebo (ⱕ55 years: 1.0%, 0.6%, 0.6%; ⱖ40 years: 1.0%, 1.6%, 3.4%). Due to the heterogeneity of patient populations, it was not possible to define age groups without significant overlap. The small differences between patient populations are likely secondary to patient Sex Med Rev 2013;1:24–41

Figure 1 Summary of hormonal pathways, sites of action, and downstream enzymes associated with 5areductase.

age and comorbid status, as there is an increased rate of BPH and prostate cancer in more elderly males. When comparing sexual AEs based on drug administered, results of drug-placebo for libido, ED, and EjD demonstrated the following: finasteride 1 mg (1.9%, 2.0%, 1.3%), finasteride 5 mg (-0.9%, -0.4%, 3.6%), and dutasteride 0.5 mg (1.2%, 2.2%, 0.7%). The lower rates of decreased libido and ED associated with finasteride 5 mg may be due to longer study lengths compared with the 1-mg dosing, particularly since a higher rate of sexual AEs is experienced during the first 6–12 months of treatment compared with later time points [12,40,44]. The increased rate of EjD is likely due to results of the Prostate Cancer Prevention Trial (PCPT), with the large sample size and high rate of EjD among prostate cancer patients [42]. The increased rate of sexual AEs with dutasteride compared with finasteride may be due to an increased participant awareness, as the dutasteride studies were conducted several years later, or possibly due to the higher rate of inhibition of both 5AR isoenzymes. This is supported by a recent retrospective review of 398 consecutive patients receiving finasteride 5 mg (N = 197) or dutasteride 0.5 mg (N = 211), which demonstrated significantly higher rates of decreased libido, ED, and EjD with the dutasteride group (dutasteride/finasteride: 2.7%/ 1.4%, 5.1%/2.1%, 2.4%/1.8%, P < 0.01) [55]. In contrast, a direct RCT comparison performed by Nickel and colleagues demonstrated no

Andriole et al. [32]

Roehrborn et al. [33] CombAT; Multicenter

2010

2008

Multicenter

Clark et al. [37]

Clark et al. [37] Debruyne et al. [15]

Multicenter Combination of 3 phase III, open label trials Roehrborn et al. [38] Multicenter

Kirby et al. [39] Lowe et al. [40]

2004

2004 2004

2003 2003

Lowe et al. [40]

McConnell et al. [41] MTOPS; Multicenter Thompson et al. [42] PCPT; Multicenter

2003

2003 2003

Multicenter

PREDICT; Multicenter Multicenter

IIEF, MSF-4

Single center

2004

Self-reported

Multicenter

Self-reported Self-reported

Self-reported

Self-reported Self-reported

Self-reported

Self-reported Self-reported

Self-reported

Self-reported

Multicenter

Self-reported

Self-reported

Self-reported Self-reported

BPH Pca

BPH

BPH BPH

BPH

BPH BPH

BPH

BPH

Healthy

Healthy

BPH

Pca

BPH BPH

32

1,611 (Placebo = tamsulosin) 32

4,126

None None

Placebo (N =)

768 9,423

231

264 552

1,128 (696 at year 4)

55 2,166

558 (at 1 year) 737 9,457

269 558

1,123 (651 at year 4)

59 2,158

55 (sexual 52 (no sexual AE discussion) AE discussion) 60 59

33

34

1,623

4,105

813 817

AE Reporting Population Drug (N =)

2007, Amory et al. [34,35] 2008 2007, Amory [34,35] 2008 2007 Mondaini et al. [36]*

REDUCE; Multicenter

EPICS; Multicenter EPICS; Multicenter

Nickel et al. [31]* Nickel et al. [31]*

2011 2011

Study/Center

Author

Age Dut 0.5 Fin 5

Drug/Dosage (mg)

1,505 ⱖ50 18,880 ⱖ55

64

Fin 5 Fin 5

Fin 5

533 50–80 Fin 5 64 Fin 1

4.5 7

1+5

1 1

2+2 Dut 0.5

2,251 ⱖ50

114 ⱖ50 4,324 ⱖ50

Dut 0.01, 0.05, 0.5 0.5, 2.5, 5.0 (0.5 charted in table) Fin 5 0.5 Dut 0.5 2+2

1, with 24 weeks f/u 1, with 24 weeks f/u 1

2

1 1(Fin vs. Dut) + 2 (Dut) 4

Duration (year) + extension

119 ⱖ50

107 45–65 Fin 5

65 18–55 Dut 0.5

Dut 0.5 Placebo = tamsulosin 66 18–55 Fin 5

3,234 ⱖ50

8,231 50–75 Dut 0.5

1,630 ⱖ50 ⱖ50

Total (N =)

Summary of study characteristics of randomized, placebo-controlled trials of finasteride and/or dutasteride reporting adverse events

Date

Table 1

Original 1 year data presented by Finasteride Study Group (1993) Orgasmic function reported (0.4 Fin vs. 0.2) Orgasmic function reported (0 Fin vs. 0.2)

Year 1 with higher rates of SAE D/P (Libido:3.6/1.7; ED:6.1/3; EjD:2/0.6)

Nocebo phenomenon

Decreased semen volume (D/P: 1.4/0.2)

Notes

5ARI Side Effects 27

Sex Med Rev 2013;1:24–41

Sex Med Rev 2013;1:24–41

Wessells et al. [43]

Whiting et al. [18] Roehrborn et al. [13]

Hudson et al. [44]

Leyden et al. [17] Kaufman et al. [16] Marberger [45] McConnell et al. [12]

Tenover et al. [46] Lepor et al. [47]

Nickel et al. [48] Byrnes et al. [49]

Stoner [50]

Gormley et al. [51] Gormley et al. [51]

2003

2003 2002

1999

1999 1998 1998 1998

1997 1996

1996 1995

1994

1992 1992

Multicenter Multicenter

Multicenter Multicenter—VA hospitals PROSPECT; Multicenter Multicenter, community based Multicenter

Multicenter Multicenter Multicenter Multicenter

Open-label extension of Gormley et al. (1992) study

Multicenter Multicenter

PLESS; Multicenter

Study/Center

Self-reported Self-reported

Self-reported

Self-reported Self-reported

Self-reported Self-reported

Self-reported Self-reported Self-reported Self-reported

Self-reported

Self-reported Self-reported

Self-reported

AE Reporting

BPH BPH

BPH

BPH BPH

BPH BPH

Alopecia Alopecia BPH BPH

BPH

Alopecia BPH

BPH

Population

298 297

310 1,759

1,736 310

133 779 1,577 1,523

186

286 1,510

1,520

Drug (N =)

300 300

303 583

579 305

123 774 1,591 1,516

300

138 1,441

1,520

Placebo (N =)

895 895

613 2,342

2,315 615

256 1,553 3,168 3,039

486

424 2,951

3,040

Total (N =)

40–83 40–83

45–80 ⱖ45

Fin 1 Fin 5

Fin 1, 5

Fin 5 Fin 5

Fin 5 Fin 5

ⱖ45 45–80

1 1 5 5

Fin Fin Fin Fin

Fin 5

Fin 1 Dut 0.5

Fin 5

Drug/Dosage (mg)

18–41 18–41 50–75 64

40–83

41–60 ⱖ50

45–78

Age

1 (1 and 5 mg) +2 (5 mg) 1 1

2 1

1 1

1+1 1+1 2 4

1+4

2 2

4

Duration (year) + extension

Baseline SD (Fin—36.6%; Plac—33.7%) 36 months open-label findings

Year 1 with higher rates of SAE D/P (Libido:6.4/3.4; ED:8.1/3.7; EjD:0.8/0.1

Year 1 with higher sexual AE: Libido (3.7/1.9), ED (6,3), EjD (1.8/0.7) Year 2: Libido (0.6/0.3), ED (1.7/1.2), EjD (0.5/0.1) Results at 1 year different from Gormley et al. study due to smaller sample size evaluated

Results reported from patients without a history of sexual dysfunction -Orgasm dysfunction D/P (0.6/0.3)

Notes

*Excluded from pooled data on RCTs given lack of true drug placebo group NS = not significant; AE = adverse events; VA = veterans administration; MSF-4 = Male Sexual Function Score-4 Item; IIEF = International Index of Erectile Function; EPICS = Enlarged Prostate International Comparator Study

Author

Continued

Date

Table 1

28 Trost et al.

Fin 5

Amory et al. [34,35]

Amory et al. [34,35]

Mondaini et al. [36]*

Clark [37]

Clark et al. [37] Debruyne et al. [15] Roehrborn et al. [38] Kirby et al. [39] Lowe et al. [40] Lowe et al. [40]

2007, 2008 2007, 2008 2007

2004

2004 2004 2004 2003 2003 2003

McConnell et al. [41]

Dut 0.5

Andriole et al. [32] Roehrborn et al. [33]

2010 2008

2003

Dut 0.5 Dut 0.5 Placebo = Tamsulosin Fin 5

Nickel et al. [31]* Nickel et al. [31]*

2011 2011

Fin 5

Dut 0.01, 0.05, 0.5, 2.5, 5.0 (0.5 charted in table) Fin 5 Dut 0.5 Dut 0.5 Fin 5 Fin 1 Fin 5

Dut 0.5 Fin 5 (+Dut 0.5 for ext)

Author

Drug/Dosage (mg)

0.7/0.2 0.5–0.8 per year

NS <1 <1%

NS

3/3

Discontinued (%) (D/P)

6 month f/u with 3% persistent ED (unclear if D/P)

Returned to baseline

Returned to baseline

Sexual A/Es resolved after discontinuing (%) (D/P)

2.4

13 0.6 (0.1) 0.5 (0) 3.4 5.1 3.8 (0.7)

4

23.6

6

18

6 5 (0–2 at 3 years) 3.3 2.8

D

1.4

2 0.3 (0.2) 0.4 (0.3) 1.9 2.3 2.3

2

7.7

3

3

1.6 1.7

P

Libido (Ext)

4.5

11 1.7 (0.4) 1.3 (0.4) 4.9 5.1 4.8 (0.4)

5

30.9

6

3

9 8 (3–4 at 3 years) 9 6

D

ED (Ext)

3.3

3 1.2 (0.4) 1.3 (0.6) 3.3 1.8 1.8

3

9.6

6

6

5.7 3.8

P

1.8

0.5 (0.1) 0.3 (0.1) 2.3 2.9 3.1 (0.4)

16.3

0

6

1.4 0.5

2 2 (1 at 3 years)

D

EjD (Ext)

0.8

0.1 (0.3) 0.1 (0.5) 1.5 1.1 1.1

5.7

0

0

0.2 0.8

P

Summary of randomized, placebo-controlled trials of finasteride and/or dutasteride reporting sexual adverse events

Date

Table 2

Breast c. in Fin alone or combination (0.3%)

0.4 0.5

1.3 (0.7) 1.6 (1)

9

24

1.9 1.8

D

0 0

0.3 (0.9) 0.2 (1.1)

6

6

1.0 0.8

1 1

P

Gynecomastia (Ext)

0/0

3/0

Depression % (D/P)

5ARI Side Effects 29

Sex Med Rev 2013;1:24–41

Sex Med Rev 2013;1:24–41

Thompson et al. [42]

Wessells et al. [43]

Whiting et al. [18] Roehrborn et al. [13] Hudson et al. [44]

Leyden et al. [17] Kaufman et al. [16] Marberger et al. [45] McConnell et al. [12]

Tenover et al. [46] Lepor et al. [47] Nickel et al. [48] Byrnes et al. [49] Stoner [50] Gormley et al. [51] Gormley et al. [51]

2003

2003

2003 2002 1999

1999 1998 1998 1998

1997 1996 1996 1995 1994 1992 1992

Fin Fin Fin Fin Fin Fin Fin

Fin Fin Fin Fin

5 5 5 5 1, 5 1 5

1 1 5 5

Fin 1 Dut 0.5 Fin 5

Fin 5

Fin 5

Drug/Dosage (mg)

1/0.3 1.3/0.3

1.5/0.5

2.2/1.4

3.7 (includes years 1–5)/ 0.7 (includes year 1) 0/0 1.4/1.0 1/1

2.1/2.2

4/2

Discontinued (%) (D/P)

100/100

12/19 resolved during therapy 50/41 resolved after discontinuing

Sexual A/Es resolved after discontinuing (%) (D/P)

5.4 5 10 2.9 (4.8) 6.0 4.7

1.5 (0) 1.9 (1.1) 4 2.6

4.9 4.2 7.7 (3.7)

9.6

65.4

D

Libido (Ext)

3.3 1 6.3 1 (2.5) 1.3 1.3

1.6 (0) 1.3 (1.3) 2.8 2.6

4.4 2.1 3.3

6.7

59.6

P

8.1 9.4 15.8 5.6 (5) 5.0 3.4

0.75 (0) 1.4 (0.7) 6.6 5.1

3.8 7.3 6.7 (9.6)

12.6

67.4

D

ED (Ext)

3.8 4.6 6.3 2.2 (2) 1.7 1.7

0 (0) 0.9 (1.1) 4.7 5.1

0.7 4.0 4

7.9

61.5

P

4 2 7.7 2.1 (3.5) 4.4 4.4

0 (0) 1 (0.2) 2.1 0.2

2.8 2.2 4.7 (2.7)

5.7

60.4

D

EjD (Ext)

0.9 1 1.7 0.5 (1.1) 1.7 1.7

0.8 (0) 0.4 (0) 0.6 0.1

0.7 0.8 1.7

1.2

47.3

P

0 0

1.1 (0.1% breast cancer)

1.8 (0% breast cancer)

Breast pain 0.7 Breast pain 0.3

0.4

0.7

2.8 (<0.1% breast cancer)

P

0.4

2.3

4.5 (<0.1% breast cancer)

D

Gynecomastia (Ext) Depression % (D/P)

*Excluded from pooled data on RCTs given lack of true drug placebo group NS = not significant; AE = adverse events; Ext = extension; VA = veterans administration; MSF-4 = Male Sexual Function Score-4 Item; IIEF = International Index of Erectile Function; EPICS = Enlarged Prostate International Comparator Study

Author

Continued

Date

Table 2

30 Trost et al.

31

0.0 1.0 1.5 1.1 1.3 0.2 1.5 1.1 1.3 0.4/0.4 1.6/0.6 3.7/2.3 1.7/0.6 2.9/1.6 0.4/0.2 4.1/2.6 1.8/0.7 2.8/1.6 Calculated differences are based on non-rounded numbers and may be slightly different than subtraction of the rounded numbers listed in the table D = drug; P = placebo; ED = erectile dysfunction; EjD = ejaculatory dysfunction; AGA = androgenic alopecia; BPH = benign prostatic hyperplasia; Ca = Cancer

0.8 1.5 9.5 0.6 3.4 1.3 3.6 0.7 3.4 1.3/0.5 2.2/0.7 42.5/33 1.0/0.4 19.4/16 2.2/0.9 30.0/26.4 1.1/0.3 18.9/15.5 1.1 2.3 5.1 0.6 1.6 2.0 -0.4 2.2 1.6 0.8 1.5 4.6 1.0 1.0 1.9 -0.9 1.2 1.0 1,198 17,873 13,528 979 31,687 2,048 19.993 10,625 32,666 AGA BPH Prostate Ca Age ⱕ 55 Age ⱖ 40 Finasteride 1 mg Finasteride 5 mg Dutasteride 0.5 mg All studies Combined

1,035 14,953 13,583 929 28,674 1,893 17,192 10,518 29,603

2,233 33,384 27,111 1,908 60,919 3,941 37,743 21,143 62,827

2.6/1.7 3.8/2.3 46.6/42.0 2.5/1.5 22.1/21.1 3.8/1.8 33.4/34.3 2.5/1.3 21.5/20.5

1.9/0.8 6.1/3.8 49.7/44.6 1.5/1.0 24.7/23.1 3.2/1.2 35.7/36.1 6/3.8 24.0/22.4

% Gynecomastia (D/P) % Difference (D-P) % EjD (D/P) % Difference (D-P) % ED (D/P) % Difference (D-P) % Decreased libido (D/P) Total (N =) Placebo (N =) Drug (N =) Categories Included

Table 3

Pooled summaries of reported sexual adverse events and gynecomastia from randomized, placebo-controlled trials of finasteride and/or dutasteride

% Difference (D-P)

5ARI Side Effects

differences with rates of SD among patients receiving finasteride 5 mg (N = 817) or dutasteride 0.5 mg (N = 813). In this study, rates of decreased libido, ED, or EjD were reported at 6%/5%, 9%/8%, and 2%/2% for finasteride/dutasteride, respectively. The presence of orgasmic dysfunction is selfreported less frequently than other forms of SD among patients undergoing treatment with 5ARIs. One study evaluating finasteride 1 mg (N = 552) vs. 5 mg (N = 231) vs. placebo (N = 558) reported orgasmic dysfunction in 0.4% of patients receiving finasteride 1 mg at 1 year, compared with 0.2% placebo [40]. Open-label extension with finasteride 5 mg demonstrated 0% orgasmic dysfunction. Similarly, Wessells and colleagues reported orgasmic dysfunction among 0.6% taking finasteride 5 mg for 4 years compared with 0.3% placebo [43]. Although data are limited, these findings suggest a low rate of orgasmic dysfunction in patients taking 5ARIs. One significant limitation of the above studies is the use of patient-reported AEs and lack of validated questionnaires. Two studies conducted among patients taking finasteride 1 mg for AGA utilized IIEF questionnaires to assess the presence of ED while on therapy [56,57]. One study included 236 men undergoing treatment with agematched controls, while the other compared scores pre- and at 6 months of treatment among 186 men. Both studies demonstrated no significant changes in IIEF scores; however, these studies assess a small number of young, healthy patients, limiting potential conclusions drawn from the data.

Persistence of Sexual AEs Over Time and Following Drug Discontinuation Patient self-reported rates of sexual AEs decreased over time, with the highest reported rates occurring between 6 months and 12 months of therapy [12,36,40,44]. Nickel and colleagues noted improvements in libido, ED, and EjD from years 1–3 (5% vs. 2%, 8% vs. 4%, and 2% vs. 1%, respectively). Similar improvements in libido, ED, and EjD were noted by Debruyne and colleagues from years 2–4 (0.6% vs. 0.1%, 1.7% vs. 0.4%, 0.5% vs. 0.1%, respectively), by Roehrborn and colleagues from years 2–4 (0.5% vs. 0%, 1.3% vs. 0.4%, 0.3% vs. 0.1%, respectively), and by Kaufman and colleagues from years 1–2 (1.9% vs. 1.1%, 1.4% vs. 0.7%, 1.0% vs. 0.2%, respectively) [15,31,38]. Only one study noted an increased rate of ED (years 1 and 5 = 6.7% and 9.6%, Sex Med Rev 2013;1:24–41

32 respectively) [44]. Decreasing rates of sexual AEs are difficult to interpret, as later results may not include earlier patient dropouts. Hence, it is unclear if those who will ultimately experience AEs are selectively removed by dropout, thus artificially lowering rates in subsequent years. Two recent publications by Irwig and colleagues have suggested that sexual AEs following 5ARI treatment may be permanent in a subset of patients, despite discontinuation of therapy [24,25]. The studies enrolled a combined 125 patients, aged 21–46, with 49% originating internationally and self-identified as experiencing persistent SD following treatment and discontinuation of finasteride 1 mg for AGA. Patients were recruited from a combination of the author’s practice, word of mouth, and an advertisement on the web site “Propeciahelp.com,” which provides a forum for information and articles regarding patient-reported AEs following treatment with Propecia. Patients were retrospectively assessed using the Arizona Sexual Experience Scale (ASEX) and were requested to recall responses to the ASEX questionnaire prior to and following finasteride use. The mean time from drug discontinuation and interview date was 40 months, with 45% of patients recalling events ⱖ3 years after discontinuation and only 13% recalling responses within 12 months of discontinuation. Patients reported new-onset, persistent SD with finasteride in 94% of cases, with low libido 92%, ED 92%, and orgasmic dysfunction 69%. Follow-ups further documented wide-ranging AEs, including alterations in cognition, ejaculate quality, and genital sensation. The significance, credibility, and generalizability of these findings are unclear at the present time given the retrospective nature, small population size, significant sampling and recall bias, lack of a true control, retrospective use of the ASEX questionnaire, and heterogeneous patient population. The ability of the population selected to represent typical users of finasteride is likely questionable, given the highly select nature of patients visiting Propeciahelp.com and electing to participate in an advertised study therein, and the influence of possible future financial legal remuneration. This is supported by a follow-up study of the population, which demonstrated persistent moderate-severe depression among 64% of the selected population vs. 0% controls and suicidal thoughts present in 44% vs. 3% controls, highlighting the atypical nature of the population selected [21]. Sex Med Rev 2013;1:24–41

Trost et al. In contrast, several studies have demonstrated improvements of sexual AEs following drug discontinuation. The Proscar Long Term Efficacy and Safety Study (PLESS) randomized 3,040 men to finasteride 5 mg or placebo with self-reported assessments of sexual AEs [43]. Sexual AEs were statistically increased in finasteride patients in the first year (15% vs. 7%), with no statistical differences identified at years 2–4. Of patients receiving finasteride, 4% discontinued therapy secondary to sexual AEs compared with 2% of placebo patients. Among patients who discontinued therapy due to AEs, 50% of finasteride, and perhaps more surprisingly 41% of placebo, experienced subsequent resolution of symptoms. Otherwise stated, 59% of patients receiving placebo therapy continued to experience sexual AEs after drug discontinuation. This suggests that reported findings of persistent sexual AEs associated with 5ARI use may be due to factors other than the drug itself. Kaufman and colleagues similarly demonstrated resolution of sexual AEs in an RCT of 1,553 men following discontinuation of 2 years of finasteride 1 mg [16]. An additional study, highlighting the difficulty of obtaining true prevalence rates of 5ARIs associated sexual AEs, was provided by Mondaini and colleagues [36]. The authors randomized 120 patients with BPH and IIEF scores >24 to receive finasteride 5 mg for 12 months, with or without specific counseling of potential sexual AEs. At 6 months and 12 months of therapy, patients completed MSHQs. Results demonstrated that patients who were reviewed potential sexual AEs experienced a higher rate of decreased libido, ED, and EjD (counseling/no counseling: 15.3%/7.7%, 43.6%/9.6%, 15.3%/5.7%, respectively) compared with those not receiving counseling. The authors termed this increased prevalence of symptoms the “nocebo effect,” suggesting that the symptoms were secondary to factors other than the medication itself. The study is limited by the absence of placebo control, as the added patient counseling may have helped patients identify symptoms that they might otherwise neglect or be too embarrassed to self-report. Limited data from animal models demonstrate contrasting findings on 5ARI-associated ED. Effects of dutasteride on rat erectile function (EF) have been reported in two studies and demonstrated significant impairments in all rats following 6–8 weeks of treatment, which persisted following a 2-week washout period [58,59]. As these findings suggest a significantly increased degree

5ARI Side Effects and prevalence of ED compared with available human studies, their overall applicability to clinical practice is unclear. Additionally, these findings are in contrast to a similar study that demonstrated no change in EF in rats treated with finasteride over a 4-week period [60]. Of note, all three studies utilized significantly elevated dosages of 5ARIs compared with human equivalents.

Study Withdrawal Due to Sexual Adverse Events Rates of study withdrawal are difficult to determine for several reasons, including lack of reason given for study withdrawal and inconsistent reporting periods for study withdrawal (number per year vs. total amount, vs. rates during the first or last year). Despite these limitations, subtracted withdrawal rates between drug and placebo secondary to sexual AEs range from 0% to 3%, with Lowe and colleagues noting an annual rate of discontinuation over a 6-year study period of ~0.5–0.8% [15–18,33,37,38,40,43–46,49,51]. The most common AE resulting in therapy discontinuation is ED, followed by decreased libido [61,62]. Mechanism of Action for 5ARI-Induced SD Several studies have described the role of androgens in restoring EF in hypogonadal men [63,64]. Conversely, administration of androgen deprivation therapy (ADT), including surgical castration, has long been recognized to impair libido and EF [65–67]. The mechanism by which T and DHT affect EF is unclear. Androgens are essential to the development, growth, and maintenance of EF, and preserve function and structure of penile neurovascular structures and smooth muscle [68–71]. Histologically, studies have demonstrated a 26% reduction in corpus cavernosal weight among rats treated with finasteride, with preservation of smooth muscle content and increased collagen deposition [58,60]. Rats undergoing castration demonstrate impaired erectile responses, with subsequent restoration following T administration [72]. When castrate rats are treated with combined T+5ARIs, EF is restored only through exogenous DHT, indicating the predominant role of DHT for maintenance of EF [73,74]. These findings are further supported by in vitro studies demonstrating improved responses to electrical field stimulation following treatment with DHT in castrated rats [75].

33 Park and colleagues have previously demonstrated increased expression of neurogenic nitric oxide synthase (nNOS) in the castrate rat corpus cavernosum following androgen administration, with endothelial NOS noted to be independent of the effects of androgens [74]. However, Shen and colleagues reported contradictory findings of no correlation between either nNOS or vasoactive intestinal peptide (VIP) and androgens in castrate animals, suggesting that androgen-mediated erections occur independent of the VIP and NOS pathways [76,77]. More recent evaluations of non-castrate animals treated with 5ARIs found alterations in nNOS and inducible NOS, with persistent impairment of endothelium-dependent responses to electrical field stimulation of rat corpus cavernosal tissue following high-dose 5ARI discontinuation [58,59] These combined findings highlight the need for ongoing study and current lack of consensus on the mechanism of penile androgenic-dependent EF. Beyond the direct effect on penile tissues, androgens play a functional role in the central regulation of sexual function. Androgen receptors and 5AR are present in neurons and glial cells that have been localized to the cortex, hippocampus, amygdala, and thalamus, among others [5,78]. These regions, associated with sexual desire and function, are mediated by dopaminergic transmission, which is regulated, in part, by 5AR activity [79,80]. 5ARIs have been shown to reduce dopamine levels through inhibition of neurosteroid biosynthesis [81,82]. As 5AR is the ratelimiting step for conversion of precursor steroids to the neurohormonal end-products, alterations of 5AR activity may, in theory, directly impact central regulation of sexual functioning.

Infertility The association between 5ARIs and infertility remains unclear, likely having greatest impact on patients with impaired baseline function. Two RCTs evaluating 5ARIs and semen parameters in healthy men demonstrate inconclusive findings. Amory and colleagues compared dutasteride (0.5 mg, N = 33), finasteride (5 mg, N = 34), and placebo (N = 32) administered daily for 1 year [35]. Semen analyses demonstrated statistically significant reductions in total sperm counts at 26 weeks (D = -28.6%, F = -34.3%), with slight improvements at 52 weeks (D = -24.9%, F = -16.2%) and following a 24-week washout (D = -23.3%, F = -6.2%). Reductions were also noted in semen volume (52 weeks; D = -29.7% Sex Med Rev 2013;1:24–41

34

Sex Med Rev 2013;1:24–41

Total sperm (-28.6*, -24.9, -23.3) Volume (-24*, -29.7*, -16.8*) Concentration (-12.9, -3.2, -10.4) Motility (-10.1*, -11.8*, -6.3*) Morphology (-0.6, -0.1, -0.5) 1, with 24-week washout 0.5 Dut 18–55 65 32 2007, 2008 Amory et al. [34,35]

*Statistically significant Fin = finasteride; Dut = dutasteride; F/u = follow-up

33

2007, 2008 Amory et al. [34,35]

Healthy

Total sperm (-34.3*, -16.2%, -6.2) Volume (-21.1*, -14.5, -4.5) Concentration (-21.5*, -7.4, -4.3) Motility (-10.5*, -10.5*, -9.7*) Morphology (-0.8, 0, 0.2) 1, with 24-week washout 5 Fin 18–55 66 32 34

Age Population Date Author

Healthy

Duration (year)

Results of semen analyses All values (% change at 26 weeks, 52 weeks, and f/u) Dosage (mg)/drug Total (N =) Placebo (N =) Drug (N =)

Summary of randomized, placebo-controlled trials of finasteride/dutasteride reporting semen analyses

Mechanism of Action for 5ARI-Associated Infertility Although a causal link of 5ARIs and impaired fertility has not been established, several studies have evaluated potential mechanisms for impaired spermatogenesis. 5AR is physiologically active in the human testes, with DHT functioning to promote expression of claudin-11, a tight junction protein present in Sertoli cells [88–90]. Disruption of this protein results in germ cell atresia and cessation of spermatogenesis [91]. 5AR inhibition with finasteride 1 mg has further been associated with an elevated DNA fragmentation index in case reports, with subsequent improvements following drug discontinuation [87]. Non-human studies with rats and tadpoles treated with 5ARIs have demonstrated impaired spermatogenesis during select stages, suggesting detrimental effects of 5ARIs during certain, sensitive time points of spermatogenesis and possible impairments to Sertoli cell proliferation [92,93]. Despite these factors, the presence of DHT is likely not crucial for spermatogenesis. Men with congenital 5AR-2 deficiency have decreased ejaculate volumes with otherwise normal spermatogenesis [94–96]. Similarly, treatment of

Table 4

[significant], F = 14.5%), sperm concentration (D = -3.2%, F = -7.4%), and motility. Neither medication affected sperm morphology. It is noteworthy that the reduced total sperm count may be partly accounted for by decreased semen volume. See Table 4 for a summary of RCTs evaluating semen characteristics with 5ARIs. A second study evaluated finasteride 1 mg vs. placebo in 181 men, over 48 weeks, with a subsequent 60-week washout [83]. Findings demonstrated no significant differences in total sperm count, sperm concentration, motility, morphology, or semen volume among men treated with finasteride. Both of the above studies utilized healthy male populations and excluded patients with prior infertility, cryptorchidism, or varicoceles. Among men with preexisting subfertility, treatment with 5ARIs may further impair semen parameters. Several case reports identify worsening of semen characteristics while receiving treatment with finasteride 1–5 mg, including development of azoospermia, decreased sperm concentration, diminished motility, and worsened morphology, which improve following drug discontinuation [84–87]. Given the limited data available, additional study is required to better assess the impact of 5ARIs on male fertility.

Trost et al.

5ARI Side Effects canines with finasteride results in reduced semen volume, with otherwise preserved semen quality [97]. Inhibition of 5AR-1 also does not likely impact spermatogenesis, as it does not alter semen DHT [8].

Cognitive/Psychiatric Decreased testosterone has long been associated with cognitive impairments and mood alterations, including increased irritability, dysphoria, and depression [98–104]. Similarly, among men with prostate cancer treated with the ADT, an increase in mood disturbances, anxiety, lack of drive, and listlessness have been described [105]. Additionally, men with symptomatic hypogonadism treated with testosterone replacement have reported improved depressive symptoms [106]. These findings are supported by animal studies, which demonstrate improvements in depressive symptoms with androgen supplementation [107]. Despite abundant research on androgens in the central nervous system (CNS), minimal data are currently available on DHT and/or the effect of 5ARIs on cognition and psychiatric symptoms. Although limited to two RCTs of 5ARIs, depressive symptoms have been identified in 0–3% (vs. 0% placebo) [34,35]. However, these studies are limited by self-reporting of symptoms and lack of validated questionnaires. An additional, retrospective study of 19 patients who developed moderate to severe depression while taking finasteride 1 mg daily for AGA noted symptom onset at 9–19 weeks, with subsequent resolution following drug discontinuation [108]. Two patients electing drug reintroduction experienced a relapse of symptoms within 2 weeks. A prospective, short-term study evaluated 128 men (age 20–38) treated with finasteride 1 mg daily for 2 months for AGA using the Beck Depression Index (BDI—scores range from 0 to 63) and Hospital Anxiety and Depression Scale (HADS—range from 0 to 21 each for depression and anxiety subgroups) [109]. Baseline depressive symptoms were present in 21.9% of patients, with a 0.69-point increase in the BDI and 0.57-point increase in the HADS-Depression score noted in the finasteride group. These findings indicate a statistically significant, although clinically minimal, effect of finasteride 1 mg in this otherwise healthy cohort with shortterm follow-up. A more recent study by Irwig and colleagues retrospectively evaluated 61 patients with self-

35 reported persistent SD following finasteride 1 mg discontinuation and compared against men with AGA, without prior finasteride use. Using a BDI-II questionnaire, former finasteride users reported moderate to severe depressive symptoms in 64% (vs. 0% controls) and suicidal thoughts in 44% (vs. 3% controls). However, these data are hindered by the same limitations previously discussed with the other two Irwig articles, with a likely highly select and non-generalizable treatment population and non-standard methodology utilized. With the limited data currently available, the true prevalence of depression, anxiety, or cognitive effects with 5ARIs is unknown. Further study with randomized/prospective studies is required, particularly among patients with baseline increased susceptibility for cognitive/psychiatric disorders.

Mechanism of Action for 5ARI-Associated Cognitive/Psychiatric Impairment As previously described, 5AR is the rate-limiting step in the conversion of testosterone, progesterone, and deoxycorticosterone to 5a-DHT, 5a-DHP, and 5a-DHDOC. In the CNS, 3AHSD subsequently converts these products to 3a-diol, 3a,5a-THP, and 3a,5a-THDOC, respectively. These end-products are neurosteroids, which modulate gamma-aminobutyric acid type A (GABAA), sigma, N-methyl d-aspartate and nicotinic acetylcholine receptors, and voltagegated calcium channels via intracrine or paracrine effects [110]. These receptors are located in several regions throughout the CNS, including cortex, hippocampus, olfactory bulb, amygdala, cerebellum, and thalamus [78]. See Figure 1 for summary of enzymatic conversions modulated by 5AR. Neurosteroids have demonstrated several physiologic functions, including regulating mood, stress, sedation, memory, anxiety, and sexual function, and likely influence neuronal and glial cell growth and survival [6,111–117]. 3a,5a-THP directly prevents neuronal apoptosis and increases neuronal survival [63,118–121]. Neurosteroids may, therefore, have an important role in preserving brain function following injury, with their inhibition potentially resulting in additive detrimental effects [122,123]. Neurosteroids are associated with mood symptoms, including depression [124]. Depressed adults have lower concentrations of 3a,5a-THP in cerebrospinal fluid and serum compared with Sex Med Rev 2013;1:24–41

36 controls [125,126]. Adults with prior histories of depressive episodes have persistently altered neurosteroid levels, suggesting baseline differences in neurosteroid synthesis [127]. The sensitivity of receptors, including GABAA, varies depending on neurosteroid withdrawal, stress, social isolation, and aging [128]. Neurosteroids are further able to regulate gene expression and modulate intracellular receptors, which secondarily attenuate symptoms of depression and sexual function [111,125]. Both of these characteristics suggest the possible increased impact of 5ARI treatment in susceptible populations. Treatment with finasteride results in decreased neurosteroid synthesis, with increases in anxiety and depressive behaviors noted in animal models [113,129–133]. Mice treated with finasteride demonstrate reduced numbers of newborn and young neurons in the hippocampus, which is improved following drug discontinuation [134]. Similarly, castrated rats treated with T or DHT experience restored cell survival in the hippocampus [135]. These mechanisms may account for the increased rate of mood-related symptoms among 5ARI patients.

Additional/Potential AEs Prostate Cancer 5ARIs have previously been investigated as chemopreventive agents against prostate cancer. The PCPT enrolled 18,882 men and randomized to placebo vs. finasteride 5 mg daily for 7 years [42]. Findings demonstrated an overall reduction of prostate cancer by 24.6% in the treatment arm, with an increased rate of development of Gleason 7–10 prostate cancers (37% treatment, 22.2% placebo). Subsequent reanalyses by several authors suggested multiple counterarguments against the increased risk for HGPC, including lack of reliability of Gleason scoring following 5ARI treatment, reduction in prostate volume and subsequent increased detection of malignancy, and increased sensitivity of prostate specific antigen (PSA) as a prostate cancer detection marker in the finasteride group, among others [136–143]. A similar RCT of dutasteride 0.5 mg administered over a 4-year period demonstrated a relative risk reduction of prostate cancer of 22.8% with no increased risk of high-grade malignancy [32]. Despite these findings, the U.S. Food and Drug Administration (FDA) rejected the application to approve dutasteride for chemoprevention of prostate cancer. Sex Med Rev 2013;1:24–41

Trost et al. Although a detailed discussion is beyond the scope of the current review, the above studies suggest that potential risks of developing HGPC are likely minimal.

Gynecomastia/Breast Cancer Gynecomastia is a known AE of 5ARIs and is reported to occur in 0.4–24% of patients vs. 0–6% in those receiving placebo [12,13,15,16,31– 35,38,40–42,51]. A pooled average of these studies results in an overall rate of 2.8% with 5ARIs vs. 1.6% placebo. The underlying mechanism is proposed to be secondary to increases in T with 5ARI administration, with subsequent conversion peripherally to estradiol, thus altering the estrogen-to-androgen ratio [144]. As estradiol increases the number of breast epithelial cells, the increased ratio experienced with 5ARIs may hypothetically increase the risk of development of breast cancer [145]. However, in contrast to the known association of 5ARIs and gynecomastia, few studies have reported development of breast cancer in men taking 5ARIs. The PCPT study noted a <0.1% incidence of development of breast cancer in both treatment and placebo arms [42]. A second study comparing placebo, finasteride, doxazosin, or combination therapies identified four cases (0.3%) of breast cancer in the finasteride and combination groups vs. 0% of placebo [41]. In contrast, a prior study by the same group noted a 0% incidence of breast cancer in finasteride-treated men vs. 0.1% of placebo patients [12]. Cardiovascular System The effect of 5ARIs on cardiovascular health and associated comorbidities is likely minimal, with no randomized studies specifically examining cardiovascular health as a predefined end point. Among the available RCTs, only the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial demonstrated a slight increase in the rate of events classified as cardiac failure among patients treated with dutasteride 0.5 mg daily (0.7% vs. 0.4% placebo, P = 0.03) [32]. However, no significant difference was noted between groups in overall incidence of cardiovascular events or deaths. In a case-control study evaluating 220 cases and 515 controls, finasteride was not associated with hospital admissions for ischemic heart disease [146]. One small study involving 12 men treated with finasteride 1 mg daily for 12 months

37

5ARI Side Effects identified initial reductions in total, high-density lipoprotein, and low-density lipoprotein levels, which subsequently normalized, and slight reductions in HbA1c levels, indicating possible slight beneficial effects on cardiovascular risk factors [147]. In assessing the impact on body mass index (BMI), the PLESS study identified larger T increases in patients with lower baseline T levels compared with mid- or upper tertiles. Following treatment with finasteride 5 mg daily for 4 years, patients in the lowest baseline T tertile experienced significant mean reductions in BMI (0.6– 0.8 kg/m2) compared with those in the mid- to upper tertiles, suggesting slight improvements in BMI in certain subgroups of patients receiving 5ARIs [148]. Potential mechanisms for the effect of 5ARIs on the cardiovascular system have not been well defined. An animal study of 5ARIs identified reduced atherosclerosis through suppression of intimal foam cell formation, indicating possible beneficial effects of 5ARIs on overall vascular health [149]. In the absence of RCTs directly evaluating cardiovascular health with 5ARIs, there are insufficient data to definitively identify any beneficial or harmful effects at the present time.

Labeling Changes/Position Statement In an attempt to address post-marketing reports of AEs, including SD and depression, several regulatory agencies, including the U.S. FDA, Medicine and Healthcare Products Regulatory Agency of the United Kingdom, and the Swedish Medical Products Agency, have revised finasteride labeling/ patient information to include the possibility of these AEs occurring with drug use and persistence following drug discontinuation. The FDA notes that although no clear causal link has been established between finasteride and SD, post-marketing reports may suggest a broader range of symptoms than previously reported [150]. Labeling changes have also been made to indicate the possibility for development of HGPC with 5ARI use [151]. The Sexual Medicine Society of North America (SMSNA) has similarly released a position statement indicating that treatment with 5ARIs is associated with undesired sexual symptoms, which may be persistent following drug discontinuation [152]. The SMSNA further notes that at the present time, there is no definitive link as to the causality of 5ARIs on patients’ symptoms, and indicated that additional research is required.

Conclusions

5ARIs are commonly prescribed medications for the treatment of BPH and AGA, and have been evaluated for their potential use as chemopreventive agents against prostate cancer. Through inhibition of 5AR, finasteride and dutasteride result in decreases in several downstream hormones, including DHT, 5a-DHP, 5a-DHDOC, 3a-diol, 3a,5a-THP, and 3a,5aTHDOC. The latter three have been identified as functional neurosteroids. Several randomized, placebo-controlled, longterm, multicenter trials with large sample sizes have evaluated the efficacy and safety of 5ARIs, with most trials reporting AEs based on patient self-reporting. A pooled analysis of over 62,827 patients demonstrated slightly increased rates of decreased libido, ED, EjD, and gynecomastia among 5ARI users over placebo (1.5%, 1.6%, 3.4%, and 1.3%, respectively). Limited data on the effect of 5ARI on mood disorders have demonstrated statistically significant, although clinically minimal, increased rates of depression. Similarly, 5ARI use may result in reversible decreases in spermatogenesis in susceptible individuals. There are currently inadequate data to suggest harms or beneficial effects of 5ARIs in regard to cardiovascular disease or risk factors, or in the development of breast cancer. Although 5ARI use has been shown to decrease the incidence of subsequent development of prostate cancer, there is ongoing debate as to its association with increased HGPC. Post-marketing surveillance of AEs associated with 5ARI use has questioned whether published results are underreported, with the possibility of some symptoms persisting beyond drug discontinuation. This has resulted in recent modifications to regulatory labeling, although no causal link has been thus far established. Additional RCTs using validated questionnaires are required to more fully assess the true prevalence, clinical relevance, and potential long-term persistence of AEs resulting from 5ARI use. Corresponding Author: Wayne J.G. Hellstrom, MD, FACS, Department of Urology, Section of Andrology, Tulane University, Health Sciences Center, 1430 Tulane Avenue, SL-42, New Orleans, LA 70112, USA. Tel: (504) 988-3361; Fax: (504) 988 5059; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Sex Med Rev 2013;1:24–41

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