Received: 27 December 2019 Revised: 15 March 2020 Accepted: 1 April 2020

DOI: 10.1111/dth.13379

REVIEW ARTICLE

5-Alpha reductase inhibitors in androgenetic alopecia: Shifting

paradigms, current concepts, comparative efficacy, and safety

Rachita Dhurat1 | Aseem Sharma2 | Lidia Rudnicka3 |

4,5,6
George Kroumpouzos | Martin Kassir | Hassan Galadari8 |
7
Uwe Wollina9 |
Torello Lotti10 | Masa Golubovic11 | Iva Binic12 | Stephan Grabbe13 |
Mohamad Goldust14,15,16
1
Department of Dermatology, LTMMC and LTMGH, Mumbai, India
2
Department of Dermatology, L.T.M.M.C. and L.T.M.G.H., Sion Hospital, Mumbai, India
3
Department of Dermatology, Medical University of Warsaw, Warsaw, Poland
4
Department of Dermatology, Alpert Medical School of Brown University, Providence, Rhode Island
5
Department of Dermatology, Medical School of Jundiaí, S~
ao Paulo, Brazil
6
GK Dermatology, PC, South Weymouth, Massachusetts
7
Worldwide Laser Institute, Dallas, Texas
8
College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
9
Department of Dermatology and Allergology, Städtisches Klinikum Dresden, Academic Teaching Hospital of the Technical University of Dresden, Dresden, Germany
10
University of Studies Guglielmo Marconi, Rome, Italy
11
Clinic for Dermatovenerology, Clinical Center Nis, Nis, Serbia
12
Psychiatry Clinic, Clinical Center Nis, Nis, Serbia
13
Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
14
University of Rome G. Marconi, Rome, Italy
15
Department of Dermatology, University Medical Center Mainz, Mainz, Germany
16
Department of Dermatology, University Hospital Basel, Basel, Switzerland

Correspondence
Mohamad Goldust, University of Rome
G. Marconi, Rome, Italy; Department of
Dermatology, University Medical Center
Mainz, Mainz, Germany; Department of
Dermatology, University Hospital Basel, Basel,
Switzerland.
Email: mgoldust@uni-mainz.de
Abstract
Androgenetic alopecia (AGA) is a multifactorial disease that carries a significant psy-
chological burden with it. Dihydrotestosterone, the main pathogenic androgen in
AGA, is produced by conversion of testosterone, which is catalyzed by the 5-alpha
reductase (5-AR) isoenzyme family. Finasteride and dutasteride are inhibitors of these
enzymes. Finasteride, which is a single receptor 5-alpha reductase inhibitor (5-ARI),
acts by blocking dihydrotestosterone (DHT). Dutasteride, a dual receptor DHT
blocker, has a higher potency than its predecessor, finasteride. This review corrobo-
rates the evidence of superiority of dutasteride over finasteride, and its comparable
safety profile concerning fertility, teratogenicity, neurotoxicity, and hepatotoxicity.

KEYWORDS

5-alpha reductase inhibitors, androgenetic alopecia, dutasteride, finasteride

Dermatologic Therapy. 2020;33:e13379. wileyonlinelibrary.com/journal/dth © 2020 Wiley Periodicals LLC 1 of 5

https://doi.org/10.1111/dth.13379
2 of 5
1 | I N T RO DU CT I O N
Androgenetic alopecia (AGA) is the commonest type of patterned alo-
pecia in both men and women. The pathophysiology includes a grad-
ual, spectral conversion of hair from terminal to intermediate to vellus
hair, a process known as miniaturization.1-3 The process of miniaturi-
zation is androgen-mediated in males. In women, female pattern hair
loss (FPHL) has emerged as the preferred term for androgenetic alo-
pecia due to the uncertain relationship between androgens and this
entity.4-6 However, literature supports the effectiveness of finasteride
7,8
and dutasteride therapy in women with FPHL. Testosterone is the
principal androgen in circulation, but it needs to be converted to dihy-
drotestosterone (DHT), which is the main pathogenic androgen of
AGA, by the catalysis of enzyme 5-alpha reductase (5-AR). Therefore,
9
5-AR inhibition is the main target for AGA therapy.
2 | 5-ALPHA REDUCTASE INHIBITORS
Five-ARIs are a class of antiandrogenic drugs, synonymous with dihy-
drotestosterone (DHT) blockers licensed for use in benign prostatic
hyperplasia.10-12 The 5-ARI enzyme family (types I, II, and III), regu-
lates the metabolism of three distinct pathways—bile, androgens, and
estrogen. Table 1 depicts the distribution of type I and II isoenzymes
and their capacity for DHT conversion.13–15 Dutasteride inhibits both
isoenzymes of 5-alpha reductase (types 1 and 2), hence known as a
dual blocker while finasteride only inhibits 5-alpha reductase type
2. US Food and Drug Administration (FDA) has approved finasteride
for use in AGA in 2007. Dutasteride is approved for AGA at an oral
dose of 0.5 mg in South Korea and Japan since 2009. Type 1 receptor
is responsible for conversion of 20% DHT from testosterone, which
can be blocked by dutasteride, proving to be superior to finasteride
for treating male AGA.16-18
3 | EFFICACY
A meta-analysis by Zhou et al19 evaluated the safety and efficacy of
5-ARIs in AGA over a 24-week treatment period. The study showed
TABLE 1 Physiological distribution and contribution of the 5-alpha reductase (5-AR) isoenzymes
Type 1 5-AR isoenzyme
Tissue distribution Adult facial and scalp sebaceous gland
Epidermis
Eccrine sweat glands
Apocrine sweat glands
Hair follicle
Dermal papilla from occipital hair
Liver
Adrenals
Kidneys
Contribution toward dihydrotestosterone 20%
conversion from testosterone
DHURAT ET AL.
superiority of dutasteride over finasteride, for the parameters of total
hair count, global photography and subjective assessment. Three ran-
domized controlled trials (RCTs) with a pooled total of 576 patients
(290 in dutasteride and 286 in finasteride groups) documented data
on the mean change in total hair count.17,20,21 Statistical analysis rev-
ealed that dutasteride showed a significant increase in the total hair
count as compared to finasteride.
Jung et al22 recruited 31 patients who showed no clinical
response to finasteride and put them on dutasteride. 77.4% of these
patients reported improvement on dutasteride. The superiority of
dutasteride over finasteride was further established in a comparative,
randomized, evaluator-blinded study in 90 men with AGA by
Shanshanwal and Dhurat.17 The authors not only studied a change in
thick and total hair count, but also thin hair count. The change in thin
hair count is a marker for reversal in miniaturization. The authors
found that the net increase in total hair count was 10.44% and 2.17%
from baseline in the dutasteride and finasteride groups, respectively.
There was a 5-fold improvement in the dutasteride group as com-
pared to the finasteride group. There was a significant change in thin
hair count in the dutasteride group (10.17% from baseline), whereas
the finasteride group showed no significant change. This study proved
that conversion from vellus hair to terminal hair occurred only with
dutasteride therapy. Van Neste23 showed that affected follicles with
miniaturized hair did not produce terminal hair, while patients were
on finasteride. From 113 miniaturized hair at baseline, 79 remained
miniature hair after 2 years on finasteride.
4 | SAFETY PROFILE
Dutasteride and finasteride are relatively well-tolerated drugs. On
comparing parameters of sexual dysfunction, primarily altered libido,
erectile dysfunction, and ejaculatory disorders, there was no statistical
difference between finasteride and dutasteride.19 In fact, Debruyne
et al discovered that dutasteride is better tolerated, with fewer
adverse events, in a study period of 4 years.24 Andriole et al reported
an increase the risk of progression of prostate cancer with long-term
use of dutasteride.25 Zhou et al19 refuted this in a meta-analysis due
to lack of sufficient evidence. Moreover, adverse effects of 5-ARIs
Type 2 5-AR isoenzyme
Dermal papilla
Inner layer of the outer root sheath
Sebaceous ducts
Proximal inner root sheath of scalp hair
follicles
Prostate
Testes
Liver
80%
DHURAT ET AL.
TABLE 2 Stand on teratogenicity by 5-alpha reductase inhibitors
Finasteride (1 mg Dutasteride (0.5 mg
daily to 6 weeks) daily to 52 weeks)
Average level in 0.26 ng/mL 3.4 ng/mL
semen
Maximum level in 1.52 ng/mL 14 ng/mL
semen
Times lesser than 750 186
dose for
teratogenicity
Semen level required 750 mL 186 mL
for teratogenicity
26,27
gradually disappear with continued treatment, over time. A Phase
III dutasteride trial demonstrated that dutasteride was well-tolerated,
with a general trend toward a reduction in incidence of the most com-
mon sexual adverse reactions over a 4-year study period. Patients ini-
tiated on dutasteride therapy after 2 years have a similar pattern of
AEs to those starting therapy at baseline, with diminishing incidences
over the 24 to 48-month period. (6.0% in year 1, 1.7% in year 2, 1.4%
in year 3, and 0.4% in year 4).24
28
The Mondaini group have proved that counseling about sexual
side effects generated a higher rate of sexual adverse effects due to
nocebo phenomenon. One group was informed about the possible
adverse effects of finasteride whereas the other arm was uninformed.
The group that was informed had a 3-fold higher incidence of sexual
side effects as compared to the uninformed arm.
An article claimed that the DHT blockade by 5-ARIs causes a
reduction in 5-alpha-tetrahydroprogesterone levels that disrupts the
neurosteroid balance. This produces deleterious effects on the central
nervous system like anxiety or depression.29 Previous studies have
proved that the neurosteroid pathway is required for fetal CNS devel-
opment, and the type 3 5-AR isoenzyme has the highest distribution
in brain, which is not acted upon by finasteride or dutasteride.30,31
Dutasteride is FDA approved for benign prostatic hyperplasia (BPH)
as first-line therapy. Another startling support is derived from the fact
that, despite the high prevalence of BPH (20–60%) among elderly,
there are no reports on dutasteride-induced severe neurotoxicity. The
increase in testosterone and decrease in DHT levels by 5-ARIs have
been studied. In a study of 399 patients, dutasteride blocked 98.4
± 1.2% of DHT at 5 mg/d dose compared to 70.8 ± 18.3% with the
32
same finasteride dose. The long-term safety of finasteride, over a
period of 10 years has been documented in studies.33,34 Recent
reports about postfinasteride syndrome have created a fear among
patients seeking treatment. While low quality studies neither confirm
nor refute postfinasteride syndrome as a valid nosologic entity, it
would be just as inappropriate to dismiss it as nonexistent. Terato-
genic potential is another factor, which plagues these drugs (Table 2).
Bowman et al studied the maximal excretion of finasteride and
dutasteride in semen and concluded that volumes of 750 and 186 mL
3 of 5
of semen are required to cause teratogenic effects in patients treated
with finasteride and dutasteride, respectively, which is scientifically
impossible. In addition, the teratogenic effects reported in murine
studies include hypospadias and marginally reduced prostatic and
seminal vesicle volumes.35 In a case report, a 39-year-old woman was
detected to have an unplanned pregnancy, with 5 weeks of exposure
to finasteride at 2.5 mg/day. She delivered a full-term, normal, fully
healthy male child with no evidence of developmental defects.36
There is a general notion among clinicians that due to the longer
half-life, the cumulative toxicity of dutasteride is higher than that of
finasteride due to the longer half-life. A pharmacodynamic study has
shown that serum levels of dutasteride remained stable and did not
increase on daily dosing, even over a period of 6 months.30 Some
studies have focused on the effects of 5-ARIs on sperm motility, vol-
ume and morphology.37 studied the effects of finasteride (5 mg) and
dutasteride (0.5 mg) daily therapy for 1 year, and analyzed baseline
and post-treatment serum and semen. They concluded that neither
treatment had any effect on sperm morphology.
A revision (“black box” warning) to the FDA prescribing label for
finasteride was issued, with its indirect effect on male breast cancer,
through gynecomastia. In a large, confounding factor-adjusted, dose-
response study on finasteride and male breast cancer in 1005
patients, Kjaerulff et al showed that there was no association between
the two.38
Regarding the effect of 5-ARIs on the liver, there is a transient
rise in serum aminotransferase levels which are well below the patho-
logical 4-fold reference range. Moreover, these drugs can be given in
pre-existing liver disease, with dose adjustment.12 Five-ARIs interact
with drugs that are metabolized by the hepatic CYP3A4 pathway.
Drugs that increase plasma levels of dutasteride and finasteride
include calcium channel blockers like verapamil and diltiazem, ritona-
vir, ketoconazole, ciprofloxacin, and cimetidine, and should be pre-
scribed with caution, or ideally avoided.
5 | CONC LU SION
Five-ARIs finasteride and dutasteride are effective in treating AGA.
The dual reductase inhibitor dutasteride is capable of reversing minia-
turization as opposed to finasteride. These drugs have a similar safety
profile, and there are no major concerns with teratogenicity, fertility,
sexual side effects and neurotoxicity. These drugs play an integral role
in the management of AGA.
CONFLIC T OF INT ER E ST
The authors declare no potential conflict of interests.
OR CID
Lidia Rudnicka https://orcid.org/0000-0002-8308-1023
Torello Lotti https://orcid.org/0000-0003-0840-1936
Mohamad Goldust https://orcid.org/0000-0002-9615-1246
4 of 5
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How to cite this article: Dhurat R, Sharma A, Rudnicka L, et al.
5-Alpha reductase inhibitors in androgenetic alopecia: Shifting
paradigms, current concepts, comparative efficacy, and safety.
Dermatologic Therapy. 2020;33:e13379. https://doi.org/10.
1111/dth.13379