Drugs (2016) 76:1349–1364
DOI 10.1007/s40265-016-0629-5
REVIEW ARTICLE
Androgenetic Alopecia: An Update of Treatment Options
Yanna Kelly1,2,5 • Aline Blanco3 • Antonella Tosti4
Published online: 23 August 2016
Ó Springer International Publishing Switzerland 2016
Abstract Androgenetic alopecia (AGA) is characterized
by a non-scarring progressive miniaturization of the hair
follicle in predisposed men and women with a pattern
distribution. Although AGA is a very prevalent condition,
approved therapeutic options are limited. This article dis-
cusses the current treatment alternatives including their
efficacy, safety profile, and quality of evidence. Finasteride
and minoxidil for male androgenetic alopecia and minox-
idil for female androgenetic alopecia still are the thera-
peutic options with the highest level evidence. The role of
antiandrogens for female patients, the importance of
adjuvant therapies, as well as new drugs and procedures are
also addressed.
& Yanna Kelly
yannakfs@gmail.com
1
Department of Dermatology, Universidade de São Paulo,
São Paulo, SP, Brazil
2
Department of Dermatology, Hospital do Servidor Publico
Municipal de São Paulo, São Paulo, SP, Brazil
3
Department of Dermatology, Universidade Federal do Mato
Grosso do Sul, Campo Grande, MS, Brazil
4
Department of Dermatology and Cutaneous Surgery,
University of Miami Miller School of Medicine, Miami, FL,
USA
5
1364, Oscar Freire Street, São Paulo, SP 05409-010, Brazil
Key Points
Androgenetic alopecia (AGA) is the most common
cause of alopecia in both men and women.
Therapeutic alternatives for AGA are limited and
include approved and off-label options.
Dermatologists should be aware of possible adverse
effects of approved treatments as well as of new
adjuvant treatment options.
1 Introduction
Androgenetic alopecia (AGA), also known as male and
female pattern hair loss, is characterized by non-scarring
progressive miniaturization of the hair follicle with a pat-
tern distribution in predisposed men and women. It is one
of the most common causes of hair consultation. Epi-
demiologic data shows that 80 % of Caucasian men and
40–50 % of Caucasian women are affected by AGA in the
course of their life, with prevalence increasing with age
[1–3]. Prevalence in the Asian population is lower: AGA
was observed in 14.1 % of Korean men at all ages [4].
Similarly, in the African population, a study revealed that
AGA prevalence was found to be 14.6 % in men and 3.5 %
in women [5]. The etiology of AGA is multifactorial and
polygenetic [6, 7]. Male AGA (MAGA) is clearly an
androgen-dependent condition and, although the mode of
inheritance is uncertain, a genetic predisposition is
observed [2, 7, 11]. In female AGA (FAGA) the role of
androgens is still uncertain [8–10].
1350 Y. Kelly et al.

AGA affects quality of life and self-esteem of patients
and their expectations about therapy results is usually
higher than reality. For this reason, it is important to clarify
that the main treatment goal is to stop progression and
prevent further thinning, and improvement and regrowth
may not always been achieved. Although AGA is a very
prevalent condition, approved therapeutic options are lim-
ited. The aim of this article is to review the current ther-
apeutic options and their possible adverse effects, as well
as the new perspectives for AGA treatment. The sources
searched were the PubMed database and ongoing clinical
trials official websites from November 2015 to February
2016.
2 Antiandrogen Therapies
2.1 5a-Reductase Inhibitors
2.1.1 Finasteride
Finasteride 1 mg and minoxidil 2–5 % solution are the
only US Food and Drug Administration (FDA)-approved
treatment options for MAGA (Table 1). Finasteride is a
type 2 5a-reductase inhibitor that decreases the conversion
of testosterone to dihydrotestosterone (DHT), which is
responsible for the miniaturization of the hair follicle seen
in MAGA.
Finasteride efficacy is established and has been
demonstrated in several studies. A systematic review
conducted by Mella et al. [12] on long-term use of finas-
teride 1 mg daily reported noticeable improvement in 30 %
of patients, with moderate quality of evidence. Similar
results were recently found by Gupta and Charrette [13] in
a meta-analysis showing that the 5a-reductase inhibitors
are significantly more effective than placebo in increasing
the hair count. Finasteride 1 mg has also been shown to be
effective in MAGA in patients aged 41–60 years, with
improvement documented by global photography and
investigator assessments. However, young patients and the
vertex/mid scalp areas usually show greater responses [14].
Treatment with finasteride should be life-long as its inter-
ruption is followed by gradual hair loss, with return to the
pre-treatment status within 1 year.
From a safety point of view, finasteride is not hepato-
toxic or nephrotoxic and has no relevant drug interactions.
However, it is recommended that this drug be avoided in
patients who have liver disease as it is metabolized in the
liver [15]. Due to its teratogenicity, patients taking finas-
teride should not donate blood in order to prevent a preg-
nant woman receive this medication during blood
transfusion [16].
The sexual adverse effects of finasteride are well-known
and documented. These include decreased libido, erectile
dysfunction and decreased ejaculated volume. Approxi-
mately 2 % of patients reported one or more sexual adverse
effects during finasteride treatment, compared with 1 % in
the placebo group [17]. Moreover, in randomized con-
trolled trials (RCTs) this rate was 3.8 % (vs. 2.1 % for
placebo). Sexual adverse effects did not necessarily require

Table 1 Main first-line treatment options for male androgenetic alopecia

Medication Treatment approval: Mechanism of action Dosage recommendationsa Major adverse effects
US FDA

Finasteride Approved 5a-reductase inhibitor 1 mg once daily Sexual adverse effects

Dutasteride Approved in several 5a-reductase inhibitor 0.5 mg once daily Sexual adverse effects
countries, e.g.,
Korea and Mexico
Topical Not approved/off- 5a-reductase inhibitor 1 % topical gel or 0.25 % Systemic absorption leading to the
finasteride label topical solution application same sexual adverse effects of oral
once daily to scalp finasteride is not clear yet
Minoxidil Approved Unknown, possible 5 % solution; topical Hypertrichosis
antiandrogenic, vasodilatory, application twice daily Contact dermatitis
and anti-inflammatory effects
Latanoprost Not approved/off- Prolongs the anagen phase 0.1 % solution; topical Erythematous reaction
label application once daily
Ketoconazole Not approved/off- Decreases hair follicle DHT 2 % shampoo; leave on for
label levels 5 min and then rinse; use
3 days a week
DHT dihidrotestosterone, FDA Food and Drug Administration
a
According to the main studies/reports about each medication
Updated Treatment Options for Androgenetic Alopecia
discontinuation of treatment [12]. Kaufman et al. [11]
reported that 1.8 % of men aged 18–41 years presented
reversible sexually related adverse effects versus 1.1 % in
the placebo group. In older men aged 41–60 years, sexu-
ally related adverse effects were seen in 8.7 % taking
finasteride versus 5.1 % on placebo [18]. In addition, a
recent meta-analysis demonstrated no significant difference
between active treatments and placebo for the outcome
‘‘global sexual disturbance’’ [13].
Recently, a few uncontrolled studies have reported
permanent sexual adverse effects and depression in patients
treated with finasteride 1 mg for AGA, thus raising safety
concerns in both patients and dermatologists [19–21].
While permanent sexual dysfunction has been reported in
post-marketing surveillance and in small uncontrolled
studies and case reports, its real prevalence appears to be
very low (less than 1 % in post-marketing data) [19].
However, although data from controlled trials show a low
incidence of sexual adverse effects as well as their reso-
lution after cessation of treatment, a recent meta-analysis
underlines that all clinical trials were sponsored and none
had adequate safety reporting [22]. Although there is very
limited evidence of permanent sexual adverse effects as a
consequence of 5a-reductase inhibitor use, this possibility
needs to be discussed with the patient.
Depression and suicide ideation have also been reported
during post-marketing monitoring and in small and
uncontrolled studies, particularly in patients with perma-
nent sexual dysfunction, and the term ‘post-finasteride
syndrome’ has been coined to include both persistent
sexual and neurological adverse effects [21, 23–25].
However, MAGA itself reduces quality of life and may
cause depression [26–28] and Yamazaki et al. [29] reported
that quality of life in patients taking finasteride 1 mg was
improved. Some patients with MAGA are very anxious and
this is not necessarily alleviated by the treatment.
Although relatively rare, gynecomastia can occur; it is
painful in some cases and can be uni- or bilateral [30–32].
Spermatogenesis and fertility have been addressed in a
few randomized controlled studies and case reports. Some
authors reported a significant change in semen parameters
and quality after long-term finasteride use that was
reversed after drug cessation [33–35]. A double-blind,
placebo-controlled study showed that finasteride 1 mg
daily for 48 weeks did not significantly affect the semen
parameters of 181 healthy patients [36]. A randomized,
double-blind, placebo-controlled trial of 99 men using
daily finasteride 5 mg or dutasteride 0.5 mg to treat benign
prostatic hyperplasia (BPH) revealed a significant influence
only on spermatozoid motility [37]. However, it should be
highlighted that these studies enrolled only men with no
history of infertility. Data from fertility clinics indicate that
finasteride should be discontinued or even not prescribed in
1351
patients who have alterations in semen analysis or have
fertility problems [38]. Finasteride concentrations in semen
are very low and men taking finasteride do not pose any
risk to a pregnant woman or her fetus [39].
Prostate-specific antigen (PSA) serum levels are reduced
by approximately 50 % during use of finasteride 1 mg
daily because of the decreased prostatic DHT levels, a
phenomenon that could mask and retard an early diagnosis
of prostate cancer. For this reason, it is recommended that
the PSA base levels are checked prior to starting treatment
in men older than 50 years [40–42]. Based on two large
randomized, placebo-controlled studies, in 2011 the FDA
added to the safety labeling that, although patients taking
finasteride are 25 % less likely to develop prostate cancer,
there is an increased risk of high-grade prostate cancer
[43, 44]. However, a recent meta-analysis concluded that
finasteride does not increase the risk of high-grade prostatic
cancer [45].
The benefits of finasteride in MAGA treatment require
indefinite use and the possible short- and long-term adverse
effects should be well-explained to patients. Dermatolo-
gists should specifically ask patients about sexual adverse
effects and mood disturbances.
The efficacy of finasteride treatment is not well-estab-
lished in women and its use in FAGA is off-label (Table 2).
Positive results have been reported in both pre- and post-
menopausal women taking finasteride 2.5–5 mg in case
reports, case series, and uncontrolled studies [46–50].
However, two large RCTs in postmenopausal women have
shown a lack of efficacy of finasteride 1 mg daily [51, 52].
A Cochrane systematic review also concluded that there is
no evidence to indicate that finasteride is more effective
than placebo [53]. In contrast, in 2011, an Asian group
evaluated the clinical response of finasteride 5 mg/day in
87 pre- and postmenopausal normoandrogenic women
during 12 months in a non-controlled and non-randomized
study; in this study, 81 % of the patients showed
improvement as assessed by global photographs, with a
low incidence (4.7 %) of mild and transient adverse effects
[54].
The limitation to finasteride use in women is not
restricted to the poor evidence, but also the known ter-
atogenicity of the drug. Women of childbearing age should
take finasteride under strict birth control measures as it can
cause feminization of the male fetus [55]. Another concern
regarding finasteride use in women is that conditions
resulting in relative estrogen excess or lack of androgen are
associated with an increased risk of breast cancer [56].
During finasteride use, estrogen excess may occur, as the
inhibition of DHT production alters the estrogen:androgen
ratio, with slightly increased estrogen levels due to the
testosterone conversion to estradiol by aromatase. The
possible effects of the increased estrogen levels in women
1352 Y. Kelly et al.

Table 2 Main first-line treatment options for female androgenetic alopecia

Medication Treatment Mechanism of action Dosage recommendationsa Major adverse effects
approval: US
FDA

Finasteride Not approved: 5a-reductase inhibitor 2.5–5 mg once daily (plus effective Teratogenicity
off-label contraception method if in fertile age) Sexual adverse effects
Increased risk of breast
cancer?
Dutasteride Not approved: 5a-reductase inhibitor 0.5 mg once daily (plus effective Teratogenicity
off-label contraception method if in fertile age) Sexual adverse effects
Increased risk of breast
cancer?
Spironolactone Not approved: Antiandrogen, reduces testosterone 100–200 mg/day Teratogenicity
off-label levels and competitive androgen
receptor antagonist
Cyproterone Not approved: Antiandrogen, competitive Cyproterone acetate 25–50 mg/day on Teratogenicity
acetate off-label androgen receptor antagonist, days 1–10 of menstrual cycle combined Hepatotoxicity
decreases testosterone levels by with OCP (cyproterone acetate 2 mg ?
suppressing LH and FSH ethinyl estradiol 35 lg) or OCP
containing cyproterone acetate alone.
Cyproterone acetate 50–100 mg/day if
postmenopausal
Minoxidil Approved Unknown, possible 2–5 % solution; topical application once Hypertrichosis
antiandrogenic, vasodilatory, and (5 %) or twice daily (2 %) Contact dermatitis
anti-inflammatory effects
Contraindicated during
pregnancy
Latanoprost Not approved: Prolongs the anagen phase 0.1 % solution; topical application once Erythematous reaction
off-label daily
Ketoconazole Not approved: Decreases hair follicle DHT levels 2 % shampoo; leave on for 5 min and
off-label then rinse; use at least 3 days/week
DHT dihydrotestosterone, FDA Food and Drug Administration, FSH follicle-stimulating hormone, LH luteinizing hormone, OCP oral contra-
ceptive pill
a
According to the main studies/reports about each medication

taking finasteride have not been addressed in any study to
date. For this reason, it is recommended that finasteride not
be used in women with a family or personal history of
breast cancer.
2.1.2 Dutasteride
Dutasteride is a 5a-reductase inhibitor that blocks the
activity of both type 1 and type 2 isoenzymes, and
reduces DHT serum levels by 90 % compared with 70 %
for finasteride [57]. Dutasteride 0.5 mg daily is approved
for the treatment of BPH worldwide, but is approved for
AGA treatment only in a few countries, including Korea
and Mexico. To date, there have only been a few ran-
domized, placebo-controlled studies analyzing the efficacy
of dutasteride to treat MAGA. In 2006, Olsen and col-
leagues [58] published the first RCT comparing the effect
of dutasteride 0.05, 0.1, 0.5, or 2.5 mg, finasteride 5 mg,
and placebo in 416 men with AGA over 24 weeks;
dutasteride 2.5 mg was shown to be superior to finasteride
5 mg in increasing hair count [58]. In addition, in 2010 a
phase III study in 153 men showed that dutasteride
0.5 mg daily for 6 months improved hair growth and was
well-tolerated, with no major differences in adverse
events compared with the placebo group [59]. In 2014, a
meta-analysis conducted by Gupta and Charrette [13]
demonstrated that finasteride and dutasteride could be
considered equally effective for AGA treatment. How-
ever, in that same year, an RCT comparing dutasteride
0.02, 0.1, and 0.5 mg daily with finasteride 1 mg daily
and placebo in 917 men during 24 weeks revealed that
dutasteride 0.5 mg was statistically superior to finasteride
1 mg and placebo at increasing hair count and thickness
after 24 weeks [60]. Moreover, there are reports showing
that concomitant therapy with both drugs produces better
results, and there is a case series showing efficacy of
dutasteride in men with AGA that is recalcitrant to
finasteride [61, 62].
In all of the RCTs evaluating dutasteride in MAGA
there were no significant differences in the adverse events
Updated Treatment Options for Androgenetic Alopecia
between the treatment groups and placebo. On the other
hand, the majority of the large dutasteride trials have
addressed BPH patients [63, 64]. The safety and tolera-
bility data in three placebo-controlled trials of 2 years’
duration involving 4300 men taking dutasteride showed
that sexual adverse effects occurred more frequently with
dutasteride than with placebo in the first 6 months,
including decreased libido (3.0 % dutasteride vs. 1.4 %
placebo), erectile dysfunction (4.7 % dutasteride vs. 1.7 %
placebo), and ejaculation dysfunction (1.4 % dutasteride
vs. 0.5 % placebo). However, at the end of 24 months, the
onset of new adverse effects was similar to placebo, with
no significant difference [64].
The available dutasteride studies in MAGA are of short
duration. Long-term, placebo-controlled trials including
both dutasteride and finasteride groups are required to
confirm the therapeutic efficacy and safety of dutasteride.
In women, data are very scarce. There is only one case
report demonstrating the efficacy of dutasteride 0.5 mg
daily used for 6 months to treat a 46-year-old woman with
FAGA, with limited response to finasteride and topical
minoxidil. No adverse effects were observed [65].
2.1.3 Topical Finasteride
In 2009, a small RCT compared the therapeutic effect of
topical and oral finasteride in 45 patients with MAGA.
One group received a 1 % finasteride topical gel and
placebo tablets while another group received finasteride
1 mg tablets and a placebo gel base for 6 months. No
significant differences were shown in hair thickness, hair
counts, and size of the bald area between the two groups,
revealing similar therapeutic results of both the finasteride
gel and tablet. No sexual adverse effects were observed in
either of the two treatment groups [66]. In 2014, the
effects on plasma androgen levels of a finasteride 0.25 %
topical solution and finasteride 1 mg tablet were com-
pared in a study of 24 men with AGA. This study showed
similar and significant inhibition of plasma DHT after
7 days of treatment in both groups, raising concerns about
systemic absorption of the topical solution [67]. Recently,
the same authors analyzed the effect of finasteride 0.25 %
in a new topical vehicle at different doses on scalp and
serum DHT [68]. They showed that when this solution
was applied once a day at doses of 100 and 200 lL, there
was a significant decrease in the scalp DHT level, but
only a 24–26 % reduction in serum DHT. The reduced
absorption of topical application can theoretically
decrease the incidence of potential adverse effects
according to these authors [68]. However, data are still
preliminary and concerns regarding topical solutions
should also include possible contamination of childbear-
ing women.
1353
2.1.4 New Topical Antiandrogen Solution
A new topical antiandrogen for AGA treatment named
cortexolone 17a-propionate (CB-03-01) solution 5 % (In-
trepid Therapeutics, Inc., San Diego, CA, USA) is cur-
rently undergoing a phase II trial. The study will analyze
the safety and efficacy of this formulation applied twice
daily for up to 26 weeks in 90 male patients with AGA
[69]. The company website indicates that this drug acts by
blocking DHT interactions with hair follicle androgen
receptors and by decreasing levels of prostaglandin D2
(PGD2), but no preliminary results are available yet [70].
2.2 Androgen Receptor Antagonists
Androgen receptor antagonists are not approved by the
FDA but are frequently used off-label for the treatment of
FAGA. Literature on the therapeutic effect of the androgen
receptor antagonists—spironolactone, cyproterone acetate,
and flutamide—is scarce, particularly in patients without
hyperandrogenism, and none of the studies is of high-
quality evidence. Most studies have evaluated the efficacy
of these drugs, singly or in association, in women with
hyperandrogenism, mainly with acne and hirsutism. It is
important to highlight that these agents are an off-label
prescription for the treatment of all of these conditions and
they require safe contraception due to their teratogenicity
[71].
2.2.1 Spironolactone
Spironolactone is a potassium-sparing diuretic that is
considered to be an antiandrogen since it decreases the
testosterone levels and blocks the androgen receptors in
target tissues [72]. It has been used to treat FAGA at doses
of 50–200 mg daily for more than 20 years and has a good
long-term safety profile [73–75]. In an open-label study,
Sinclair et al. [76] evaluated the effect of spironolactone
and cyproterone acetate in 80 women with FAGA for a
minimum of 12 months in which 40 women received
spironolactone 200 mg daily and 40 women received
cyproterone acetate 50 mg daily or 100 mg for 10 days per
month if premenopausal. No significant difference was
found between the two groups. The results revealed that
oral antiandrogens produced an improvement in hair
regrowth in 44 % of patients, no change in 44 %, and
persistence of hair loss in 10 % [76]. Regarding safety,
spironolactone can cause dose-dependent adverse effects
due to both its diuretic effects (hyperkalemia, hypotension,
fatigue, weight loss, and increased urinary frequency) and
its antiandrogenic effect (breast tenderness, menstrual
irregularities). The hyperkalemia rates were recently ana-
lyzed in a retrospective study of 974 young women taking
1354
spironolactone for acne and in 1165 healthy young women
taking and not taking spironolactone in order to obtain a
baseline rate of hyperkalemia in this population. The
authors concluded that the rate of hyperkalemia in healthy
young women taking spironolactone for acne is equivalent
to the baseline rate of hyperkalemia in this population,
suggesting that frequent potassium monitoring is not nec-
essary for healthy young women receiving spironolactone
for acne [77]. This information may also be applied to
treatment of AGA in young healthy women, reducing
concerns regarding hyperkalemia monitoring during
spironolactone use.
2.2.2 Cyproterone Acetate
Cyproterone acetate is an androgen receptor antagonist
that directly blocks the DHT binding to its receptors and
reduces testosterone levels by decreasing the release of
follicle-stimulating and luteinizing hormone. In most
countries, it is available as an oral contraceptive pill
(OCP) in combination with ethinyl estradiol as well as as
an isolated drug, but no form of cyproterone acetate is
available in the USA. The few existing studies addressing
its therapeutic efficacy to treat FAGA are controversial.
Peereboom-Wynia and colleagues [78] compared two
groups of women for 1 year: one group received an OCP
(containing ethinyl estradiol 50 lg and cyproterone acet-
ate 2 mg) and cyproterone acetate 20 mg on days 5–20 of
the menstrual cycle and the second group received no
treatment. The authors observed a significant improve-
ment in the anagen percentage in the treated group [78].
Vexiau et al. [79] performed a 12-month RCT in 66
women comparing cyproterone acetate 50 mg in combi-
nation with an OCP (ethinyl estradiol 35 lg and cypro-
terone acetate 2 mg) and 2 % topical minoxidil in
combination with another OCP (ethinyl estradiol 30 lg
and gestodene 75 lg). The overall data showed a better
result in the minoxidil 2 % solution group. Their study
also showed that minoxidil 2 % was more effective in
increasing the hair count in patients with absence of
hyperandrogenism, while cyproterone acetate was more
effective in patients with evidence of hyperandrogenism
[79]. The previously mentioned study comparing cypro-
terone acetate and spironolactone in FAGA treatment
showed no differences between the two groups [76]. In
addition, a subgroup analysis of a meta-analysis con-
cluded that patients with clinical signs of hyperandro-
genism respond better to treatment with cyproterone
acetate for 12 months than do women without hyperan-
drogenism, but with limited evidence [80]. Adverse
effects of this drug include hepatotoxicity, weight gain,
decreased libido, breast tenderness, and feminization of
the male fetus.
Y. Kelly et al.
2.2.3 Flutamide
Flutamide is an antiandrogen that strongly blocks androgen
binding to its receptor. So far, there are no randomized
placebo-controlled studies that support its use in FAGA
[81, 82]. A prospective study of 101 patients with FAGA
comparing flutamide (250, 125, or 62.5 mg/day) with flu-
tamide combined with an OCP documented mild
improvement in alopecia scores that lasted up to 2 years. A
number of patients (4 %) dropped out of the study due to
hepatic dysfunction [83]. In addition, a randomized trial
reported that flutamide 250 mg daily provided only a
modest improvement, documented using non-objective
methods, after 1 year in hyperandrogenic women. In this
study, cyproterone acetate and finasteride were not effec-
tive [84]. Nevertheless, Yazdabadi and Sinclair [85]
reported on a patient who did not respond to topical
minoxidil and oral spironolactone but had hair growth with
flutamide. Although low doses such as 62.5 mg/day could
be effective and well-tolerated, according to one report
[83], the risk of severe hepatotoxicity (3/10,000 users),
which is dose-dependent, limits flutamide use.
Other oral antiandrogens such as progestogens with
antiandrogenic properties (drospirenone and chlormadi-
none acetate) have not been studied for the treatment of
FAGA [80]. Moreover, the aforementioned meta-analysis
concluded that there is poor evidence that inclusion of oral
antiandrogens is an effective option for treating FAGA and
preventing its progression [80]. In the same way, a
Cochrane systematic review did not include the of
spironolactone, cyproterone acetate, and finasteride studies
in their analysis as they were not randomized and con-
trolled, and reports that only minoxidil has good-quality
evidence as a treatment for FAGA [53, 81].
3 Androgen-Independent Therapies
3.1 Minoxidil
Minoxidil was first used as an oral treatment for severe and
refractory cases of hypertension during the 1970s. It is a
direct arteriolar vasodilator that acts by opening potassium
channels. Unwanted hair growth was observed as an
adverse effect in 24–100 % of patients [86]. Minoxidil was
the first and is the only topical drug approved by the FDA
to treat AGA. For men, the 2 % solution was approved in
1988, the 5 % solution in 1991, and the 5 % foam in 2016.
For women, the 2 % solution was approved in 1991 and the
5 % foam was approved in 2014.
The exact mechanism of action of minoxidil on hair
growth is still unclear but is probably mediated via potas-
sium channel opening, which leads to an increased
Updated Treatment Options for Androgenetic Alopecia
cutaneous blood flow and enhanced levels of vascular
endothelial growth factor (VEGF) and hair growth pro-
moters in dermal papilla [87]. Some studies suggest that it
also promotes hair growth by increasing the production of
prostaglandin E2 (PGE2) through stimulation of pros-
taglandin endoperoxide synthase-1 [88, 89].
The active metabolite that stimulates hair growth is
minoxidil sulfate, which is converted from minoxidil by
sulphotransferase enzymes in the outer root sheath of anagen
follicles [90]. There are inter-individual variations in scalp
levels of these enzymes and patients with higher enzyme
activity have a better response to topical minoxidil [91].
The efficacy of topical minoxidil to treat MAGA as well
as FAGA has been established by several double-blind,
randomized, and placebo-controlled trials. Moreover,
recent meta-analysis studies have confirmed the high
quality of evidence for use of minoxidil to treat AGA in
both sexes [53, 80]. In MAGA, the 5 % solution is more
effective than the 2 % solution and an RCT confirmed that
5 % minoxidil foam could induce significant hair growth
[92, 93]. In FAGA, Bluemeyer et al. concluded that there is
no evidence to support the use of minoxidil 5 % instead of
the 2 % solution [80]. A randomized single-blinded trial
also revealed that once-daily 5 % minoxidil foam had
similar efficacy to 2 % minoxidil solution twice a day in
FAGA [94].
The most common adverse effects of minoxidil include
contact dermatitis and facial hypertrichosis. Ingredients of
the vehicle, particularly propylene glycol, can cause skin
irritation or allergy, although true allergic reactions to
minoxidil itself are rare. The foam formulation is an option
in case of irritation as it does not contain propylene glycol.
Adverse effects have been shown to be more common with
the 5 % solution twice daily than with the 2 % solution
twice daily [95, 96]. Hypertrichosis is reported more fre-
quently in women than in men, but it is unclear whether
this occurs because it is truly more common or just more
noticeable. Hypertrichosis usually resolves 1–3 months
after drug discontinuation. Transitory increase in hair
shedding at the beginning of treatment is seen in some
patients. However, this is just a sign of minoxidil efficacy
as it indicates that telogen follicles are re-entering the
anagen phase, and this should be explained to patients. It
usually lasts for a few weeks.
In MAGA treatment, the recommended dosage for
minoxidil 5 % solution is 1 mL twice daily on dry scalp,
while the dosage for the minoxidil 5 % foam is half a
capful twice daily. Both formulations should be left in
place for at least 4 h. For women, the recommended dosage
is 1 mL of 2 % minoxidil solution twice daily or half a
capful of the 5 % foam formulation once a day. Patients
should be treated for at least 6 months prior to efficacy
assessment and treatment should be prolonged indefinitely
1355
to maintain efficacy. Patients should also be informed that
drug interruption will cause acute hair shedding after
3–4 months.
Although there is no evidence of teratogenicity in ani-
mals, data in humans are still lacking. For this reason,
minoxidil is not advised for women who are pregnant.
Since minoxidil is excreted into breast milk in very low
concentrations and no adverse effects have been reported in
infants, the American Academy of Pediatrics considers
minoxidil to be compatible with lactation [97].
3.2 Prostaglandin Analogs and Antagonists
Elongation and pigmentation of eyelashes and eyebrows
was observed as a side effect in patients using the topical
prostaglandin F2 (PGF2) analog latanoprost for glaucoma
treatment. This effect is apparently due to prolongation of
the anagen phase [98, 99]. In 2008, the FDA approved
bimatoprost, another PGF2 analog, for the treatment of
eyelash hypotrichosis.
In 2012, a randomized, double-blind, placebo-controlled
trial in 16 men using latanoprost 0.1 % daily versus pla-
cebo on a small scalp area for 24 weeks showed a signif-
icant increase in the hair density compared with baseline
and placebo, with no adverse effects besides a localized
erythematous reaction [100]. Bimatoprost has been studied
for the treatment of AGA in men and women [101] and
there are currently clinical trials in progress analyzing the
efficacy and safety of different concentrations of bimato-
prost in men [102]. The only published case is a woman
who received mesotherapy with 0.03 % bimatoprost with-
out improvement [103]. There is a recent report of erosive
pustular dermatosis following the use of topical latanoprost
for AGA [104].
Garza et al. [105] recently showed that PGD2 and its
synthetase are highly expressed in the scalp of men with
AGA. In addition, they demonstrated that high levels of
PGD2 induced miniaturization, sebaceous gland hyper-
plasia, and alopecia in mice and that topical PGD2 inhib-
ited hair growth in the application area in mice [105]. They
also showed that levels of PGE2, which is a hair growth
promoter, are higher in normal scalp than in AGA scalp.
This article suggests that the balance between the different
prostaglandins can control hair growth. Furthermore, they
showed that the PGD2 receptor, known as GPCR44, is a
potential target for treatments [106]. Setipiprant, a selective
oral antagonist to the PGD2 receptor, will possibly be
developed for this indication.
3.3 Ketoconazole
Ketoconazole is an antifungal used topically as a 2 %
shampoo to treat seborrheic dermatitis. It has anti-
1356
inflammatory properties due to its effect in decreasing
Malassezia colonization [107]. Ketoconazole also has
antiandrogenic properties as it can interfere with steroido-
genesis [108]. Its use in combination with oral finasteride
1 mg might produce an additional decrease in scalp DHT
levels [109]. A possible beneficial antiandrogenic effect of
ketoconazole 2 % in women with FAGA and hyperan-
drogenism was also reported [110]. Nevertheless, larger
and placebo-controlled studies are necessary to clarify the
real effectiveness of ketoconazole 2 % as a coadjuvant
treatment in AGA.
4 Coadjuvant Therapies
4.1 Laser Therapy
A variety of laser and light sources have been promoted for
the treatment of hair loss. The idea to use laser and light
therapy originates from experimental observations that the
low-powered ruby laser (694 nm) could increase hair
growth in mice [111]. Clinical evidence increased when
clinicians noticed paradoxical hypertrichosis in adjacent
areas following laser hair removal with the diode laser
(810 nm) [112]. Nevertheless, the mechanism of action is
not yet known. It has been hypothesized that light may
activate dormant hair follicles, increase blood flow, and
upregulate the production of growth factors and adenosine
triphosphate that stimulate anagen hair [113].
Low-level light therapy (LLLT) is a fairly new tech-
nique used in the treatment of AGA with different types of
devices, such as a comb, hood, and helmet. In 2007, a
device with a wavelength of 655 nm, the HairMax
LaserCombÒ (Lexington International LLC, Boca Raton,
FL, USA), was approved by the FDA for treatment of
MAGA, with subsequent approval for FAGA in 2011
(Table 3). Some studies have investigated the efficacy of
LLLT for AGA. A company-sponsored small prospective
study of 35 male and female patients with patterned
alopecia reported increased hair counts and tensile strength
of the hair in both the temporal and vertex areas for men
and women using the HairMax LaserCombÒ [114]. In
2009, a double-blind, sham device-controlled, multicenter,
randomized 26-week trial of MAGA demonstrated a sig-
nificant increase in mean terminal hair density with the
device, which was used three times a week for 15 min
[115]. A more recent randomized, double-blind, sham
device-controlled trial evaluated a helmet-type device
consisting of laser diodes emitting wavelengths of 650 nm.
Participants used the device for 18 min daily for 24 weeks.
Results showed a significant difference in hair density and
hair thickness in the active device group, although no
Y. Kelly et al.
significant difference in subjective global assessments of
hair growth was shown [116]. Another randomized, dou-
ble-blind, sham device-controlled trial assessed the efficacy
of a different helmet-type device containing 205 mW
lasers and 31 LEDs operating at 655 nm. The device was
used every other day for 16 weeks and the primary out-
come measure was the percentage increase in hair counts
from baseline. Results showed a 35 % increase [117].
The high-energy lasers have also been explored for
treatment of hair loss. The fractional erbium-glass 1550 nm
laser has been used successfully to treat both MAGA [118]
and FAGA [119]. A clinical pilot study involving 20 male
subjects treated over five sessions at 2-week intervals
reported incremental improvement in hair density and
growth [118]. In a female study, hair density and thickness
markedly increased after ten treatments [119]. Associated
adverse effects were immediate erythema and pruritus in
some patients.
However, the best laser parameters to have an effect on
stem cell activity and hair cycle are unknown. There is only
one study analyzing the effects of 1550 nm fractional laser
on the hair cycle in mice using different beam energies
(5–35 mJ) and beam densities (500–3500 microthermal
zones/cm2). The results revealed a direct thermal injury to
hair follicles early after irradiation, mainly in higher-beam
energy with an ‘all or nothing’ change in anagen induction
in irradiated skin. In addition, the lowest beam energy of
5 mJ failed to induce anagen entry, while anagen induction
and ulcer formation were influenced by the combination of
beam energy and density. The authors concluded that the
adverse effects, including hair follicle injury and scarring,
could be avoided after future studies of the adequate
combination of beam energy and density have been
undertaken, since parameters outside the therapeutic win-
dow may result in both no anagen induction and ulcer
formation [120]. In conclusion, the 1550 nm fractional
erbium–glass laser may be an effective and safe coadjuvant
treatment option for AGA. However, more studies must be
performed to establish the best parameters and treatment
intervals.
4.2 Hair Transplantation
In patients older than 25 years with stabilized hair loss, hair
transplantation (HT) is a complementary therapeutic
option. The mechanism of action of HT is supported on the
principle of donor dominance: hair follicles localized in
androgen-insensitive areas keep their properties even when
transplanted into androgen-dependent scalp.
Although HT is a very popular treatment for AGA, the
quality of evidence on the efficacy of HT is poor as studies
have variable results due to differences in techniques and
Updated Treatment Options for Androgenetic Alopecia 1357

Table 3 Main adjuvant and emerging therapies for androgenetic alopecia

Treatment Treatment Mechanism of action Suggested protocolsa Major adverse
options approval: effects
US FDA

Low-level laser Approved Possibly activation of dormant hair 20 min/day, 3 times a week
therapy follicles, increased blood flow,
(655 nm) upregulated growth factors and adenosine
triphosphate, and stimulation of anagen
hair
Fractional Not Possibly activation of dormant hair 5–10 sessions at 2-week intervals Thermal hair
erbium-glass approved/ follicles, increased blood flow, follicle injury and
laser off-label upregulated growth factors and adenosine scarring?
(1550 nm) triphosphate, and stimulation of anagen
hair
Platelet-rich Not Possibly induces differentiation of bulge Various: 4 sessions at 2-week intervals; 3 Minimal pain,
plasma approved/ stem cells into hair follicles, prolongs sessions at 3-week intervals ? 1 session redness at the
off-label anagen phase, and protects cells from after 6 months; 2 sessions at 3-month time of injection,
apoptosis intervals; or 3 sessions at 1-month pinpoint bleeding
interval
Scalp Not Possibly induces release of platelet-derived 1 session per week for 12 weeks; or 1 Minimal pain,
microneedling approved/ growth factor, activation of follicle stem session per week for 4 weeks ? 1 session pinpoint bleeding
off-label cells, and overexpression of hair growth- every other week for 24 weeks total
related genes
FDA Food and Drug Administration
a
According to the protocols for each treatment option given in the published articles

surgeon abilities as well as in the individual characteristics 4.3 Camouflage

of the patients [121].
In MAGA, good long-term cosmetic results can be
achieved, since this technique requires preservation of hair
growth over the occipital donor area, which is observed in
men with AGA. On the other hand, hair density in the
donor area is often decreased in FAGA because of the more
diffuse scalp thinning that can include the occipital area. It
is important to highlight to the patient that the surgical
treatment of AGA does not prevent progression of the
disease, reinforcing the importance of concomitant medical
therapy [80, 122]. Topical minoxidil may speed the
regrowth of transplanted follicles following the surgical
procedure [123].
Follicular unit transplantation, considered the gold
standard technique, uses small follicular units, leading to a
more physiological and natural result and offering a better
outcome in terms of the final aspect. The patient should be
informed that temporary post-operative telogen effluvium
may occur. Complications are rare and include infection,
pain, and failure of the transplanted hair to grow [80, 124].
Lichen planopilaris has also been reported and should
always been considered if the transplant does not last [125].
In the right candidate, HT can lead to a long-lasting,
natural result that becomes evident 6–8 months after the
procedure and the new hair will help reframe the patient’s
face and renew their self-confidence.
Patients who do not achieve sufficient hair density with
medical treatment or are not ideal candidates for HT can be
offered camouflage methods. These can also be used as an
adjuvant therapy in association with medical or surgical
treatments [126].
For those with mild to moderate thinning, hair fibers,
masking lotions, topical shading, and scalp spray thicken-
ers may be used, giving the impression of thicker hair.
These options are compatible with topical minoxidil and
are easily removed with shampooing [127]. One recently
developed camouflage option is micropigmentation [128].
Hair extensions and wigs are other options. However,
extensions cause traction and the weight of the attached
hair needs to be considered. Good-quality synthetic,
acrylic, or natural hairpieces can easily be found. Possible
adverse effects of hairpieces are limited to traction alopecia
and irritant dermatitis. Special attention should be given
when choosing attachment methods (glue, pins) to mini-
mize scalp injury. Hats, scarves, bandanas, and turbans
may also be used and have, as with wigs, the additional
advantage of protecting the scalp from sun exposure.
Camouflage methods have increasingly been accepted
by patients to improve their appearance. Sometimes, a
different haircut or hairstyle can be recommended which
may help to give an impression of better hair density.
1358
Dermatologists should be updated about these techniques
to offer patients reasonable camouflage options.
5 Emerging Therapies
5.1 Platelet-Rich Plasma Injections
Platelets contain growth factors and cytokines that stimu-
late stem cells. Platelet-rich plasma (PRP) is an autologous
preparation of plasma with a high concentration of plate-
lets. The revitalization qualities of PRP are well-known and
have been used for 30 years in various medical fields,
particularly wound healing [129]. A study by Li et al. [130]
showed that PRP acts in the dermal papilla cells by
increasing the expression of b-catenin (which induces
differentiation of bulge stem cells), fibroblast growth factor
7 (which prolongs the anagen phase), and B-cell lymphoma
protein (Bcl)-2 (which protects cells from apoptosis).
PRP was first utilized for HT in order to enhance hair
follicle growth and accelerate the time of hair formation
[131]. However, studies of PRP as an adjunctive tool in HT
have shown controversial results [132–134].
In the last few years several studies have addressed the
use of PRP in AGA. In 2014, Khatu et al. [135] utilized
PRP in 11 patients with AGA who had not responded to
minoxidil and finasteride treatment after 6 months.
Patients received four injections at 2-week intervals. After
12 weeks the patients showed improvement on global
photography and an increased hair count. Another study
evaluated the results of PRP in 20 patients with AGA
after 1 year. This study included 18 males and two
females who had not received any treatment in the pre-
vious 6 months. Patients had three PRP injections at
intervals of 21 days and one extra injection 6 months
after the first treatment. Evaluation at 6 and 12 months
showed a significant increase in the hair density [136]. A
pilot study evaluated PRP in 64 patients who received
two injections at intervals of 3 months. The results were
evaluated by macrophotographs taken at baseline and
after 6 months. The proportion of patients who achieved a
clinically important difference was 40.6 and 54.7 %,
according to the two evaluators of the study [137].
Finally, a recent RCT compared hair regrowth with PRP
versus placebo using computerized trichograms in a half-
head group of 20 patients. Three treatments were per-
formed with a 1-month interval. At the end of the three
treatment sessions, clinical improvement in the mean
number of hairs as well as a mean increase in total hair
density compared with baseline values was noticed. At
the 12-month follow-up, four patients experienced hair
loss, which was more evident 16 months after the last
procedure, and had to be re-treated [138]. In these studies,
Y. Kelly et al.
the adverse effects included pain, redness at the time of
injections, and pinpoint bleeding.
PRP has a theoretical scientific basis to support its use in
both hair restoration surgery and clinical treatment of
AGA, and preliminary evidence suggests that it might have
a beneficial role in hair regrowth. However, as yet there is
no evidence-based information on the administration pro-
tocol and no data exist on the optimal dose and frequency
of injections [139]. There is a need for randomized, pla-
cebo-controlled trials involving a large number of patients
to establish real efficacy and duration of results for PRP.
5.2 Scalp Microneedling
Scalp microneedling was first reported in 2012, when two
studies showed enhanced expression of hair-related genes
after microneedling in mice [140, 141]. The following
possible mechanisms of action were proposed: (a) release
of platelet-derived growth factor (PDGF) through platelet
activation and skin wound regeneration mechanisms;
(b) activation of follicle stem cells under wound healing
conditions; and (c) overexpression of hair growth-related
genes, including VEGF, b-catenin, Wnt3a, and Wnt10b
[142, 143].
One year later, a 12-week randomized, comparative,
evaluator-blinded study conducted by Dhurat et al. [142]
analyzed 100 patients with mild to moderate AGA. One
group received weekly microneedling treatment and 5 %
topical minoxidil twice daily, while the other group
received only 5 % topical minoxidil twice daily. The
results showed that the mean hair count was significantly
higher in the microneedling group. Investigator and
patient evaluations also revealed satisfactory results
compared with minoxidil alone [142]. In 2015, the same
group published a case series of four men who had
received finasteride and minoxidil treatment for
2–5 years with no new hair growth. They received four
microneedling sessions weekly followed by 11 sessions
at 2-week intervals, for a total of 24 weeks of treatment,
at which point response was evaluated by photography
and patient subjective assessments. The patients were
advised to continue treatment with finasteride and
minoxidil. After 6 months, three patients rated more than
75 % improvement and one rated more than 50 %
improvement. According to the authors, at the 18-month
post-procedure follow-up, all of the patients maintained
the improvement [143].
Although scalp microneedling appears to be a promising
alternative, more studies are needed in order to standardize
the procedure, including the size and length of the needles,
intervals between sessions, duration of treatment, and
intensity of bleeding that need to be achieved. In addition,
future studies utilizing microneedling as the sole treatment
Updated Treatment Options for Androgenetic Alopecia
are necessary to clarify the potential efficacy of the pro-
cedure itself.
5.3 Wnt Signaling
A large number of molecular signals are involved in the
normal hair cycle. The activation of Wnt/b-catenin/Lef1,
Sonic Hedgehog, and signal transducer and activator of
transcription (STAT) 3 pathways and down-regulation of
bone morphogenetic protein signaling initiate and maintain
the anagen phase [144–146]. Wnt pathway activation also
induces endogenous dermal progenitor cells to differentiate
into a hair bulge, leading to the formation of new hair
follicles [147]. In addition, it has been demonstrated that
androgens may inhibit Wnt/b-catenin signaling in AGA
[148].
Although the factors that may stimulate and regulate
follicular neogenesis are still unknown, there are a num-
ber of studies showing that drugs that can act by acti-
vating Wnt signaling may be useful. For example, Follica
Inc. is researching molecules that can be delivered to the
scalp using lasers or other techniques, since studies in
mice indicate that cells become susceptible to Wnt sig-
naling during wound healing [149]. Valproic acid (VPA)
activates the Wnt/b-catenin pathway [150], and topical
VPA was able to induce hair regrowth through induction
of anagen as efficiently as minoxidil in mice [151]. A
phase II RCT compared topical VPA (8.3 % sodium
valproate) versus placebo for 24 weeks in 27 men with
moderate AGA. The mean change in total hair count was
significantly higher in the VPA group than in the placebo
group [152].
Hair Stimulating Complex (HSC) is a bioengineered,
non-recombinant, human cell-derived formulation con-
taining Wnt7a protein, epidermal growth factors, and fol-
listatin. A study evaluating efficacy of HSC in patients with
MAGA showed a significant increase in hair shaft thick-
ness and terminal hair density with no relevant adverse
effects. Moreover, a statistically significant increase in
total hair count continued to be seen after 1 year [153].
Phase II of this study is currently in progress with no
published results available [154].
A small molecule—SM04554—shown to activate the
Wnt pathway is currently undergoing clinical trials. In a
phase I clinical trial, this topical solution appeared to be
safe, well-tolerated, and potentially efficacious [155].
According to a company report, in phase II trials the
SM04554 topical solution (0.15 and 0.25 %) produced a
statistically significant increase for both objective outcome
measures: non-vellus hair count (primary outcome mea-
sure) and hair density (secondary outcome measure)
[153, 156].
1359
5.4 Stem Cells
Stem cell treatment modalities have been studied in dif-
ferent fields in medicine as a regenerative therapy in cases
of organs damaged by disease, injury, or aging. In one
study, intracutaneous implantation of a bioengineered fol-
licular germ was able to develop a follicle with all its
structures, which also presented restored hair cycle and
piloerection. This study showed that it is possible to create
a functional hair follicle from stem cells, enhancing the
possibility of developing bioengineered hairs that can be
used in transplants [157].
Culture-expanded follicular cells obtained through a
patient’s scalp biopsy can be injected into the bald areas to
stimulate hair growth [158]. RepliCelTM (Vancouver, BC,
Canada) is currently conducting a phase II trial to analyze
the possibility of creating new hair follicles by injecting
autologous dermal cells [159]. According to the Repli-
CelTM website, results after 6 months in 19 patients
showed increased proportions of vellus hair (24.9 %) and
terminal hair (14.9 %), increased total hair density
(19.2 %), and increased overall hair thickness per area
(15.4 %). The phase IIb trial is in progress and is analyzing
different injection regimens [160].
Adipose-derived stem cells (ADSCs) are a new treat-
ment modality. Adipose tissue was found to have abun-
dant mesenchymal stem cells that can produce growth
factors, including VEGF, hepatocyte growth factor, insu-
lin-like growth factor, and PDGF, and may be an
emerging therapeutic option in AGA [161–167]. Shin
et al. [168] retrospectively analyzed 27 patients with
FAGA who were treated with a commercial product
containing an extract of ADSC (Advanced Adipose-
Derived Stem Cell Protein Extract) applied after scalp
microneedling for 12 weeks. Phototrichogram images
were used to analyze the results. Patients did not receive
any treatment in the 6 months prior to the study. The
authors concluded that hair density and hair thickness
significantly increased after 12 weeks without consider-
able adverse effects [168]. Another study evaluated the
effects of the same product injected intradermally in 22
AGA patients (11 women and 11 men) for a total of six
sessions at 3- to 5-week intervals. An additional group of
ten patients was submitted to a half-side comparison
study. Results, analyzed by trichograms, which unfortu-
nately is not an appropriate method, showed that the hair
count significantly increased in both male and female
patients. In the half-side comparison study, the hair count
on the treatment side was higher than on the placebo side
[169].
A phase II clinical trial using adipose stem cells
obtained by liposuction (Kerastem Technologies, LLC,
1360
Solana Beach, CA, USA) in 70 patients with early MAGA
and FAGA has recently been started [170, 171].
5.5 JAK–STAT Signaling
Pharmacologic inhibition of the Janus kinase (JAK)–
STAT pathway can induce hair regrowth in alopecia areata
in mice and humans [172]. However, during their studies
in mice with alopecia areata, Harel et al. [173] observed
that the topical use of JAK–STAT inhibitors promoted
anagen growth in normal mice as well as hair follicle
growth in humans [173]. These findings reveal new per-
spectives to be explored regarding the efficacy of JAK
inhibitors in AGA.
6 Conclusion
AGA treatment remains a challenge for dermatologists.
This article has addressed the updated treatment alterna-
tives to treat AGA, including their efficacy, safety profiles,
and quality of evidence; however, it is important to
emphasize that further studies should be performed to
establish the efficacy and safety of new treatment options,
especially those widely used without high-quality evi-
dence. Studies of new therapies that could be an alternative
for those patients who do not respond to first-line therapy
are very much needed.
Compliance with Ethical Standards
Funding The authors did not receive funding to develop this article.
Conflicts of interest Yanna Kelly, MD and Aline Blanco, MD have no
conflicts of interest. Antonella Tosti, MD has the following conflicts of
interest: served on advisory boards for Khytera, Incyte, and Aclaris;
acted as a consultant for P&G, DS Laboratories, and Polichem; and
received royalties from Springer/Verlag and Taylor&Francis.
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