Expert Opinion on Investigational Drugs

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Experimental and early investigational drugs for

androgenetic alopecia

Hongwei Guo, Wendi Victor Gao, Hiromi Endo & Kevin John McElwee

To cite this article: Hongwei Guo, Wendi Victor Gao, Hiromi Endo & Kevin John McElwee
(2017) Experimental and early investigational drugs for androgenetic alopecia, Expert Opinion on
Investigational Drugs, 26:8, 917-932, DOI: 10.1080/13543784.2017.1353598

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EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2017
VOL. 26, NO. 8, 917–932
https://doi.org/10.1080/13543784.2017.1353598

REVIEW

Experimental and early investigational drugs for androgenetic alopecia

Hongwei Guoa,b, Wendi Victor Gaoa, Hiromi Endoa,c and Kevin John McElweea,d
a
Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada; bDepartment of Dermatology, Affiliated Hospital
of Guangdong Medical University, Zhanjiang, China; cDepartment of Dermatology, Ohashi Hospital, Toho University, Tokyo, Japan; dVancouver
Coastal Health Research Institute, Vancouver, Canada

ABSTRACT ARTICLE HISTORY

Introduction: Treatments for androgenetic alopecia constitute a multi-billion-dollar industry, however, Received 9 June 2016
currently available therapeutic options have variable efficacy. Consequently, in recent years small Accepted 6 July 2017
biotechnology companies and academic research laboratories have begun to investigate new or KEYWORDS
improved treatment methods. Research and development approaches include improved formulations Androgenetic alopecia;
and modes of application for current drugs, new drug development, development of cell-based pathogenesis; hair follicles;
treatments, and medical devices for modulation of hair growth. treatment
Areas covered: Here we review the essential pathways of androgenetic alopecia pathogenesis and
collate the current and emerging therapeutic strategies using journal publications databases and
clinical trials databases to gather information about active research on new treatments.
Expert opinion: We propose that topically applied medications, or intra-dermal injected or implanted
materials, are preferable treatment modalities, minimizing side effect risks as compared to systemically
applied treatments. Evidence in support of new treatments is limited. However, we suggest therapeu-
tics which reverse the androgen-driven inhibition of hair follicle signaling pathways, such as prosta-
glandin analogs and antagonists, platelet-rich plasma (PRP), promotion of skin angiogenesis and
perfusion, introduction of progenitor cells for hair regeneration, and more effective ways of transplant-
ing hair, are the likely near future direction of androgenetic alopecia treatment development.

1. Introduction is 1 mg oral finasteride and 5% topical minoxidil, alone or in

combination for men, and 2% topical minoxidil for women
Androgenetic alopecia (AGA) is a hereditary, androgen-depen-
[12]. However, these medications offer moderate results, they
dent, progressive thinning of scalp hair that follows a defined
must continue to be used to have a continued benefit, and
pattern [1]. It can begin around puberty in some men and
may produce adverse side effects. Hair transplantation is the
onset at an early age is known to significantly affect self-
only current successful permanent treatment option, but it
esteem and the individual’s quality of life [2]. AGA affects
requires a fairly invasive surgical procedure [13]. So it seems
60–70% of the adult population worldwide [3], up to 40% of
appropriate to identify alternative active substances for the
women and 50% of men by the age of 50 are affected to some
treatment of AGA.
degree [4]. The lowest incidence rate of AGA is observed in
Here, we performed information and literature searches
aboriginal Americans and Africans/African-Americans. AGA in
with Clinicaltrials.gov, ISRCTNregistry, PubMed, and Google
Asian populations also shows different clinical and genetic
Scholar search engines [14], using combinations of the key
characteristics compared to European populations [5].
words: Androgenetic alopecia (AGA); treatment OR therapy;
Vertex pattern AGA is associated with a significant
experimental; investigational; new; novel; clinical trial. We
increased risk for prostate cancer, though no statistically sig-
introduce and discuss the newest therapeutic options which
nificant association between AGA (any pattern) and prostate
have the potential to execute in the near future. Clinical trials,
cancer has been identified [6]. Other studies suggest AGA in
experimental studies, and reported patents that are <10 years
men and women is associated with increased risk of diabetes
old were evaluated in this review. Also, we briefly present
mellitus and heart disease [7]. However in general, hair loss
some updates about the pathogenesis of AGA in order to
due to AGA is not directly life threatening, but it can be
better understand the following therapies.
emotionally devastating for some and psychologically depres-
sive for others [8,9]. The psychosomatic impact of hair loss
among women appears to be more severe than for men [10]. 2. Diagnostic features relevant to treatment
Consequently, many affected individuals seek treatment. development
Treatment for AGA constitutes a multibillion dollar industry
Clinically, AGA involves altered hair-growth cycling with a
[11]. In North America, the current gold standard of treatment
reduction in the anagen growth phase and increased duration

CONTACT Kevin John McElwee kmcelwee@mail.ubc.ca Department of Dermatology and Skin Science, University of British Columbia, 835 West 10th Avenue,
Vancouver, BC V5Z 4E8, Canada
© 2017 Informa UK Limited, trading as Taylor & Francis Group
918 H. GUO ET AL.
Article highlights
● Androgenetic alopecia is a very common hair loss condition affecting
roughly 50% of the adult population.
● The androgenetic alopecia disease mechanism is still relatively poorly
understood, but involves a strong genetic contribution as well as
some environmental input.
● Provision of treatments for androgenetic alopecia is already a multi-
billion dollar industry, though current therapeutic approaches have
limited penetrance into the potential market.
● In the last 5 years, a rapid expansion in the commercial development
of new and improved treatments has occurred.
● Multiple drug treatments are under pre-clinical development or are in
clinical trials, as well as cell therapeutics and medical devices, and
may be launched on the market in the near future.
This box summarizes key points contained in the article.
of the telogen resting phase in affected hair follicles. The
prolonged telogen interval, combined with the continued
shedding of telogen hairs (exogen), gradually increases the
numbers of empty (kenogen) hair follicles [15]. Thus, AGA
manifests as a noticeable reduction of scalp hair coverage,
shorter miniaturized telogen vellus hair follicles [16], and sig-
nificantly slower rates of hair growth [17].
Therefore, the overall objective of any treatment for AGA,
both for men and women, is to return hair follicle growth cycles
to normal and/or to increase the size of the affected follicles,
and/or to increase the density of terminal scalp hair [18].
There are distinctive patterns of hair loss in women and
men, but in both genders the central scalp is most severely
affected. Several different standardized scales of alopecia in
men and women have been developed and used in the ana-
lysis of AGA treatment efficacy [19]. Male AGA is usually asso-
ciated with normal levels of circulating androgens; very rarely
blood tests indicate increased androgen activity [20]. In con-
trast, a minority of AGA affected women exhibit enhanced
circulating androgens. When female AGA is associated with
high levels of androgens, systemic antiandrogenic therapy
may be needed. However, treatment of female AGA with oral
antiandrogens is usually ineffective suggesting that most
female AGA cases are not systemic androgen dependent [21]
and topical treatment may be more appropriate.
3. New developments in the pathogenesis of AGA
3.1. Increased conversion of testosterone to
dihydrotestosterone in skin
It has generally been assumed that both male and female AGA
result from an increased sensitivity of scalp hair follicles to
circulating androgens [20]. Under the influence of androgens
bound to their receptors on hair follicle cells, there is a reduc-
tion of the cellular hair matrix volume, associated with a short-
ening of the anagen growth phase resulting in progressive
miniaturization of the follicle, in the involved scalp area [22].
The essence of AGA involves androgen-driven changes in the
morphology and growth dynamics of hair follicles.
The circulating androgens include dehydroepiandrosterone
sulfate (DHEA-S) and androstenedione which are primarily
produced in the adrenal glands, and testosterone and 5α-
dihydrotestosterone (DHT) which are mainly synthesized in
the gonads. There are similar high serum levels of DHEA-S
and androstenedione in both males and females, which are
considered to be the most important regulators of sebum
secretion. In contrast, the relatively low serum levels of testos-
terone and DHT in adults are enhanced approximately 10
times in males compared to females [23]. DHT is generated
from testosterone by the enzyme steroid 5-alpha-reductase
(5αR) in certain tissues including the prostate gland, seminal
vesicles, skin, hair follicles, liver, and brain [24]. DHT binds to
the androgen receptor (AR) with higher affinity than testoster-
one and plays a major role in the effects of androgens in the
periphery.
The skin is regarded as a peripheral organ that locally
expresses and synthesizes significant amounts of androgens
and associated enzymes with autocrine and paracrine actions
[23]. Usually the circulating androgen levels in both male and
female AGA patients are not significantly different from con-
trols with no hair loss [25,26]. However in balding scalp skin,
the conversion of testosterone to DHT is locally increased due
to an upregulation of 5αR [27,28]. The 5αR and AR are inten-
sely expressed in outer root sheath (ORS) according to some
studies, though the data on ORS expression is conflicting
[29,30]. AR are generally recognized to be expressed by the
dermal papilla (DP) cells of hair follicles, indicating that 5αR
mediated DHT conversion and DHT-AR effects may initially
impact DP, and potentially ORS cells of hair follicles, then in
turn modulating the growth of hair epithelial cells to induce
hair follicle miniaturization [25,27]. Indeed, it has been shown
that androgens abrogate bulge hair follicle stem cell differen-
tiation in vitro [25]. Therefore the DP and ORS are generally
considered to be the main sites of androgen action in hair
follicles [28].
3.2. DHT-AR mediated miniaturization of hair follicles
is promoted via interaction with hair follicle
developmental pathways
AR mediate DHT action via transcription and translation con-
trol of cellular proteins [27]. Notably, DP cells from balding
scalp in the frontal and vertex regions contain higher concen-
trations of AR and AR coactivator Hic-5/ARA55, potentially
further upregulating net sensitivity to androgen signaling
[31,32]. Differences in AR density and co-factor expression in
cells may also account for the different clinical presentations
of AGA in women and men [27].
Androgens have been shown to suppress the growth of
follicular epithelial cells through inducing secretion of patho-
genic mediators transforming growth factor-beta 1 and 2
(TGF-b1/2) and Wnt signaling inhibitory factor dickkopf 1
(DKK-1) by DP cells [31]. There is reciprocal activation of AR
and antagonism of Wnt/β-catenin signaling in cells of the hair
follicle bulb during mouse epidermal development [33].
Remarkably, it has been revealed that androgens abrogate
hair differentiation in AGA patients via the inhibition of the
Wnt signaling pathway [25]. The mouse and human studies
suggest that DHT-AR signaling interfere with hair follicle
developmental pathways, particularly the Wnt pathway, to

induce hair follicle miniaturization. Notably, progressive hair
thinning and loss is accompanied by a reduction of size and
numbers of hair follicle DP cells [34]. Wnt and BMP signaling
define the hair inductive activity of DP cells [35,36], highlight-
ing that DHT-AR cause hair miniaturization and loss by target-
ing DP cells and the crosstalk between DP cells and
keratinocytes.
3.3. Genetic predisposition in AGA
The familial occurrence of AGA is well documented; twin
studies show that heritability is higher in early-onset AGA
families (25–36 years) that in elderly males (>70 years). The
largest genome-wide association studies (GWAS) meta-analy-
sis of male AGA identified 63 genomic regions of interest,
including genes involved in deregulation of anagen-to-cata-
gen transition (FGF5, EBF1, DKK2), increased androgen sensi-
tivity (SRD5A2), and the transformation of pigmented terminal
hair into unpigmented vellus hair (IRF4) [37]. Other smaller
studies reported that strong genetic risk loci for male AGA
are the X-chromosome AR/EDA2R locus, the PAX1/FOXA2
locus on chromosome 20, deacetylase 9 (HDAC9) on chromo-
some 7p21.1 and deacetylase 4 (HDAC4) on chromosome
2q37, and WNT10A (wingless-type MMTV integration site
family member 10A) on chromosome 2q35 [38–40]. Notably,
there are very few gene studies on female AGA; so far no
significant association has been reported between female
AGA and AR genes, though increased levels of AR and ster-
oid-converting enzymes have been detected in the balding
scalps of both men and women [41].
Expression of AR and EDA2R have been defined in human
and/or mouse hair follicles, though to-date the data can
neither fully confirm nor exclude AR and/or EDA2R as the
key AGA causative gene locus [40]. Both PAX1/FOXA2 proteins
are developmentally important transcription factors that
might have some direct role in hair cycle control [42]. Both
HDACs play a role in the regulation of AR signaling via direct
or indirect interaction with the AR protein, indicating that
HDACs could contribute to the AGA-specific androgen-
induced miniaturization of hair follicles [40]. WNT10A shows
a significant reduction of expression in AGA hair follicles,
suggesting that the genetic risk allele at this locus may con-
tribute to the observed premature catagen entry and pro-
longed latency period between catagen and anagen re-entry
in balding hair follicles [43]. Overall, genomics studies provide
strong evidence of the underlying mechanisms of specific
genes and their control of hair follicle development and
growth pathways, highlighting that the modification of hair
follicle signaling pathways determines the incidence of AGA.
3.4. Follicular microinflammation
Follicular microinflammation and fibrosis may also be involved
in AGA development. The miniaturization of terminal hairs is
frequently associated with activated T-cell infiltrates about the
follicular bulge, and progressive fibrosis of the perifollicular
sheath [1,44]. The potential trigger factors for the microinflam-
mation might be resident microbial flora in the case of asso-
ciated seborrhea, toxins and oxidative stress, the aging
EXPERT OPINION ON INVESTIGATIONAL DRUGS 919
process in general, ultraviolet radiation exposure, smoking,
and/or environmental pollutants [45]. Indeed, increased stress,
increased smoking, having more children, and having a history
of hypertension and cancer, may all be associated with
increased hair thinning [46]. It is assumed that cumulative
inflammatory responses to microbial activity and stress could
damage normal tissues in follicles. Additionally, AR activation
may promote the inflammatory response [28]. A recent study
shows that androgen-AR interaction can induce premature
senescence of DP cells via DNA damage, the release of the
cell debris may subsequently elicit an inflammatory
response [47].
In short, the primary components underlying AGA patho-
genesis are genetically susceptible hair follicles, the elevated
conversion of DHT in the skin from circulating androgens,
accumulated DHT-AR inducible suppressors of hair follicle
growth, microinflammation, and cell senescence induced in
part by androgen-mediated DNA damage (Figure 1). The
androgen-dependent modulation of hair follicle growth and
developmental pathways [25] are assumed to be the critical
action in determining AGA. In addition, deficient perifollicular
vascularization [48] and decreased force required to remove
hair due to active protease activity [49] may also contribute to
hair loss. The further understanding of AGA pathogenesis
would facilitate the development of new or improved
treatments.
4. The principle of AGA treatments
The ultimate aim of therapy is to increase hair coverage over
the scalp and/or to retard progression of further hair thinning
[44]. The current and near future treatment strategies essen-
tially comprise: decreasing local DHT production, targeting the
interaction between DHT-AR signaling and regulation of
developmental and growth cycle signaling in hair follicles,
improving perifollicular vascularization, curbing microscopic
follicular inflammation, preventing DP cell senescence, and
possibly controlling connective tissue remodeling by balan-
cing protease/antiprotease systems (as shown in Figure 1).
To date, only two FDA-approved drugs, topical minoxidil
and oral finasteride, are approved to treat AGA with varied
efficacy, remission and side effects [3]. Hair transplants are
the only current permanent successful operation, while
weaves and wigs also serve as practical cosmetic options
[50]. Nutritional supplements and light therapy may play an
adjuvant role for the treatment of AGA. Also, there are
numerous non-prescription products that claim to be effec-
tive in restoring hair in AGA-affected individuals [2]. Other
than surgical options, all treatments work best when
initiated early, but any gains are likely to be lost if the
treatment protocol is stopped. Combinations of therapies
tend to be more efficacious than single treatments [51].
More effective topical AGA treatments with fewer systemic
side effects are highly desirable. Antiandrogens used topi-
cally appear to hold the most promise while avoiding their
systemic side effect risks. Androgen-driven modulation of DP
cells has been accepted as a key to AGA development.
Identification of such modulators could lead to novel ther-
apeutic approaches [52].
920 H. GUO ET AL.
Figure 1. Current recognition of AGA pathogenesis and treatment targets.
The primary components underlying AGA pathogenesis are genetically susceptible hair follicles, the conversion of DHT in the skin from circulating androgens, accumulated DHT inducible
suppressors of hair follicle growth, microinflammation, and cell senescence induced in part by androgen-mediated DNA damage. The current and near future treatment strategies
essentially comprise: decreasing local DHT production, targeting androgen-regulated factors in follicular epithelial cells and DP cells, improving perifollicular vascularization, curbing
microscopic follicular inflammation, and possibly controlling connective tissue remodeling by balancing protease/antiprotease systems.
Here, we review the therapies currently under investigation
and briefly comment on the well-known treatments of AGA.
Since there are recent published S3 guidelines for existing
AGA treatment (S3 guidelines are based on a consensus
from systematic literature research with evaluation of evi-
dence levels and a systematic decision process) [53,54], and
our goal is to initiate the idea of treatment development
rather than systematic evaluation of current treatments, we
have not included evidence assessment grades in this article.
Instead, we predominantly focused on new potential treat-
ments for AGA and have dissected conventional AGA treat-
ments to shed light on new innovations. Also, we categorize
the therapies for AGA by their mechanisms instead of the
chronological order of the invention or application in order
to integrate the molecular characteristics and targeted treat-
ments for AGA.
4.1. Targeting the conversion of testosterone to
dihydrotestosterone
4.1.1. Oral/systemic 5aR inhibitors
The enzyme 5αR, which converts testosterone to DHT, exists in
two primary forms: type 1 and type 2. Recently, an alternative
type 3 5αR was revealed in benign and malignant prostate
cancer [55]. There are several drugs that inhibit the classical
type 1 and type 2 5αR; dutasteride inhibits both, whereas
finasteride inhibits type 2 5αR only. Available data show that
systemic dutasteride, in contrast to finasteride, provides
greater suppression of DHT, and is more effective against
genetic variants of 5αR [56]. Oral finasteride 1 mg and dutaste-
ride 0.5 mg/day for 12 months have both been shown to be
effective in male AGA, but are largely ineffective in women
[54]. Efficacy of higher doses (2.5 mg or 5 mg/day) in women
might produce better results; however, the long-term adverse
effect potential in both genders has become a fundamental
concern with all 5αR inhibitors [57].
4.1.2. Topical 5αR inhibitors
The potential side-effect risks around oral/systemic 5αR inhi-
bitors have driven preliminary investigations into adapting
drug formulations for localized administration. Topical applica-
tion of 5αR type 2 inhibitor finasteride, in analogy with topical
flutamide, causes local inhibition of sebaceous gland growth
in hamsters, demonstrating the potential for topical 5αR inhi-
bitor formulas [58]. However, the skin barrier makes topical
application of high molecular weight drugs difficult [59].
Further, for effective AGA treatment, topical drugs would
need to penetrate deep into the skin to have the strongest
effect at the level of hair follicle DP cells. Unofficially, several
topical formulations of 5αR inhibitor drugs are already avail-
able through ‘internet pharmacies’ or by local pharmacy com-
pounding, but the skin penetration efficacy and duration of
drug effect in the skin of these formulations have not been
evaluated. So far topical finasteride is not FDA approved for
treatment of AGA; any use of finasteride or other 5αR inhibi-
tors in topical formulations is ‘off label’.
A few topical formulations to deliver finasteride to hair
follicles are undergoing investigation [60]. It has been shown
that topical application of hydroxypropyl chitosan (HPCH)-
based formulations on hairless rats can be better than anhy-
drous formulations, promoting a cutaneous depot of finaster-
ide in the region of hair bulbs without systemic absorption
[60]. Encasement of drug molecules in the interior of vesicular
compartments (liposomes) has been developed and evaluated
 EXPERT OPINION ON INVESTIGATIONAL DRUGS 921

as a plausible transepidermal therapeutic system for finaster-

ide application [61]. Liquid crystalline nanoparticles (LCN) have

TetraLogic Pharmaceuticals
References or source
also been proven as carriers for topical delivery of finasteride

Cassiopea and Intrepid

in the treatment of AGA, suggesting that finasteride-loaded
LCN could be a viable alternative to oral administration of the

[66–69] Proskelia
Therapeutics
drug [62]. Also, it has been shown that enhancement of

Polichem Co
percutaneous absorption of finasteride can be produced by

[70–72]
using cosolvents, cosurfactants, and surfactants [63]. The main

[64]

[65]

[73]
[74]
investigational topical antiandrogen medications are summar-
ized (Table 1).

Not applicable
Efficacy
4.1.3. MorrF

Yes

Yes

Yes

Yes
A lipid based topical formulation of MorrF is prepared by

No
dissolving 50 mg/mL minoxidil, 1 mg/mL finasteride, and
5 mg/mL soy phosphatidylcholine in an isopropyl alcohol–

Time of clinical
propylene glycol–water solution. A preclinical study of MorrF

response

Not applicable
on rats, and a clinical study on 120 male AGA patients, sug-

6 months

3 months

3 months
6 months
4 months
gested that topical MorrF had a clinically significant effect with

7 days
improvement in hair growth as compared to minoxidil (5%)
alone [64].

5% CB-03–01 solution twice-

1 mL MorrF twice daily

0.25% finasteride daily

4.1.4. P-3074

70 mg/ml twice daily

Clinical trial, no disclosure of details
Clinical trial, no disclosure of details
The first clinical trial of P-3074 (ClinicalTrials.gov Identifier:

0.025% once daily

Usage

2% fluridil daily
NCT03004469), a new topical finasteride solution with HPCH
as film-forming agent, funded by Swiss company Polichem,

2% lotion
daily
was completed in Switzerland in May 2014. The data showed
that 0.25% topical finasteride reduced DHT levels to the same
level as standard 1 mg finasteride pills. A total of 450 patients
with AGA are expected to be recruited to complete the phase
Subjects

Male and
female
3 clinical trials (ISRCTNregistry identifier: ISRCTN19708972) by

Female
February of 2018.
Male

Male
Male

Male

Male
Table 1. Investigational topical antiandrogen medications for androgenetic alopecia treatment.

Suppression of androgen activity

Androgen receptor antagonist

4.2. Topical AR antagonists

Estrogen receptor antagonist
Androgen receptor blockade
Synthetic androgen receptor
Mechanisms

4.2.1. Cortexolone 17α-propionate

Combination treatment

Cortexolone 17α-propionate (developmental code name CB-

Finasteride solution

Topical estrogens

03–01; tentative brand names BreezulaTM for AGA; WinleviTM

HDAC inhibitor
antagonist

for acne), under development by Cassiopea and Intrepid

Therapeutics, is a synthetic AR antagonist for use as a topical
medication in the treatment of androgen-driven conditions
including acne vulgaris [75], suggesting it may also be a
candidate treatment for AGA. Indeed, a phase 2, multicenter,
MorrF: Minoxidil, Finasteride,
Soy Phosphatidylcholine

randomized, double-blind, controlled study of CB-03–01 solu-

tion 5% applied twice-daily for 26 weeks to men with AGA has
Agents

been completed by Intrepid Therapeutics (ClinicalTrials.gov

Identifier: NCT02279823); however, no result is posted.
Ketoconazole

Fulvestrant
Alfatradiol
CB-03–01

RU58841
P-3074

Fluridil

SHAPE

4.2.2. Fluridil
Fluridil is a novel topical antiandrogen that suppresses the
human AR. 2–6% fluridil in anhydrous isopropanol is highly
hydrophobic, hydrolytically degradable, and systemically non-
Androgen receptor

receptor
receptor
receptor
receptor
receptor
receptor
5-alpha-reductase

5-alpha-reductase

resorbable. In a double-blind, placebo-controlled study, apply-

ing the fluridil as an occlusive patch to the forearms of 43
Androgen
Androgen
Androgen
Androgen
Androgen
Androgen

male AGA patients for 21 days showed that topical fluridil

Targets

could increase the anagen percentage of hair, and was devoid

of systemic activity [65].
922 H. GUO ET AL.
4.2.3. RU-58841
RU-58841 (also known as PSK-3841 or HMR-3841), a synthetic
nonsteroidal antiandrogen, displays high affinity for the ham-
ster prostate and flank organ and competes with DHT for
binding to receptors. When topically applied, it exerts a potent
dose-dependent regression of the flank organ area, indicating
its value as a candidate topical treatment for androgen driven
conditions [66]. A study in a rodent model of androgen-
dependent hyperplasia of the sebaceous glands showed that
RU-58841-induced glandular and ductal regression equivalent
to that in castrates, whereas topical finasteride induced a more
moderate degree of lobular and ductal reduction, and MK 386
(5αR type I inhibitor) caused only ductal regression [67].
Another study revealed a significant increase in density, thick-
ening, and length of hair in the macaque model of AGA, while
no systemic effects were detected after topical RU-58841
application [68].
RU-58841-myristate (RUM) loaded on solid lipid nanopar-
ticles (SLN) can be rapidly metabolized to the potent anti-
androgen RU 58841 by cultured human foreskin fibroblasts
and keratinocytes and show more topical action of RU
58841. Thus, RUM-loaded SLN has been suggested for topi-
cal antiandrogen therapy of acne and AGA [69]. Proskelia
Pharmaceuticals apparently completed Phase I and Phase II
clinical trials of RU-58841 after licensing it and changing its
name to PSK 3841. However until now no further attempts
have been made to bring it to market (ISRCTNregistry iden-
tifier: ISRCTN49873657). The company declares that RU-
58841 is currently intended as a research chemical for in
vitro testing and laboratory experimentation only.
4.2.4. Histone deacetylase (HDAC) inhibitors
The finding of high-risk allele variants by genomics may pro-
vide an opportunity for early medical intervention in AGA [76].
A genome-wide association study of more than 1000 cases of
AGA and controls suggested that HDAC9 is the third AGA
susceptibility gene after the two major genetic risk loci of
AGA: the AR/EDA2R locus and PAX1/FOXA2 locus [38].
HDAC9 might interact with AR through the myocyte enhancer
factor-2 (MEF2) transcription factor modulating AR transcrip-
tional activity [5]. The histone deacetylase inhibitors (HDAC
inhibitors, HDIs) might be potential therapeutic strategies for
AGA [38]. A novel HDAC inhibitor, SHAPE (suberohydroxamic
acid (4-methoxycarbonyl) phenyl ester) is being developed for
topical treatment of AGA, and additionally for alopecia areata
(ClinicalTrials.gov Identifier: NCT02636244) by TetraLogic
Pharmaceuticals.
4.2.5. Ketoconazole
Ketoconazole (KCZ) is an imidazole antifungal agent.
Reportedly, topical application of KCZ stimulates hair growth
in C3H/HeN mice [70]. An open trial of topical 2% KCZ lotion
(trade name, Nizoral) in combination with shampoos was
performed on six Japanese males with AGA of which three
showed a significant improvement of AGA. An in vitro transi-
ent transfection study suggested that KCZ may improve AGA
by suppression of AR activity [71]. The effect of 2% KCZ
shampoo was compared to that of an unmedicated shampoo
used in combination with or without 2% minoxidil therapy.
Hair density, size, and proportion of anagen follicles were
almost similarly improved by both KCZ and minoxidil regi-
mens [72]. Ketoconazole and related azoles may provide an
adjunctive treatment for AGA; however, there are a lack of
high-quality randomized controlled trials.
4.2.6. Topical estrogen-related solutions
In Europe and South America, topical estrogens are available
and used for various hair disorders [13]. 17α-estradiol (trade
names Alfatradiol™, Ell-Cranell Alpha™, and Pantostin™ in
Germany) is used topically for the treatment of AGA in both
males and females. In contrast to 17β-estradiol, 17α-estradiol,
while it still binds to the estrogen receptor, has less or no
feminizing estrogen activity, but acts as an inhibitor of 5αR. An
open, randomized, multicenter comparative phase IV study in
female AGA patients showed that treatment with 17α-estra-
diol resulted in deceleration or stabilization of hair loss, and a
significant increase in cumulative hair thickness and absolute
hair density were achieved after 17α-estradiol to minoxidil
switch treatment [73]. Subsequently, an open-labeled, single-
arm, single institution clinical trial concluded that 0.025% 17α-
estradiol solution was a safe alternative for the effective treat-
ment of female pattern hair loss [77]. However, two rando-
mized studies showed that a topical solution of fulvestrant
(trade name, Faslodex™), a complete estrogen receptor
antagonist, had no effect on male AGA or postmenopausal
female AGA [74].
4.3. Improving perifollicular vascularization
There is evidence that substantial angiogenesis is associated
with hair follicle cycling leading to rearrangement of the skin
vasculature and skin perfusion [48]. Furthermore, it has been
shown that the upper hair follicle bulge is associated with a
perivascular niche during the establishment and maintenance
of this specialized region [78], and hair follicle stem cells in the
bulge region can develop skin blood vessels and form a
follicle-linking network [79]. Therefore, modulation of angio-
genesis is considered a potential therapeutic strategy of
importance for hair growth [80].
VEGF is a key regulator in vasculogenesis and a potent
vasodilator while acute VEGF treatment increases skin perfu-
sion [81,82]. VEGF-induced perifollicular angiogenesis controls
normal hair growth and hair follicle size [83]. The loss of VEGF
has been detected in human AGA affected hair follicles [84].
New investigational treatments and the novel mechanisms
advanced in support of old treatments which are associated
with skin perfusion and VEGF production, are reviewed as
follows and listed in Table 2.
4.3.1. Minoxidil and related solutions
Minoxidil (trade name, Rogaine™, or Regaine™ in Europe), is an
adenosine-triphosphate-sensitive potassium channel opener
that can be used by both men and women with AGA [85].
The mechanisms by which minoxidil is effective for AGA still
remain to be fully elucidated. However, one mechanism of
minoxidil action on AGA could be via its vasodilatory and
angiogenesis facilitating effects. Minoxidil can stimulate
Table 2. Targeting angiogenesis and developmental signaling pathways for androgenetic alopecia treatment.
Time of clinical
Targets Agents Mechanisms Subjects Usage response Efficacy References or source
Skin vasculature and perfusion Minoxidil Potassium channel opener Male and female 2–5% minoxidil once daily 6 months Yes [85–87]
Skin vasculature and perfusion Pinacidil, Nicorandil and Potassium channel openers Yes [80]
Diazoxide
Skin vasculature and perfusion Adenosine Increases cutaneous blood Male and female 0.75% lotion twice daily 6 months Yes [88–90]
flow, prolongs anagen
phase, increases the size of
smaller hair follicles
Cell proliferation and skin All-trans retinoic acid Regulates epidermal cell Follicle cells and mice Yes [91–95]
angiogenesis proliferation and promotes
vascular cell proliferation
Cell proliferation and skin Copper peptides Increasing VEGF production, Male and female Cream, lotion, spray, and [96]
angiogenesis decreasing TGF-b shampoo
production
Cell proliferation and skin Platelet-rich plasma (PRP) Various growth factors Male and female Subcutaneous injection 3 months – varies Yes – ongoing [97–102]
angiogenesis
PGF receptor Bimatoprost PGF2 analog Male and female 0.03 % solution 3 months Yes [103,104]
PGF receptor Latanoprost PGF2 analog Male and female 0.1 % daily 6 months Yes [105]
PGE receptor Viprostol PGE2 analog Male Yes [106]
PGD2 receptor AM211 Antagonist to PGD2 Ongoing Kythera
Biopharmaceuticals,
Inc
Hair follicle growth and cycling JAK inhibitors JAK-STAT inhibition In vitro, mouse and JAK-STAT inhibitors dissolved 4 weeks Yes [107–109]
pathways human skin in DMSO and used at 2–3%
Hair follicle transition from anagen FGF5 inhibitors Anagen inducer Male and female 0.095–0.5% twice daily 16 weeks Yes [110,111] Cellmid Ltd
to catagen
Wnt pathway SM04554 Wnt pathway activator Clinical trial, no disclosure of details Ongoing Samumed Llc
Hair follicle signaling pathways Hair-stimulating complex Various growth factors Clinical trial, no disclosure of details Ongoing Histogen Inc
(HSC)
EXPERT OPINION ON INVESTIGATIONAL DRUGS
923
924 H. GUO ET AL.
production of VEGF in cultured DP cells which possess adeno-
sine receptors and sulfonylurea receptors [86]. Minoxidil can
also activate cytoprotective prostaglandin synthase-1 which
could be a possible explanation for its hair growth-stimulating
effect [87]. The collective effects of minoxidil lead to increased
cutaneous blood flow, prolongation of the anagen growth
phase, and increase in the size of smaller hair follicles. Other
potassium channel openers such as pinacidil, nicorandil, and
diazoxide, which share the common properties of minoxidil,
have also been reported to stimulate hair growth with in vitro
studies [80].
4.3.2. Adenosine
Adenosine, as a mediator of VEGF production, can upregulate
the expression of VEGF and fibroblast growth factor 7 (FGF7)
in cultured DP cells [88]. It has been shown that an adenosine-
mediated signaling pathway underlies minoxidil-induced VEGF
production for hair growth [86]. It was reported that 0.75%
adenosine lotion twice daily improved hair loss in Japanese
women as compared to placebo [89]. AGA patients were sig-
nificantly more satisfied with adenosine because of faster hair
loss prevention and appearance of newly grown hairs, though
the effect of adenosine had no statistical superiority to that of
5% topical minoxidil on male AGA [90]. A hair care product
(trade name, Adenovital™) developed by Shiseido is based on
adenosine and an onion extract. Interestingly, it has been
shown that use of crude onion juice in the treatment of
patchy alopecia areata patients gave significantly better hair
regrowth as compared to placebo [112].
4.3.3. Topical all-trans retinoic acid (ATRA)
Topical prototypic retinoid ATRA (tretinoin) alone and in
combination with 0.5% minoxidil has been shown to be
effective for the promotion of hair growth in vitro [91,92]
and in mice [93]. Tretinoin can promote and regulate cell
proliferation and differentiation in the epithelium and may
promote vascular proliferation to prolong the anagen phase
of the hair cycle [91]. Indeed, ATRA can induce angiogenesis
via the retinoic acid receptor by enhancement of endogen-
ous VEGF signaling [94]. The activation of Erk- and Akt-
dependent signal transduction pathways and the prevention
of apoptosis by increasing the Bcl-2/Bax ratio may also be
involved in hair growth promotion by tretinoin [92]. Some
doctors suggest that 2% minoxidil combined with retinoids
work to treat hair loss as well as, or better than, 5% minox-
idil alone. Combinations of retinoids and minoxidil-type
compounds for hair growth have been patented. However,
it has to be borne in mind that tretinoin can also cause
diffuse hair loss [95].
4.3.4. Copper peptides
Copper is particularly useful to the body when it is attached to
amino acids. Tripeptide-copper complexes (called copper pep-
tides) are reported to stimulate hair growth by increasing the
production of VEGF, decreasing secretion of TGF-β, and pre-
cluding apoptosis of DP cells [96]. Hair care products (cream,
lotion, spray, and shampoo) have been developed by Tricomin
and Folligen based on copper peptide formulations.
4.3.5. Hair stimulating complex (HSC)
Hair Stimulating ComplexTM (HSC) sponsored by Histogen is
described as a kind of ‘cell conditioned media extract’ devel-
oped as an injectable for hair regrowth. The proteins within
HSC, including keratinocyte growth factor (KGF), VEGF, and
follistatin, are involved in signaling stem cells in the body.
HSC clinical trials for treating AGA were initiated in 2012
(ClinicalTrials.gov Identifier: NCT01501617); however, the sta-
tus of the clinical trial is unknown and the planned completion
date of the trial has passed.
4.3.6. Platelet-rich plasma (PRP)
PRP is an autologous blood-derived product with 3–8 times
increased concentration of platelets in plasma [97]. The PRP
is used to deliver supraphysiological levels of growth factors
to hair follicles by intradermal injection. Platelet-derived
growth factor, TGF-β, VEGF, and insulin-like growth factor
type I (IGF- I) are well-known growth factors in PRP [98] that
have been shown to stimulate the production of pivotal
bioactive molecules involved in wound healing and hemos-
tasis [99]. The main growth factors involved in the establish-
ment of hair follicles are likely VEGF, epidermal growth
factor (EGF), IGF-1, and fibroblast growth factors (FGFs)
[100]. Activated PRP has been shown to increase the pro-
liferation of DP cells by upregulating the cells’ own produc-
tion of FGF7, as well as beta-catenin expression, and
stimulating extracellular signal-regulated kinase (ERK) and
Akt signaling, suggesting that PRP helps hair growth via
regulation of several hair follicle developmental pathways.
The injection of mice with activated PRP induced faster
telogen-to-anagen transition, shortened the duration of
hair follicle formation, and enhanced the number of newly
formed hair follicles [101]. Microscopic findings showed
thickened epithelium, increased collagen fibers and fibro-
blasts, and more blood vessels around follicles after PRP
treatment [102].
A non-comparable study showed that a protocol of three
treatment sessions performed with an interval of 21 days, and
a booster session at 6 months following the onset of therapy,
reduced hair loss in 20 patients with AGA during one year
period [113]. A case-control half head treatment of non-acti-
vated PRP and activated PRP on 23 AGA patients showed a
clinical improvement in the number of hairs in the target area
and in total hair density after three months post-treatment
[114]. A recent review of PRP for the treatment of AGA con-
cludes that, though in its nascent stages, the use of PRP is
promising and the side effects are minimal [115].
When used as an adjunct to hair restoration surgery, grafts
that were pretreated with a PRP solution demonstrated better
graft survival and improved hair density [116]. Notably, the use
of topical minoxidil after hair transplantation can enhance the
growth of new follicles as well [102]. Dalteparin and protamine
microparticles (D/P MPs) can effectively carry growth factors
(GFs) in PRP. In one study, the addition of D/P MPs to PRP

resulted in significant stimulation in hair cross-section, though
not in hair numbers [117]. Controlled, multiple needle injection
techniques may further facilitate effective PRP implementation.
4.4. Restoring inhibited hair follicle development and
cycling pathways
Developmental pathways such as Wnt/β-catenin, Sonic
hedgehog (Shh), Bone morphogenic protein (BMP), trans-
forming growth factor-beta (TNF-β) [118], TNF family mem-
ber ectodysplasin (EDA) and its receptor (EDAR) [119], and
Notch [120] have been revealed as key hair follicle develop-
mental signaling pathways, which also regulate adult hair
cycling. Notably, a novel Wnt inhibitor, adenomatosis poly-
posis down-regulated 1 (APCDD1) is mutated in hereditary
hypotrichosis simplex (HHS), which is a rare autosomal
dominant form of hair loss characterized by hair follicle
miniaturization, highlighting that Wnt and Wnt inhibitors
play an essential role in human hair growth [121]. EDA/
EDAR is a member of the tumor necrosis factor (TNF) super-
family that signals predominantly through the nuclear fac-
tor-kappaB (NF-kB) and c-jun N-terminal kinases (JNK)
pathways. Genetic and experimental studies suggest that
EDA/EDAR signaling is involved in the control of hair follicle
development and hair cycling by cross-talking with Wnt,
TGF-β, BMP, and Shh signaling pathways [122,123].
Notably, it has been reported that Ectodysplasin-A (EDA1)
is sufficient to rescue both hair growth and sweat glands in
Tabby mice [124].
The strategies to modify the molecules and pathways that
regulate hair follicle formation and adult hair growth and
cycling could provide new therapeutic possibilities for hair
loss conditions. However skin cells’ response to these devel-
opmental pathways is restricted in time and space [125], and it
must be borne in mind that these molecules can also poten-
tially cause the formation of benign cysts or tumors such as
pilomatricoma and basal cell carcinoma [118]. The compli-
cated interaction of signals from different hair developmental
pathways needs to be considered when designing effective
and safe therapeutic strategies.
4.4.1. Prostaglandin analogs
Prostaglandin D2 synthase (PTGDS or lipocalin-PGDS), as well
as its product, prostaglandin D2 (PGD2) are increased in bald-
ing scalp skin. Hair growth inhibition requires the PGD2 recep-
tor G protein coupled receptor 44 (GPR44) [126], suggesting
that PGD2 and PTGDS are inhibitors of hair growth in AGA.
Inhibitors of prostaglandin endoperoxide synthase (PTGS, also
known as COX), such as aspirin, were shown to block prosta-
glandin synthesis and inhibit hair growth [103]. However,
different prostaglandins often have opposing functions;
while PGD2 inhibits hair growth, PGE2 and PGF2a stimulate
hair growth [127]. It has been shown that minoxidil can acti-
vate prostaglandin endoperoxide synthase-1 (COX-1) to
increase PGE production by human DP cells and mouse fibro-
blasts in culture, suggesting that PGE and COX-1 might be
more potent second-generation hair growth-promoting drugs
[87]. Later it was shown that exogenous or endogenous PGE2
can induce keratinocyte proliferation both in vitro and in vivo
EXPERT OPINION ON INVESTIGATIONAL DRUGS 925
through signaling pathways including cAMP/PKA, EGFR, Ras-
MAPK, and PI3-K/AKT pathway [128]. Prostaglandins might act
as the modulatory factors upstream of these hair follicle devel-
opmental pathways [127]. Also, prostaglandins interact with
the prostanoid receptors in hair follicles to regulate the hair
growth cycle [106]
Consequently, there are currently four registered clinical
trials (three completed, one recruiting) on the use of
Bimatoprost in male and female patients with AGA [104].
Bimatoprost (trade names, Latisse™ and Lumigan™) is a PGF2
analog in a 0.03% solution, FDA approved for eyelash hypo-
trichosis [103] and currently undergoing trials for AGA
(ClinicalTrials.gov Identifier: NCT02676310). Another PGF2 ana-
log, 0.1% Latanoprost (trade name, Xalatan™), applied daily in
16 male AGA subjects significantly increased hair density and
pigmentation at 24 weeks compared with baseline and pla-
cebo-treated subjects [105]. Viprostol, a synthetic PGE2 analog
exhibited an effect on hair growth, though to a lesser extent
than the PGF series analogs [106]. The investigation of a
selective oral antagonist to the PGD2 receptor, AM211 (trade
name, Setipiprant™), for hair loss has recently been assigned to
Kythera Biopharmaceuticals.
4.4.2. JAK inhibitors
Small-molecule inhibitors of the Janus kinase (JAK)-signal
transducer and activator of transcription (STAT) pathway
are approved by the FDA for the treatment of immune-
driven myeloproliferative diseases (ruxolitinib) and rheuma-
toid arthritis (tofacitinib) [107]. Interestingly, the stat3/
socs3 pathway has been identified to promote cell regen-
eration through stem cell activation, division, and differen-
tiation [108]. Recently, it was reported that topical
treatment of mouse and human skin with JAK inhibitors
results in rapid onset of anagen and subsequent hair
growth. Hair growth after JAK-STAT inhibition mimics nor-
mal anagen initiation by activating the Wnt and Shh sig-
naling pathways, also the genes of TGF-β, BMP, and Notch
pathways are modified by topical JAK inhibitors [109].
Therefore, JAK inhibitors might be potentially useful for
treatment of AGA by awakening inhibited hair follicle
developmental pathways.
4.4.3. FGF5 inhibitors
It has been revealed that mutations within FGF5 underlie
familial trichomegaly, excessive eyelash growth. FGF5 has
been identified as a crucial regulator of hair length in humans
by inducing catagen, suggesting that inhibition of FGF5 might
selectively enhance eyelash and other hair follicle growth
[110]. Cellmid sells an FGF5 inhibitor formulation (trade
name; évolis oneTM) which is claimed as the first clinically
validated FGF5 inhibitor hair growth product. The company’s
recent single-blind placebo-controlled clinical study of 32 sub-
jects showed that majority of individuals in the treatment
groups showed improvement in anagen ratio and hair density
at day 112 treatment [111].
4.4.4. SM04554
SM04554 is a small-molecule that activates the Wnt pathway.
Samumed has launched a phase 2 trial of SM04554 in a topical
926 H. GUO ET AL.
solution (ClinicalTrials.gov Identifier: NCT02275351 and
NCT02503137), including an analysis of scalp biopsies prior
to and post dosing of SM04554.
4.5. Protease/antiprotease system regulators
Hair follicle extracellular matrix exhibits significant hair
cycle-associated plasticity, suggesting that modulation of
the extracellular compartment might be important during
hair follicle morphogenesis, cycling, and growth [129,130].
There are distinct hair cycle-dependent changes in metallo-
proteases and their inhibitor systems [131]. Matrix metallo-
protease MMP-9 is located in the lower part of the inner
root sheath (Henle’s layer) of human anagen hair follicles
[132], thus MMP-9 may promote the formation of the initial
lumen, prepare the hair canal for the hair shaft emergence,
and prevent its walls from damage induced by the newly
growing hair fiber [129]. The migration of melanocyte pre-
cursors (melanoblasts) from the ORS of hair follicles into
depigmented epidermis requires MMP-2 [133], suggesting
that MMP-2 might also be involved in hair growth since
follicular melanogenesis is tightly coupled to the hair
growth cycle [134]. Notably MMP-2 and MMP-9 can promote
hair growth by inducing the expression of VEGF, IGF-1, and
TGF-β [131].
Additionally, the serine proteinase, hepatocyte growth fac-
tor (HGF) activator expressed in hair follicles is involved in
HGF-dependent hair follicle elongation. This elongation can
be partially abrogated by the serine proteinase inhibitor, apro-
tinin [135]. Lysosomal protease cathepsin L (CTSL)-deficient
mice develop periodic hair loss due to alterations of hair
follicle morphogenesis and cycling, dilatation of hair follicle
canals, and disturbed club hair formation [136], suggesting
that CTSL is essential for regulation of keratinocyte and mela-
nocyte differentiation and epidermal cell homeostasis during
hair follicle morphogenesis and cycling [130]. A recent study
indicated that there was proteolytic activity in the tissue sur-
rounding human hair telogen club roots, and a novel protease
inhibitor system (combination of Trichogen and climbazole)
could inhibit this activity and reduce excessive hair shed-
ding [49].
4.6. Hair growth promoter melatonin
Melatonin (N-acetyl-5-methoxytryptamine) is primarily
synthesized and secreted by the pineal gland and it is
involved in the regulation of circadian rhythms, seasonal
responses, and has antioxidative effects [137]. Human skin
has been shown to have its own active melatoninergic anti-
oxidative system [138]. Melatonin in low doses enhances in
vitro human hair follicle proliferation, though it inhibits hair
growth in high doses. Stimulation of hair follicles can be
suppressed by potent melatonin antagonists indicating a
specific receptor-mediated mechanism of melatonin action
on hair follicles [45]. Keratinocytes, melanocytes, and fibro-
blasts all feature functional melatonin receptors [139], the
melatonin receptors are located in the root sheath of the
hair, which may assist in the regulation of hair growth and
stabilization of the hair shaft [140]. Clinical trials with topical
application of melatonin (0.0033%) have been performed in
patients with AGA. At 3 and 6 months, patients exhibited
significant increases in hair density of 29% and 41%, respec-
tively [45].
4.7. Cell-mediated treatments
Several companies and academic research groups are focused
on the development of cell-mediated treatments for AGA [50].
It has been shown that cells from hair follicle mesenchymal
tissue can be cultured and then applied to induce new hair
follicle formation from epithelial tissue in rodent models. Also,
the injected cells may migrate to resident hair follicles to
increase their size [141]. Distinct populations of DP and dermal
sheath (DS) cells have been patented as hair growth modula-
tors. Research indicates DS ‘cup’ cells are retained within the
hair follicle bulb mesenchymal niche over several consecutive
cycles of hair follicle regeneration. At the onset of each ana-
gen growth stage, they are mobilized to regenerate a new DS
and supply new cells to the DP [142]. In principle, the supple-
mentation of DP and DS cup cells may prevent and reverse
hair follicle loss in AGA and other hair loss conditions.
RepliCel Life Sciences will launch a Phase 2 clinical trial
using autologous cultured DS cup cells for treating AGA
(RCH-01TM). A phase II randomized, blinded, and controlled
investigation by Kerastem Technologies intends to evaluate
the safety and feasibility of processing and preparing an auto-
logous fat graft enriched with adipose-derived regenerative
cells for the treatment of early AGA. Sanford-Burnham Medical
Research Institute has developed a technology based on turn-
ing human-induced pluipotent stem cells into DP-like cells to
induce hair growth. The goal is to potentially produce an
unlimited amount of differentiated DP cells for hair restoration
purposes. The Berlin University of Technology is working on
development of hair follicles outside the body using stem cells
and invention of a 3D micro hair follicle culturing technique.
These and other laboratories and companies are working on
bringing cell based treatments to clinical trials in the near
future.
4.8. Micronutrients or functional foods
It has been observed that deficiencies of essential fatty acids,
zinc, selenium, iron, or biotin (vitamin H) can manifest as hair
loss [143]. Vitamin B variants, vitamin C, vitamin E, and miner-
als iron and zinc are considered by a minority of dermatolo-
gists to prevent hair loss by improving blood flow, improving
hair quality, decreasing cholesterol, and/or promoting oxygen
uptake, thus protecting hair and scalp cells from free radical
damage [80].
Biotin is an essential water-soluble vitamin that is involved
in fatty acid synthesis, amino acid catabolism, gluconeogen-
esis, and helps support mitochondria. Biotinidase is a critical
enzyme in releasing biotin from foods and biotin-containing
peptides for absorption. Alopecia in rats resulting from val-
proic acid administration for epilepsy was shown to be
reversed with biotin supplementation [144]. Biotin administra-
tion also produced a beneficial effect in children who experi-
enced alopecia after valproic acid treatment [13].

Consequently, biotin supplements are sometimes suggested
as adjunctive treatments for AGA [145].
Iron supplements are sometimes used as an adjunctive
treatment for hair loss. It is suggested that women in particu-
lar are susceptible to iron deficiency due to the regular loss of
iron rich blood through menstruation. The required iron levels
and their significance for telogen effluvium type hair loss are
still an object of discussion, with various studies producing
different conclusions [146]. Regardless, iron deficiency may be
a factor that can exacerbate AGA [147,148]. Of note, excess
iron is toxic and may promote a telogen effluvium due to
hemochromatosis.
Functional ‘antiaging foods’ for skin may exert their influ-
ence mostly through their antioxidant and anti-inflammatory
effects, abrogating collagen degradation and/or increasing
procollagen synthesis. Their usage has also been suggested
for hair growth. Some clinical evidence supporting a role in
preventing cutaneous aging is available for oral supplements
with carotenoids, polyphenols, chlorophyll, aloe vera, vitamins
C and E, squalene, and omega-3 fatty acids [149]. However for
the most part, these supplements have only been used anec-
dotally for hair loss and their potential for the treatment of
AGA remains undetermined.
4.9. Medical device therapies
4.9.1. Low-level light therapy
Low-level light therapy (LLLT) has recently been approved by
the FDA as safe to use for the treatment of hair loss [150].
Many light therapy devices are now available for both home
use and for in clinic treatments. However, the efficacy of LLLT
devices remains unclear due to the lack of well-conducted
randomized controlled trials [151]. A retrospective observa-
tional study of 655 nm laser light treatment on AGA using a
comb device (trade name, Hairmax laser combTM) showed that
LLLT may potentially be an effective treatment for both male
and female AGA, either as monotherapy or combination with
minoxidil and finasteride [152]. A clinical investigation sug-
gested efficacy for both male and female pattern hair loss
[153]. A clinical trial of an LLLT over-the-counter home use
device (trade name, Theradome LH80proTM) for the treatment
of AGA (ClinicalTrials.gov Identifier: NCT02528552) is under-
way. An evidence-based review of LLLT for hair regrowth
suggests that FDA-cleared LLLT devices are both safe and
effective in men and women who did not respond, or were
not tolerant to, standard treatments [154].
4.9.2. Electric field stimulation
A noninvasive, nonthermal technique with pulsed electric
fields can lead to proliferation of the epidermis, formation of
microvasculature, release of growth factors, and secretion of
new collagen at treated areas without scarring, thus might
potentially serve as a novel noninvasive therapy for AGA [155].
4.9.3. Microneedling
Microneedling (also called dermarolling) has recently become
a popular therapeutic approach for AGA. Various rollers and
stamps with microneedles attached are applied to the scalp,
either on their own or with subsequent application of topical
EXPERT OPINION ON INVESTIGATIONAL DRUGS 927
treatments such as minoxidil [156]. The objective is to elicit a
mild erythema response which, over time, initiates improve-
ment in hair growth. Small-scale studies and case reports
suggest relatively significant hair growth improvement can
be obtained [157,158]. While the mechanism of efficacy has
not been investigated in any detail, microneedling may
increase related gene expression and localized growth factor
release [159].
5. Conclusions
Significant progress is being made in understanding the
mechanisms of AGA, particularly with regards candidate AGA
susceptibility genes. However, more research will be needed
to characterize the intracellular signaling mechanisms
involved in AGA. There are a number of potential treatment
options for AGA currently under development, though in most
cases the clinical trial data proving hair growth efficacy remain
quite poor. The development of topically applied drug medi-
cations, injected or implanted biological materials, and locally
applied medical devices are the focus for multiple small-scale
pharmaceutical and startup companies.
6. Expert opinion
The potential market for effective AGA treatments is signifi-
cant with more than 50% of the general population affected
to some degree. The development of new AGA treatments is
quite pressing since current therapeutics are largely unsatis-
factory. Due to changing lifestyles and greater emphasis on
outward appearance, and with technological advancement
and biotech innovation, the global AGA therapeutic market
is expected to grow rapidly. However, current investigation of
new treatments remains restricted to small startup biotech
companies and academic research laboratories. The reluctance
of big pharma industry to get involved may be due to the
historical ‘snake oil’ reputation of the current market and the
lack of a comprehensive, coherent understanding of AGA
pathogenesis. Consequently, the field of AGA treatment
research and development still retains elements of a ‘wild
west frontier’ attitude.
The current recognized components of AGA pathogenesis
involve degrees of genetic predisposition, additional environ-
mental exacerbation which is poorly defined, production of
dihydrotestosterone (DHT) in skin, interaction of androgens
with their respective cell receptors, enhanced expression of
hair follicle growth suppressors, cell senescence, and variable
microinflammation of unknown significance. The modification
of hair follicle growth parameters, and thereafter hair follicle
cell loss, are assumed to be the critical factors in determining
AGA development. Research and development of new and
improved treatments has rapidly increased in the last
5 years, apparently undeterred by the still relatively limited
understanding of the AGA disease mechanism. Our review of
the current state of progress in the field revealed active devel-
opment of new therapeutics involving a wide range of
approaches focused on drugs, cells, and medical devices.
We propose that topically applied medications, or intrader-
mal injected or implanted materials, are preferable treatment
928 H. GUO ET AL.
modalities, minimizing side-effect risks as compared to sys-
temically applied treatments. Therapeutics which reverse the
androgen-driven inhibition of hair follicle developmental path-
ways, such as prostaglandin analogs and antagonists, PRP,
promotion of skin angiogenesis and perfusion, introduction
or promotion of progenitor cells for hair regeneration, and
perhaps more effective ways of transplanting hair follicles,
are the likely near future direction of AGA treatment develop-
ment. Combinations of therapies are likely to be more effica-
cious than single treatments. The further development of light
therapies and microneedling techniques could play adjuvant
roles in AGA treatment. Given the diversity of companies,
laboratories, and individuals involved in AGA research, and
the equally diverse range of approaches to treatment devel-
opment, we expect to see some significant new AGA treat-
ments come to market in the near future.
Funding
The authors are funded by the Canadian Dermatology Foundation and
Canadian Institutes of Health Research
Declaration of interest
K. J. McElwee is Chief Scientific Officer for Replicel Life Sciences Inc. The
authors have no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
from those disclosed.
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23. Zouboulis CC, Degitz K. Androgen action on human skin – from
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26. Urysiak-Czubatka I, Kmiec ML, Broniarczyk-Dyla G. Assessment of
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28. Lai JJ, Chang P, Lai KP, et al. The role of androgen and androgen
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29. Choudhry R, Hodgins MB, Van der Kwast TH, et al. Localization of
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37. Heilmann-Heimbach S, Herold C, Hochfeld LM, et al. Meta-analysis
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38. Brockschmidt FF, Heilmann S, Ellis JA, et al. Susceptibility variants
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39. Li R, Brockschmidt FF, Kiefer AK, et al. Six novel susceptibility Loci
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