DOI: 10.1111/exd.
12024
www.blackwellpublishing.com/EXD
Androgen actions on the human hair follicle: perspectives
Shigeki Inui and Satoshi Itami
Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University, Osaka, Japan
Correspondence: Shigeki Inui, MD, PhD, Department of Regenerative Dermatology, Graduate School of Medicine, Osaka University,
2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan, Tel.: +81-6-6879-3960, Fax: +81-6-6879-3962, e-mail: inui@r-derma.med.osaka-u.ac.jp
Abstract: Androgens stimulate beard growth but suppress hair
growth in androgenetic alopecia (AGA). This condition is known
as ‘androgen paradox’. Human pilosebaceous units possess
enough enzymes to form the active androgens testosterone and
dihydrotestosterone. In hair follicles, 5a-reductase type 1 and 2,
androgen receptors (AR) and AR coactivators can regulate
androgen sensitivity of dermal papillae (DP). To regulate hair
growth, androgens stimulate production of IGF-1 as positive
mediators from beard DP cells and of TGF-b1, TGF-b2, dickkopf1
and IL-6 as negative mediators from balding DP cells. In addition,
androgens enhance inducible nitric oxide synthase from occipital
Scope
Hair growth and cycling are regulated by many hormones (1),
and the effect of androgens, in particular, has been well known
for a long time. However, many questions about androgen metab-
olism and function in hair follicles remain unanswered. In this
review, we have examined published evidence and reconsidered
the perspective on molecular physiology and pathophysiology of
the effect of androgens on hair growth.
Clinical view of androgens and hair growth
Androgens regulate human hair growth, and their effects vary
depending on body sites. Before puberty, there is only vellus hair
in the pubic and axillary areas of males and females, but when
androgens increase in puberty, vellus hair follicles develop into
terminal ones, producing larger, curlier and darker hair shafts. In
males, androgens stimulate beard growth but suppress hair growth
in androgenetic alopecia (AGA) and this reciprocal effect is known
as the ‘androgen paradox’ (2,3). Historically, the first scientific
description of the effect of androgens on AGA was published by
James B Hamilton in 1942 (4) based on his clinical observation of
androgen induction of AGA in the males with testicular insuffi-
ciency. On the other hand, Margaret Chieffi was the first to scien-
tifically prove the positive action of androgen on beard growth in
males in clinical experiments to investigate the effect of testoster-
one injection on beard growth of elderly males (5). In male
pseudohermaphrodites, with 5aR2 deficiency, normal axillary and
female-pattern pubic hair growth but no or little beard growth
and no AGA is seen (6–9), indicating that 5aR2 is necessary for
beard growth and AGA development but not for pubic and axil-
lary hair growth. In female hirsutism patients, androgenic factors,
including polycystic ovary syndrome, are responsible for up to
80% of the condition (10), suggesting that androgens can regulate
hair growth in not only males but also in females, so that oral
antiandrogenic contraceptives are recommended as a first-line
treatment (11). Because the basic features of androgens in relation
to female hair growth and female AGA or female pattern hair loss
168
Viewpoint
DP cells and stem cell factor for positive regulation of hair growth
in beard and negative regulation of balding DP cells. Moreover,
AGA involves crosstalk between androgen and Wnt/b-catenin
signalling. Finally, recent data on susceptibility genes have
provided us with the impetus to investigate the molecular
pathogenesis of AGA.
Key words: 5a-reductase – androgen – androgen receptor – growth factor
– Wnt
Accepted for publication 31 August 2012
(FPHL) have not been sufficiently studied, the effect of androgen
on FPHL has been merely speculated on through clinical observa-
tion of antiandrogenic therapy. A controlled trial of oral cyproter-
one acetate (CPA) for FPHL showed that it significantly increases
the ratio of anagen to telogen in the fronto-cranial scalp (12).
However, Vexiau et al. (13) failed to show that CPA stimulates
hair growth in women with FPHL, and moreover, FPHL can also
occur in complete androgen insensitivity syndrome (14), speculat-
ing other possible pathogenetic factors besides an androgenetic
aetiology (15). Observation of the positive relationship between
hormones and axillary hair growth in 177 normal women has
suggested that weak adrenal androgens such as dehydroepiandros-
terone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S),
rather than testosterone, may play dominant roles in the preserva-
tion of female axillary hair (16).
Androgen metabolism in human pilosebaceous unit
The weak proandrogens DHEA and DHEA-S are mainly produced
from the adrenal cortex, while androstenedione is produced in
equal quantities from the adrenal cortex and ovaries, and in lesser
quantity by the testes (17,18). These prohormones are then
converted into more potent androgens such as testosterone and
dihydrotestosterone (DHT). Testosterone, a major circulating
androgen, is mainly produced by testes from puberty onward but
in reproductive-age females, it is secreted from the adrenal cortex
and ovaries through conversion from androstenedione. DHT is
synthesized in peripheral tissues including skin. In addition,
DHEA, DHEA-S and androstenedione are converted by sebocytes,
sweat glands and dermal papilla (DP) cells into more potent
androgens in the skin (19).
As the first step of androgen metabolism in human piloseba-
ceous units, steroid sulfatase in DP (20) can hydrolyze DHEA-S to
DHEA (Fig. 1). Next, 3b-hydroxysteroid dehydrogenase (3b-HSD)
type 1 in sebaceous glands (21) and DP (22) converts DHEA into
androstenedione. Furthermore, androstenedione is converted into
testosterone by 17b-hydroxysteroid dehydrogenase (17b-HSD),
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Experimental Dermatology, 2013, 22, 168–171

DHEA-S Estrone (E1)
Sulfotransferases Steroid sulfatase Aromatase
3β-HSD 5α-reductase
DHEA Androstenedione
17β-HSD 17β-HSD
3β-HSD 5α-reductase
Androstenediol Testosterone
Aromatase
17β-Estradiol (E2)
Figure 1. Androgen metabolism in skin. DHEA, dehydroepiandrosterone; DHEA-S,
dehydroepiandrosterone sulfate; 3b-HSD, 3b-hydroxysteroid dehydrogenase;
17b-HSD, 17b-hydroxysteroid dehydrogenase.
whose enzyme activity has been detected in DP (23). Additionally,
human sebaceous glands provide the cellular machinery for tran-
scribing the genes for 17b-HSD types 1–5 (21,24,25), indicating
the possible role of sebaceous glands for the regulation of local
androgen metabolism. Alternatively, DHEA can be converted into
androstenediol and testosterone by 17b-HSD and 3b-HSD in the
pilosebaceous unit, respectively and in that order (26). Cyto-
chrome P450 aromatase is required for bioconversion of andro-
gens to oestrogens. Aromatase activity is detectable in hair follicles
(27,28), and its expression in the outer root sheath of anagen hair
follicles and in sebaceous glands (29), suggesting the presence of a
local balance system for androgens and oestrogens and that hair
follicles function as oestrogen targets and sources (30). A compari-
son of aromatase content in frontal hair follicles from men and
women with pattern baldness has shown that it is six times greater
in women (27), which has led to speculation that this difference
may account for the difference in clinical presentations of pattern
baldness.
5a-reductase type 1 and 2
The two isoforms of human 5aR1 and 5aR2 are encoded by the
Steroid5-alpha-reductase 1 and 2 (SRDA1 and SRDA2) genes,
respectively. They convert testosterone to a more potent androgen
DHT in target cells. 5aR1 consists of 259 amino acids and has an
optimal pH of 6–9, whereas 5aR2 consists of 254 amino acids and
has an optimal pH of 5.5. 5aR1 is detected in various androgen-
independent organs such as liver and brain, while 5aR2 is
predominantly observed in androgen-dependent organs such as
epididymis and prostate (31). In 1972, Takayasu and Adachi first
identified 5a-reductase activity in human growing and resting hair
follicles plucked from male scalps and found that the optimal pH
was 7.5, not 5.5 (32). Consistent with this finding, it was reported
that an inhibitor of 5aR1 and 5aR1/2 can suppress endogenous
5a-reductase activity in plucked hairs from females but selective
5aR2 inhibitors cannot (33). These observations seem to indicate
that 5aR1 may be dominant in hair follicles. Another more recent
study detected activity of both 5aR1 and 5aR2 in microdissected
hair follicles and found that it was higher in balding hair follicles
than occipital hair follicles from both men and women (27). In
contrast with plucked hair follicles, beard DP cells show higher
5aR2 activity than occipital DP cells in vitro (34,35). At the
mRNA level, 5aR2 mRNA is higher in DP cells from AGA and
beard than in those from the occipital scalp while 5aR1 is equally
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Experimental Dermatology, 2013, 22, 168–171
Androgen actions on the human hair follicle
expressed in all scalp sites (36). These discrepancies may be
ascribed to differences in sampling and methodology but a more
plausible explanation has been provided by the report by Asada
(37) that 5aR1 mRNA is expressed in all components of scalp hair
5α-Androstenedione
follicles, but that 5aR2 mRNA is constitutively expressed only in
freshly microdissected scalp DP and connective tissue sheath. The
17β-HSD
expression of 5aR2 disappears during subcultivation, suggesting
that 5aR2 is unstable in scalp cells in vitro. Finally, the clinical
5α-dihydrotestosterone phenotype of pseudohermaphrodites with 5aR2 deficiency as men-
tioned above presents very strong evidence that beard and AGA
formation is dependent on 5aR2 activity but not 5aR1. As for
gender differences, 5aR1 and 5aR2 contents in female frontal hair
follicles were 3 and 3.5 times less than in male frontal follicles
(27), respectively, indicating that female AGA/FPHL is less depen-
dent on 5a-reductase, which may explain the inefficiency of finas-
teride for FPHL (38).
Androgen receptors
The action of steroid hormones including androgens is mediated
by the intracellular nuclear receptors, which function as hormone-
inducible transcription factors. Previously reported immunohisto-
chemical results for distribution of androgen receptors (AR) in
hair follicles were inconsistent as summarized in Table S1 (39–
50). AR is generally expressed in the DP and sebaceous glands,
but the results for its expression in follicular epithelium are con-
troversial, probably due to differences in the antibodies used and
in the skin portions of the hair follicles examined. More recent
data show that AR is not found in the outer root sheath, hair bulb
and bulge (45,48,49). In line with these results, endogenous AR
transactivity was undetectable in Hacat keratinocytes, indicating
that human keratinocytes are unlikely to be target cells for andro-
gens (51). In addition, AR expression was detected in only the DP
of red deer hair follicles (47). However, it may be possible that
AR is expressed in the hair epithelium of specific body sites or
hair diseases. Indeed, AR mRNA has been detected in the micro-
dissected inner and outer root sheath (37) of male and female
sexual hairs, and it was found that type I hair keratin hHa7 is
directly regulated by androgens through the androgen response
element in its promoter (49).
Previous semiquantitative RT-PCR as well as immunohisto-
chemical and hormone binding assays demonstrated that AR
expression is significantly higher in beard and AGA DP than in
non-bald occipital scalp cells (36,50,52–55), indicating that AR is
one of the key molecules which regulate androgen sensitivity in
DP. A recent study demonstrated that DNA methylation of the
AR promoter is increased in hair follicles from occipital scalp
compared with those from vertex AGA scalp, indicating efficacy
by the DNA methylation for protecting occipital hair follicles
against AR expression (56). Moreover, AR content in female fron-
tal hair follicles was found to be approximately 40% lower than in
male frontal follicles (27), again pointing to a possible cause of
the different presentations of pattern baldness.
Downstream androgen receptors and hair growth
Downstream of AR there are many AR coregulators such as
coactivators, integrators or corepressors. One of the AR coactiva-
tors, Hic-5/ARA55 (57), is highly expressed in DP cells from
androgen-sensitive sites such as AGA and beard, suggesting
that Hic-5/ARA55 can enhance androgen sensitivity in DP (58).
On the other hand, another in situ labelling study showed that
169
 Inui and Itami

expression of another AR coactivator, ARA70, was weaker in the
DP of balding recipient areas than in those from the donor areas
(59), thus indicating that selective AR coactivators may be
involved in the pathogenesis of AGA.
Embryonic induction of hair follicles and maintaining the func-
tional integrity of adult follicles are governed by the interaction
between DP and follicular epithelium, possibly through paracrine
mediators (60). Such mediators can, therefore, also be involved in
androgen regulation for hair growth. In a study using a coculture
system of outer root sheath cells and beard DP cells, IGF-1 was
first identified as a testosterone-inducible positive paracrine medi-
ator from beard DP cells (45) (Table S2). In addition, testosterone
reportedly induced autocrine stimulatory factors from beard DP
cells (61), which suggests that autocrine behaviour is also involved
in androgen regulation for beard growth. Furthermore, TGF-b1
(62,63), TGF-b2 (64), dickkopf1 (65) and IL-6 (66) have been
identified as androgen-inducible negative mediators for AGA
development in a number of studies using various in vitro experi-
mental methods (Table S2), thus providing new clues for clarify-
ing more details of androgen action in AGA. Moreover, the
finding that DHT increases inducible nitric oxide (NO) synthase
(iNOS) from occipital DP cells suggests that iNOS and NO are
downstream effectors of AR in DP cells (67) (Table S2). Other
reported findings are that beard DP cells produce more stem cell
factor (SCF) than non-balding scalp DP cells (68) and conversely
that balding DP cells produce less SCF than non-balding scalp DP
cells (69). However, testosterone did not alter the amount of SCF
from balding DP cells. These findings may link hair growth
regulation to melanocyte activity because this factor stimulates
melanogenesis (70).
Crosstalk between androgen and Wnt/b-catenin
signalling
The Wnt signalling pathway is essential for maintaining the hair-
inducing activity of DP cells (71) and for the development and
regeneration of hair follicles in vivo (72,73). Recent reports have
promoted the notion that crosstalk occurs between androgen and
Wnt/b-catenin signalling in AGA pathogenesis. DHT was shown
to suppress Hacat keratinocyte proliferation stimulated by Wnt-3a
in a coculture of Hacat and DP cells from AGA (74). It was also
found that DHT suppresses Lef/Tcf-mediated transcriptional activ-
ity in DP cells of AGA. However, these phenomena could not be
observed in DP cells of non-AGA males. Moreover, a very recent
study showed that DHT inhibits hair follicle stem (HFS) cell
differentiation, possibly through upregulation of glycogen synthase
kinase-b in DP cells, but that Wnt signalling activation by LiCl
restores the ability of DHT-treated DP cells to induce differentia-
tion in the coculture of HFS cells and DP cells from AGA (75).
These findings suggest that the crosstalk between Wnt/b-catenin
and androgen receptor signalling performs an important function
in androgen’s action on hair growth. Indeed, a recent phase 1 trial
revealed intradermal administration of a ‘Hair Stimulating
Complex’ containing Wnt and follistatin improved hair growth in
subjects with AGA (76). As HFS cells are preserved in AGA, these
signalling interactions represent potential therapeutic targets in
AGA (77).
Perspectives
Very recently, the large-scale meta-analysis of seven genome-wide
association studies for early-onset AGA in 12 806 European indi-
viduals identified susceptibility loci at chromosomes 1, 2, 7, 17,
18, 20 and X (78). Among the genes harbouring or nearest to the
SNP, FOXA2 encodes a transcription factor Foxa2, which interacts
with AR through DNA biding domain to regulate gene expression
(79), and HDAC4 (histone deacetylase 4) encodes HDAC4, which
plays a critical role in suppression of AR transcriptional activity
through interacting with other transcriptional factors such as
androgen receptor corepressor-19 (80) and CR6-interacting factor
1 (81). From these findings, the regulation of AR transcriptional
activity is critical for AGA development. In this line, AR coactiva-
tors/coreppressors and other pathways influencing AR activity can
be hopeful targets to study for delineating AGA pathogenesis. On
the other hand, the recent microarray study using human scalp
skin revealed that prostaglandin D2 synthase (PTGDS) is elevated
at the mRNA and protein levels in bald scalp compared with
haired scalp of men with AGA and the product of PTGDS enzyme
activity, prostaglandin D2 is similarly elevated in bald scalp (82),
suggesting that pathogenic mechanisms beyond androgen pathway
play important roles in AGA. Alternatively, there may be any link-
age between AR and prostaglandin D2. We are still on the way to
figure out the complex physiological and pathogenic network in
androgen regulation for hair growth and AGA pathogenesis.
Acknowledgement
We appreciate helpful discussion for this manuscript with Dr. Oh Sang
Kwon at Department of Dermatology, Seoul National University College of
Medicine. Writing of this viewpoint was supported in part by Grants-
in-Aid for Scientific Research (KAKENHI) to Sh I. Sh I wrote the study,
and Sa I revised it critically and approved the submitted and final version.
Conflict of interests
The authors have declared no conflicting interests.

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Supporting Information
Additional Supporting Information may be found in
the online version of this article:
Data S1. Impetus from genetic studies of AGA.
Table S1. Summary of immunohistochemical studies
of androgen receptor localization in pilosebaceous unit.
Table S2. Summary of cell culture studies of andro-
gen-inducible factors in dermal papilla cells.
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