Dermatologic Therapy, Vol. 21, 2008, 314–328 © 2008 Wiley Periodicals, Inc.

Printed in the United States · All rights reserved

DERMATOLOGIC THERAPY
ISSN 1396-0296

Androgens and hair growth

Blackwell Publishing Inc

VALERIE ANNE RANDALL

Centre for Skin Sciences, School of Life Sciences, University of Bradford,
Bradford, UK

ABSTRACT: Hair’s importance in human communication means that abnormalities like excess hair
in hirsutism or hair loss in alopecia cause psychological distress. Androgens are the main regulator of
human hair follicles, changing small vellus follicles producing tiny, virtually invisible hairs into larger
intermediate and terminal follicles making bigger, pigmented hairs. The response to androgens varies
with the body site as it is specific to the hair follicle itself. Normally around puberty, androgens stimu-
late axillary and pubic hair in both sexes, plus the beard, etc. in men, while later they may also inhibit
scalp hair growth causing androgenetic alopecia. Androgens act within the follicle to alter the mesen-
chyme–epithelial cell interactions, changing the length of time the hair is growing, the dermal papilla
size and dermal papilla cell, keratinocyte and melanocyte activity. Greater understanding of the
mechanisms of androgen action in follicles should improve therapies for poorly controlled hair
disorders like hirsutism and alopecia.

KEYWORDS: alopecia, balding, hirsutism, hormones, review

our hair when cold or nervous (goosebumps)

Introduction indicate the evolutionary history. The visible hairs
produced in childhood are mainly protective;
Functions of human hair eyebrows and eyelashes stop things from entering
Human hair growth is very important to our the eyes, while scalp hair probably protects the
health and well-being. This is despite its growth head and neck from sunlight, cold, and physical
being so reduced compared to most other mammals damage (6). Head hair is also important for social
that we are termed the “naked ape.” Although communication. Good scalp hair signals health,
often seen as rather irrelevant medically because contrasting with the sparse, brittle hair seen during
human hair loss is not life-threatening, hair is disease or starvation (7). Many cultures across
highly significant for people in many different history exhibit customs involving head hair. Hair
cultures around the world (1,2). Many Western removal generally has strong depersonalizing roles,
men spend a great deal of time and effort shaving for example, shaving prisoners and Christian or
daily, while “having a bad hair day” is a common Buddhist monks, or covering female hair, while
expression for days when everything goes wrong! long uncut hair has positive connotations like
This reflects the important roles hair plays in Samson’s strength in the Bible or among Sikhs.
human communication in both social and sexual Human hair is also involved in sexual commu-
contexts. nication. The development of visible pubic and
Human hair’s main functions are protection axillary hair signals puberty in both sexes (8–10),
and communication; it has virtually lost the while men exhibit sexual maturity with visible
insulation and camouflage roles important in beard, chest, and upper pubic diamond hair
mammals (1), although seasonal variations in (FIG. 1) (10). The beard’s strong signal of mascu-
growth (3–5) and our remaining ability to erect linity and its potential involvement in threatening
display behavior like the lion’s mane (2,6,11) may
Address correspondence and reprint requests to: Professor explain its common removal. These important
Valerie Anne Randall, School of Life Sciences, The University of communication roles explain why hair disorders
Bradford, Bradford BD7 1DP, UK, or have serious psychological consequences and
email: [Link]@[Link]. negative impact on the quality of life even among

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 Androgens and hair growth

FIG. 1. Human hair patterns under differing endocrine conditions.

Visible (i.e. terminal) hair with protective functions normally develops in children on the scalp, eyelashes, and eyebrows. Once
puberty occurs, more terminal hair develops on the axilla and pubis in both sexes and on the face, chest, limbs, and often on
the back in men. Androgens also stimulate hair loss from the scalp in men with the appropriate genes in a patterned manner
causing androgenetic alopecia. People with various androgen insufficiency syndromes (lower panel) demonstrate that none of
these occurs without functional androgen receptors and that only axillary and female pattern of lower pubic triangle hairs are
formed in the absence of 5α α-reductase type 2. Male pattern hair growth (hirsutism) occurs in women with abnormalities of
plasma androgens or from idiopathic causes and women may also develop a different form of hair loss, female androgenetic
alopecia. Reproduced from Randall 2000 (132).

people who have never sought medical help (12). loss) (14). Whether the high incidence of androge-
These include both excessive hair growth, such as netic alopecia indicates a natural phenomenon,
hirsutism, or drug-induced abnormal hair growth, that is, a secondary sexual characteristic, rather
and hair loss, such as alopecia areata, an auto- than a disorder can be debated (1), but in the
immune disease affecting both sexes (13) or even current youth-oriented culture, looking older is
androgenetic alopecia (common male-pattern hair not beneficial.

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Randall

until puberty most hair produced is so tiny and

Hormonal control
virtually colorless (vellus hair) that this is not well
Hair is produced by the hair follicle, a highly recognized; many people think that children’s hair
dynamic organ only found in mammals and crucial is only found on the head, eyebrows, or eyelashes
for their evolutionary success. It has an almost unique as they only notice the protective larger, and
ability in mammals to regenerate itself during more pigmented, terminal hairs (FIG. 1). Outside
regular hair cycles which each produce a new hair, the skin hairs are flexible tubes of dead, fully
the previous hair being shed (15,16). Hormones keratinized epithelial cells that vary in thickness,
coordinate hair growth with an individual mam- length, cross-sectional shape, and color. They are
mal’s age and stage of development or alterations produced by individual living hair follicles,
to their environment, like day-length or tempera- cylindrical epithelial downgrowths into the dermis,
ture (1,17). Follicles undergo appropriate changes and subcutaneous fat that enlarge at the base
in response to hormonal instructions so that during into the hair bulb surrounding the regulatory
the next hair cycle, the new hair produced may mesenchyme-derived dermal papilla (FIG. 2) (23).
differ in color and/or size like the white winter, Unlike other organs, the hair produced by a hair
but brown summer coat of the Scottish hare (18). follicle frequently needs to be changed because of
The main hormones regulating changes in human its important roles in camouflage, temperature
hair follicles are the androgens. regulation, such as developing a thicker coat for
Androgens stimulate tiny vellus follicles pro- cold winters, or social and sexual signaling, like
ducing fine, virtually colorless, almost invisible the lion’s mane or a man’s beard. Hair follicles
hairs in many parts of the body to transform into possess a unique ability in a mammalian tissue of
larger, deeper follicles forming longer, thicker, being able to partially regenerate via the hair
more pigmented hairs (FIG. 2). Although andro- follicle growth cycle (15,16,24), replacing a hair
gens stimulate hair growth in the axilla and pubis with a new one that may differ from the previous
of both sexes (8–10) and greater hair on the face, one in size or color (18) or be the same like
upper pubic diamond, chest, etc. in men (19), human eyelashes (FIG. 3). Exactly how differently
they can also have the opposite effect on specific sized a hair can be to its immediate predecessor
scalp areas, often in the same individual, causing is currently unclear because many changes take
balding (20). This involves the reverse transforma- several years like producing a full beard (19). Hair
tion of large, deep follicles producing long, follicles pass through many cycles during an
often heavily pigmented terminal scalp hairs to individual’s life each consisting of a growth phase,
miniaturized vellus follicles forming tiny, almost anagen, during which the hair is produced, a short
invisible hairs (FIG. 2). In this way, human follicles regressive stage, catagen, and a resting phase,
pose a unique endocrine paradox as the same telogen (FIG. 3). The upper parts of the hair
hormones, the androgens, cause enlargement of follicle, the infundibulum and the isthmus, are
an organ, the hair follicle, in many areas while permanent, whereas the lower follicle, the
simultaneously inhibiting the same organ on the suprabulbar area and the hair bulb, regenerates in
scalp causing balding (1,21,22). the anagen phase of each hair follicle cycle.
This paper focuses on the effects of androgens
on human hair follicles. It also outlines important
The hair follicle growth cycle
background information about how a follicle
alters the type of hair it produces, how hormones In anagen, the hair bulb contains extensively dividing
affect other mammals’ hair growth, seasonal variation keratinocytes and pigment-producing melano-
in human scalp and androgen-stimulated hair growth, cytes of the hair matrix surrounding a pear-shaped
and the effects of other hormones on human hair dermal papilla. The dermal papilla consists of
growth. specialized fibroblast-type cells embedded in an
extracellular matrix and separated from the kerat-
inocytes by a basement membrane (25). Under
Changing the hair produced by a dermal papilla cell regulation (26,27), the hair matrix
follicle via the hair growth cycle keratinocytes divide and move upwards differenti-
ating into the various layers of the hair and its sur-
rounding inner root sheath; matrix melanocytes
Human hair follicles
transfer pigment into the developing hair kerati-
Human skin produces hair everywhere except for nocytes to give the hair color. Surrounding the
the glabrous skin of the lips, palms, and soles, but inner root sheath, the epithelial outer root sheath

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 Androgens and hair growth

FIG. 2. Androgens have paradoxically different effects on human hair follicles depending on their body site.
During, and after, puberty androgens stimulate the gradual transformation of small follicles producing tiny, virtually colorless,
vellus hairs to terminal follicles producing longer, thicker and more pigmented hairs (upper panel) (19). These changes involve
passing through the hair cycle (see FIG. 3). At the same time many follicles on the scalp and eyelashes continue to produce the
same type of hairs, apparently unaffected by androgens (middle panel). In complete contrast, androgens may inhibit follicles
on specific areas of the scalp in genetically susceptible individuals causing the reverse transformation of terminal follicles to
vellus ones and androgenetic alopecia (20). Diagram reproduced from Randall 2000 (132).

317
Randall

FIG. 3. The hair follicle growth cycle.

Hair follicles go through well-established repeated cycles of development and growth (anagen), regression (catagen), and rest
(telogen) (1,2) to enable the replacement of hairs, often by another of differing color or size. An additional phase, exogen, has
been reported where the resting club hair is released (42–44).

contains both the epithelial (28,29) and melano- which grows back down into the dermis, inside
cyte stem cells (30) in its permanent mid-region the guidelines of the dermal sheath which sur-
and becomes continuous with the epidermis at rounded the previous follicle. The new hair then
the skin surface. The connective tissue, or dermal, grows up into the original upper follicle (FIG. 3).
sheath encloses the follicle, separating it from the The existing hair is generally lost; although previ-
dermis. The dermal papilla produces paracrine ously thought due to the new hair’s upward move-
factors determining the size and color of the hair ment (24), a further active shedding stage, exogen,
produced (26,27,31); it is also believed to interpret involving the activation of proteolytic processes
circulating signals such as hormones for the has now been identified (42–44).
follicle (1,21) (discussed in 5). Although the cell
biology and biochemistry of hair growth are not
Significance of the hair cycle for hair length
fully clarified, factors implicated in anagen so far
include insulin-like growth factor-I (IGF-I) (32), The length of the hair cycle stages varies dramati-
keratinocyte growth factor (KGF) (33), hepatocyte cally in different parts of the human body (45).
growth factor (HGF) (34), noggin, and bone Scalp follicles have the longest anagen phases,
morphogenic protein (BMP)/Wnt5a (35) (reviewed which can last up to several years; waist length
in (36–38)). In addition, stem cell factor (SCF) hair will have grown for about 7 years. They have
from the dermal papilla (39,40) is essential for a much shorter catagen phase (1–2 weeks) and a
the proliferation, differentiation, and melanin telogen phase lasting several months. This means
production by follicular melanocytes expressing that the majority of normal scalp follicles are in
its receptor c-kit (40,41). anagen (80–85%), with the rest either in catagen
Once a hair reaches its full length, a short involu- (2%) or in telogen (10–15%), though this varies
tion phase, catagen, occurs. During this phase where with the time of the year for people living in
cell division and pigmentation stops, extensive temperate zones (see Seasonal changes in human
apoptosis occurs, and the dermal papilla shrinks; hair growth). The anagen phase in other body
the hair becomes fully keratinized with a swollen regions is substantially shorter; on the arms, legs,
“club” end and moves up in the skin with the and thighs it is about 3 to 4 months (45). Anagen
regressed dermal papilla, stopping near the arrector length generally determines hair length; long
pili muscle insertion. After a period of rest, telogen, scalp hairs are produced by follicles with anagen
the dermal papilla cells and associated keratinocyte periods of over 2 years, while short finger hairs
stem cells reactivate and the cycle begins again; only grow for around 2 months (45). The rate
another anagen phase develops a new lower follicle of hair growth varies much less over the body

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 Androgens and hair growth

usually being close to 0.3–0.4 mm per day (45,46). levels are negatively correlated with hair loss
This means that to change the amount of hair in rhesus macaque monkeys (56). In contrast,
produced for clinical reasons the main target is to thyroid hormones in rodents advance anagen
alter the length of anagen either by decreasing it while thyroidectomy or propylthiouracil delays it
for hirsutism or by increasing it for alopecia. (17,50). How these circulating hormones interact
is still unclear, but the main drivers in seasonal
coat changes are light, melatonin, and prolactin.
Hormonal factors affecting
mammalian hair growth Seasonal changes in human hair growth
Mammalian hair follicles, including human Seasonal alterations are much less obvious in human
follicles, are under hormonal regulation due to the beings, where follicle cycles are not usually
importance of coordinating alterations in insula- synchronized after the first year, other than in
tive and color properties of a mammal’s coat to groups of three follicles called Demeijère trios
the environment or its visibility to changes in (45). Regular annual cycles in human scalp (3–5)
sexual development. This is of life-threatening and beard and other body hair growth (3) were
importance to many mammals as too thin or only recognized relatively recently. Scalp hair
incorrectly colored hair could mean death from showed a single annual cycle with over 90% of
cold or predation. follicles in anagen in the spring, falling to around
80% in autumn in 14 healthy Caucasian men
aged 18–39 in Sheffield, UK (latitude 53.4°N); the
Hormonal coordination of seasonal changes
number of hairs shed in the autumn also more
in animals
than doubled (3). Similar increased autumnal
Seasonal changes usually occur twice a year in hair shedding has been reported in New York
many mammals living in temperate or polar women (4) and French men (5). Since scalp hair
regions with coordinated waves of growth and usually grows for at least 2–3 years and often
moulting to produce thick, warm winter coats longer (45), detection of an annual cycle indicates
and shorter summer pelage. These are linked to a strong response to seasonal hormonal changes
day-length and, to a lesser extent, temperature, such by any follicles able to react, presumably those in
as seasonal breeding activity (17,47). Nutrient later stages of the hair anagen phase.
availability can also affect hair type because of the Androgen-dependent body hair also showed
high metabolic requirements of hair production annual changes in men (3). Winter beard and
(48). Studies in many species show that long thigh hair growth rate were low, but increased
daylight hours initiate short periods of daily significantly in the summer (see (1)). French men
melatonin secretion by the pineal and summer coat showed similar summer peaks in semen volume,
development, while short day-length increases sperm count and mobility (57) suggesting androgen-
melatonin secretion and stimulates a longer, related effects, while higher summer testosterone
warmer pelage (47,49 reviewed in 1,17). The pineal levels with lower winter values were also reported
gland acts as a neuroendocrine transducer in European men (58,59) and pubertal boys (60).
converting nerve impulses stimulated by daylight Although testosterone changes probably alter
to reduced secretion of melatonin, normally beard and thigh hair growth, they seem less likely
secreted during the dark. Melatonin signals are to regulate scalp follicles as women also show
generally translated to the follicle via the hypo- seasonal changes. Annual fluctuations of thyroid
thalamus–pituitary route; prolactin particularly, hormones, with peaks of thyroxine (T3) in September
but also growth hormone and IGF-1 are impli- and free triiodothyronine (T4) in October (61),
cated at the follicle level (reviewed in 1). could also influence scalp growth, but hypothy-
Other hormones implicated in regulating roidism is normally associated with hair loss (62).
mammalian hair growth cycles include the sex Thigh follicles also showed biannual changes in
steroids, estradiol and testosterone, and the the numbers of hairs actually growing, reaching
adrenal steroids (1,17); these delay anagen in rats 80% in May and November, but falling to around
(17,50). Topical application of 17β-oestradiol to 60% in March and August (3). This pattern is
mice skin inhibits hair growth and accelerates similar to the spring and autumn moults of many
catagen, while antiestrogens promote early anagen temperate mammals and our seasonal study
(51–54). Testosterone also delays seasonal hair population definitely exhibited seasonal behavior
growth in badgers (55), while urinary cortisol despite indoor occupations (3); these cycles are

319
Randall

presumably controlled like those discussed earlier

Androgens have paradoxically different effects
in “Hormonal coordination of seasonal changes in
on human hair follicles
animals.” Human beings can respond to altered
day-length by changing melatonin, prolactin, and The importance of androgens is shown when
cortisol secretion, but artificially manipulated pubertal pubic and axillary hair develops (8–10) in
urban lighting suppresses these responses (63). girls before boys (73,74), paralleling increasing
Nevertheless, people in Antarctica (64) and those circulating androgens. Testosterone also stimulates
with seasonal affective disorder (65) maintain beard growth in eunuchs and elderly men (75),
melatonin rhythms. while castration inhibits beard (19) and balding (76).
The roles of androgens and androgen receptors in
Significance of annual seasonal human hair changes adult hair are emphasized in XY individuals with
for patients and therapies. These annual changes complete androgen insufficiency, i.e., unable to
are important for any investigations of androgen- respond to androgens due to dysfunctional androgen
dependent or scalp hair growth, particularly in receptors (77); they develop a female-type pheno-
individuals living in temperate zones. Hair loss may type, but lack pubic and axillary hair or androgenetic
be exacerbated during the increased autumnal alopecia (FIG. 1). Sexual hair development is inhibited
shedding in both male and female patients. in growth hormone deficiency (78), suggesting that
They also have important implications for any growth hormone is also essential.
assessments of new therapies or treatments to When androgens stimulate the tiny vellus follicles
stimulate, inhibit, or remove hair; to be accurate, to produce longer, thicker, more pigmented hairs
measurements need to be carried out over a (FIG. 2), the follicles must pass through the hair
year to avoid natural seasonal variations. cycle, regenerating the lower follicle to carry out
such changes (see “The hair follicle growth cycle”).
Although androgens stimulate hair growth in many
Androgen regulation of human hair areas, causing greater hair on the face, upper pubic
growth diamond, chest, etc. in men (19), they can also
have the opposite effect on specific scalp areas,
often in the same individual, causing balding (20).
Endocrine control of human hair growth
This involves a reverse transformation via hair
Androgens are the clearest regulators of human hair follicle cycles, changing large, terminal follicles
growth, as long as individuals have good nutrition producing long, often heavily pigmented scalp
(7,66) and normal thyroid function (62,67); hairs to miniaturized vellus follicles forming tiny,
hypothyroidism is associated with hair loss (62). almost invisible hairs (FIG. 2). This balding usually
Pregnancy hormones also alter hair growth, keep- occurs in men in a precise pattern starting with
ing follicles in anagen, but many enter catagen regression on the forehead and thinning in the
and telogen postpartum, causing diffuse hair loss center of the vertex and may continue exposing large
due to a synchronized partial shedding or moult areas of scalp (20,79); the lower sides and back
(68). Hair loss can be obvious in the autumn due normally retain terminal hair. A different pattern
to seasonal shedding (see Seasonal changes in of androgen-dependent alopecia may present
human hair growth): which hormones control this in women; the frontal hairline usually remains
shedding is unclear, but estrogen and prolactin unaffected while generalized thinning occurs on
are possible. Human follicles have prolactin (69) the central scalp and vertex (80) (FIG. 1). Andro-
and 17β-estradiol (70) receptors, but 17β-estradiol genetic alopecia is reviewed elsewhere (14). At the
inhibits cultured human follicles (71) and rodent same time, androgens have no apparent effect in
hair growth, stimulating catagen (52–54), the other areas such as the eyelashes (FIG. 2). How
opposite to pregnancy. Prolactin reduces human does this paradoxical effect occur of one hormone
follicular growth in vitro (69) supporting a role in frequently stimulating hair follicles, but also
postpartum shedding. Estrogens are used as having no effect or inhibiting the same organ in
treatment for androgen-dependent disorders, but the same person?
their effects are probably due to interfering with There are also significant differences between
androgen action, for example, by reducing androgen androgen-stimulated follicles. Female androgen
availability by increasing blood sex hormone levels affect axillary and lower pubic follicles,
binding levels, rather than direct effects on hair while other follicles require male levels (72,73).
follicles. The role of estrogens in hair growth is Follicle sensitivity also varies; facial follicles
currently under investigation (71,72). enlarge first above the mouth (moustache) and on

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 Androgens and hair growth

the chin in boys and hirsute women, spreading with androgen metabolism or receptors (reviewed
gradually over the face and neck (10). Similar (1)). Interestingly, women with polycystic ovaries
gradual progression occurs elsewhere taking and their brothers with early balding show links to
many years to show the full response like on a the steroid metabolism gene, CYP17 (90). A recent
man’s chest (19) or balding (20,79); terminal hairs study of androgenetic alopecia families suggests a
may only appear on the ear canal in the fifties new susceptibility gene on chromosome locus
(49). Interestingly, these slow changes resemble 3q26 (91).
the late androgen-dependent responses in the
prostate-causing prostatic benign hypertrophy
and carcinoma (81). Beard and axillary hair How do androgens carry out these
growth show another paradox; after their pubertal changes?
growth spurt, beard growth remains high, while
axillary hair growth decreases rapidly in both
General mechanism of action of androgens
sexes (19).
Steroid hormones diffuse through cell membranes
to act on target cells by binding to specific intrac-
Why do follicles respond so differently?
ellular receptors. These hormone-receptor complexes
These contrasts must be due to intrinsic differences undergo conformational changes, exposing DNA
in gene expression within follicles at different sites, binding sites, and bind to specific DNA hormone
since all receive the same circulating hormones response elements (HRE) often in combination
and use the same receptors. A follicle’s retention of with accessory (coactivating) proteins, promoting
its original androgen response when transplanted, expression of specific, hormone-regulated genes.
the basis of cosmetic hair transplants, confirms Androgen action is more complex than other
this (82). Presumably, this genetic programming steroids (92). The main male androgen, testosterone,
occurs during embryonic patterning processes. The binds receptors in some tissues, for example,
molecular mechanisms involved in the develop- skeletal muscle; in others, including secondary
ment of different follicle types are not clear, but sexual tissues like prostate, testosterone is meta-
secreted signaling factors (such as Eda, sonic bolized intracellularly by 5α-reductase to more potent
hedgehog, Wnt) and various growth factor families 5α-dihydrotestosterone (DHT), which binds more
(like the BMPs), nuclear factors (including various strongly to the androgen receptor (see FIGS 4 and
homeobox genes), and others such as Hairless 5) (93).
and Tabby, plus transmembrane and extracellular
matrix molecules are all implicated (83,84).
The mechanism of androgen action in hair
Human follicles require androgens to initiate
follicles
these marked changes. However, if adult men are
castrated, although beard growth falls (19) and Androgen-dependent follicles all require androgen
balding halts (85), neither returns to prepubertal receptors to respond (“Endocrine control of human
levels, indicating that androgens have altered hair growth”), but the need for 5α-reductase varies
some gene expression permanently or that the with body region. Men with 5α-reductase type 2
lower androgen levels provided by the adrenals deficiency only produce female patterns of pubic
can maintain a partial effect. Increased summer and axillary hair growth (94) (FIG. 1), indicating
beard growth (3), probably due to raised andro- that DHT is necessary for male-specific follicles
gens (Seasonal changes in human hair growth), like beard, while testosterone can stimulate the
and inhibition of hirsutism (86) or regrowth stim- axilla and pubic triangle in both sexes. Why
ulation in androgenetic alopecia (87,88) by drugs some follicles need DHT and others testosterone
interfering with androgen action confirms that to stimulate the same cell biological changes
androgens are also needed to maintain follicular is unclear; presumably, the cells use different
responses. intracellular coactivating proteins to act with the
Genetics also appears important (reviewed in receptor. Since 5α-reductase type 2 deficient men
1). Heavy beard growth (19) and balding (75) run do not show alopecia and the 5α-reductase type 2
in families and Caucasians generally exhibit inhibitor, finasteride, can restore hair growth (87),
more hair than Japanese (19) and more baldness 5α-reductase type 2 also seems important for
than Africans (89). Several genes have been inves- androgen-dependent balding. Skin contains many
tigated for association with androgen-sensitive enzymes that can metabolize weak androgens,
hair disorders with some links with those involved like dehydroepiandrosterone, to more powerful

321
Randall

FIG. 4. Simple schematic of the general mechanism of androgen action.

Androgens diffuse from the blood through the plasma membrane. Inside the cell, like other steroid hormones, testosterone may
bind to specific androgen receptors (upper scheme). This occurs in many tissues such as skeletal muscle and axillary and pubic
hair follicles. However, in certain tissues, particularly the secondary sexual organs such as prostate or beard and balding hair
follicles, testosterone is metabolized to the more potent androgen, 5αα-dihydrotestosterone (lower scheme). If both are available
in similar quantities, the receptor will bind 5αα-dihydrotestosterone. Once hormone has bound, the receptor complex
undergoes a conformational change, exposing DNA binding sites, and the hormone-receptor complex, in conjunction with
other coactivating proteins, will bind to specific hormone response elements (HREs) in the DNA altering the expression of
specific androgen-dependent genes.

ones, or testosterone and androstenedione to

Current model for androgen action in hair
estrogens, 17β-estradiol or estrone (see FIG. 5).
follicles
However, hairs’ absence when androgen receptors
are dysfunctional (“Endocrine control of human Hair follicle growth is complex but rarely abnormal
hair growth”) indicates that androgens binding to indicating a highly controlled system. This sug-
the receptor, i.e., testosterone and DHT, are the gests that androgen action is coordinated through
most important. one part of the follicle. The current hypothesis,
proposed in 1990 by Randall et al. (98), focuses
on the dermal papilla with androgens acting directly
Specific effects of androgens on hair follicle cells
on dermal papilla cells where they bind to androgen
Androgens must alter many aspects of follicular receptors and then initiate altered gene expression
activity to change the hair produced. They must of regulatory factors which influence other target
modify the ability of epithelial matrix cells to divide, cells (FIG. 6). These factors could be soluble para-
determine whether they should differentiate into crine factors and/or extracellular matrix factors;
the central medulla (found in some large hairs), extracellular matrix forms much of the papilla
and regulate the pigment (color) produced and/or volume and dermal papilla size corresponds to
transferred by follicular melanocytes. They hair and follicle size (95,96). In this model, the
must also change dermal papilla size, as this is dermal papilla is the primary direct target, while
proportional to the hair and follicle size (95,96), other cells such as keratinocytes and melanocytes
and ensure that the surrounding dermal sheath are indirect targets.
adjusts to fit the new sized follicles. Androgens This hypothesis evolved from several concepts
definitely alter these aspects as interfering with (reviewed in 21,98) including: dermal papilla
androgen action reduces hair diameter, growth determination of the hair type produced (27);
rate, length, pigmentation, and medullation in adult follicle cycles partially recapitulating their
hirsute women (97) and increases them in alopecia embryogenesis; strong parallels in androgen-
(87). dependency and age-related changes between

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 Androgens and hair growth

FIG. 5. Androgen metabolism.

Circulating androgens such as testosterone from the testis in men and weaker androgens such as dehydroepiandrosterone and
androstenedione from the adrenals and ovaries in women can be metabolized in many skin tissues. Some metabolism causes
α-dihydrotestosterone (DHT) as the androgen receptor binds DHT more
an increase in potency, e.g., from testosterone to 5α
strongly even than testosterone, another potent androgen. Other metabolisms form weaker androgens normally involved in
excretion pathways, e.g., the androstanediols or steroids which act via the other steroid receptors, i.e. the estrogens.

follicles and prostate; and androgens acting on because of hair’s necessity for mammalian survival
embryonic prostate epithelium via the mesenchyme and/or sheath cells may respond directly to androgens
(81). This model now has strong experimental support. to facilitate alterations in sheath, or dermal papilla,
Androgen receptors are found in the dermal size to form a differently sized follicle.
papilla and cultured dermal papilla cells derived Investigations into keratins in the hair medulla
from androgen-sensitive follicles including beard, (only seen in the middle of large human hairs)
balding scalp, and deer manes (99–103). Cells from found a specialized keratin, hHa7, in beard, pubic,
androgen-sensitive sites contain higher levels of and axillary hair (109). Beard medulla cells showed
specific, saturable androgen receptors than androgen- coexpression of keratin hHa7 and the androgen
insensitive ones (99,101,102). Importantly, beard, receptor. Since the hHa7 gene promoter also
but not pubic or nonbalding scalp, dermal papilla contained sequences with high homology to the
cells metabolize testosterone to DHT in vitro (104– androgen response element (ARE), keratin hHa7
106), reflecting hair growth in 5α-reductase defi- expression may be androgen-regulated. However,
ciency; 5α-reductase type 2 gene expression also no stimulation occurred when the promoter was
supports this (103). transfected into prostate cells and keratin hHa7
However, some recent observations suggest with the same promoter is also expressed in
minor modifications. It is now clear that the der- androgen-insensitive body hairs of chimpanzees
mal sheath has other roles as well as isolating the making the significance unclear. Nevertheless, the
follicle; it can form a new dermal papilla and current model needs modification to include
stimulate follicle development (107). Cultured possible specific, direct action of androgens on
dermal sheath cells from beard follicles contain lower dermal sheath and medulla cells.
similar levels of androgen receptors to dermal
papilla cells (personal observations) and balding
The alteration of signaling molecules in the hair
dermal sheath express 5α-reductase type 2 mRNA
follicle by androgens
(108), indicating that the dermal sheath can
respond to androgens without the dermal papilla The last aspect of androgen action involves the
acting as an intermediary. The sheath may be a alteration of paracrine signaling factors produced by
reserve to replace a lost dermal papilla’s key roles dermal papilla cells. Although paracrine signaling

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FIG. 6. Model of androgen action in the hair follicle.

In the current hypothesis androgens from the blood enter the hair follicle via the dermal papilla’s blood supply. If appropriate
they are metabolized to 5αα-dihydrotestosterone (DHT) (see FIG. 4). They bind to androgen receptors in the dermal papilla cells
causing changes in their production of regulatory paracrine factors; these then alter the activity of dermal papilla cells,
follicular keratinocytes, and melanocytes. T = testosterone; ? = unknown paracrine factors. Reproduced from Randall 2000
(132).

in developing and cycling follicles is currently a This all supports the model (FIG. 6) and shows that
major research focus, there are few practical animal the paradoxical androgen effects in vivo are reflected
models for studying androgens (110) because of in vitro, strengthening the use of cultured dermal
their special effects on human follicles. Cultured papilla cells as an in vitro model system.
dermal papilla cells from follicles with different Identifying the factors androgens alter could
sensitivities to androgens offer a useful, though lead to novel treatments for hair disorders. So far,
difficult to work with model in which to study only insulin-like growth factor (IGF-1), a potent
androgen effects (reviewed in 1). They secrete both mitogen, is identified as secreted by beard cells under
extracellular matrix (111) and soluble proteina- androgens in vitro (100). Beard cells also secrete
ceous factors that stimulate growth in other dermal more SCF than nonbalding scalp cells (118), while
papilla cells and various epithelial cells (98,112– balding cells produce less (119). Since SCF plays
114). Soluble factors from human cells can cross important roles in hair pigmentation (reviewed in
species affecting rodent cell growth in vitro and in 119), the dermal papilla probably provides local
vivo (115), paralleling the ability of human dermal SCF for follicular melanocytes. Androgens in vivo
papillae to induce hair growth in vivo in athymic appear to alter scf expression by facial dermal
mice (116). papilla cells to change melanocyte activity thus
Importantly, testosterone in vitro increases the altering hair color (119). Recently, DNA microarray
ability of beard cells to promote increased growth methods also revealed that three genes, sfrp-2,
of other beard dermal papilla cells and kerati- mn1, and atp1β1, were expressed at significantly
nocytes (112–114) but decreased that of androge- higher levels in beard than normal scalp cells, but
netic alopecia dermal papilla cells from both no changes were detected due to androgen in vitro
men (114) and stump-tailed macaques (117). This (120). Despite difficulties in culturing androgenetic
implies that an autocrine mechanism is involved; alopecia dermal papilla cells (121), androgens
androgen-mediated changes do involve alterations inhibit their expression of protease nexin-1, a potent
in dermal papilla cell numbers as well as the amount inhibitor of serine proteases, which regulate
of extracellular matrix (96). A need to modify the cellular growth and differentiation in many tissues
autocrine production of growth factors could (122). Androgens also stimulate their production of
contribute to the slow androgenic response that transforming growth factor-β (TGF-β) and TGF-β2
often takes many years to reach full effect (19). (123,124) and dickkopf 1(DKK1) (125). TGF-β is a

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strong candidate for an inhibitor of keratinocyte biology, particularly androgen action, should lead
activity in alopecia (reviewed in 1), although TGF-β2 to new ways to treat hair disorders.
and TNF-α were actually slightly reduced in bald-
ing cells in a limited DNA macroarray analysis
(126). Thus, studying dermal papilla cells implicates
several factors already: IGF-1 in enlargement; SCF References
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