Chapter

Androgens and hair: a biological paradox

7 with clinical consequences

Valerie Anne Randall

7.1 Introduction 154 7.5 Androgen-dependent hair growth

7.2 Structure and function of the hair follicle 156 conditions 164
7.2.1 The roles of human hair 156 7.5.1 Androgenetic alopecia in men 164
7.2.2 Structure of the hair follicle 157 7.5.1.1 Incidence, role and
7.2.3 Changing the hair produced by a follicle consequences 164
via the hair growth cycle 158 7.5.1.2 Roles of androgens and
genes 165
7.3 The paradoxical effects of androgens on
7.5.2 Androgenetic alopecia in women 166
human hair growth 159
7.5.3 Hirsutism 166
7.3.1 Human hair growth before and after
puberty 159 7.6 Treatment of androgen-potentiated hair
disorders 167
7.3.2 Evidence for the role of androgens 160
7.6.1 Androgenetic alopecia 167
7.4 The mechanism of androgen action in the hair
7.6.1.1 Surgery 167
follicle 161
7.6.1.2 Non-hormonal therapy 167
7.4.1 Hair growth in androgen insufficiency
7.6.1.3 Endocrine-based
syndromes 161
treatments 168
7.4.2 The current model for androgen action
7.6.2 Hirsutism 168
in the hair follicle 161
7.6.2.1 Non-hormonal approaches 168
7.4.2.1 The role of the dermal papilla 161
7.6.2.2 Endocrine-based treatments 168
7.4.2.2 Paracrine factors implicated in
7.7 Key messages 169
mesenchyme–epithelial interactions
in the hair follicle 163 7.8 References 170

7.1 Introduction example, the widespread customs of daily shaving of

Hair growth plays important roles in human social and men’s beards and women’s axillary hair in Northern
sexual communication. People throughout the world Europe and the USA. Therefore, we should not be
classify a person’s state of health, sex, sexual maturity surprised that hair growth abnormalities, either more
and age, often subconsciously, by assessing their scalp or less than “normal,” even common male pattern
and body hair. Hair’s importance is seen in many social baldness, cause widespread psychological distress.
customs in different cultures. Hair removal generally Androgens are the most obvious regulators of
has a strong depersonalizing effect, such as shaving the human hair growth. Although hair with a major
heads of soldiers, prisoners and Buddhist or Christian protective role, such as the eyelashes, eyebrows and
monks. In contrast, long hair often has positive conno- scalp hair, is produced by children in the absence of
tations, like Samson’s strength in the Bible and the androgens, the formation of long pigmented hair on
uncut hair of Sikhs. Body hair is also involved; for the axillae, pubis, face etc. needs androgens in both

Testosterone: Action, Deficiency, Substitution, ed. Eberhard Nieschlag and Hermann M. Behre, Assoc. ed. Susan Nieschlag.
Published by Cambridge University Press. © Cambridge University Press 2012.

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 Chapter 7: Androgens and hair

(A) Hair changes during the human life cycle

Baby Childhood Puberty Reproductive Stages Aging Death

(B) Abnormal hair growth

Androgen insufficiency
syndromes

XY XY Female androgenetic
no androgen 5 α-reductase Hirsutism alopecia
receptors deficiency
Gradual thinning on
Child hair Female hair Male hair vertex – retention of
pattern only distribution distribution frontal hairline
Fig. 7.1 Human hair varies with life stage and endocrine state. (A) Changes in hair distribution and color signal a person’s age, state of
maturity and sex. 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 back in men.
Androgens also stimulate hair loss from the scalp in men with the appropriate genes in a patterned manner, causing androgenetic alopecia. As
age increases hair follicles lose their ability to make pigment, causing graying (canities). (B) People with various androgen insufficiency
syndromes demonstrate that none of this occurs without functional androgen receptors and that only axillary and female pattern of lower
pubic triangle hairs are formed in the absence of 5a-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 or female pattern hair loss (FPHL). See plate section for color version.

sexes. In contrast, androgens may also inhibit hair sometimes stimulate hair growth, and the recognition
growth on the scalp, causing baldness (Figs. 7.1 and of its regenerative capacity. However, we still know
7.2). How one type of hormone can simultaneously relatively little about the precise functioning of this
cause these contradictory effects in the same tissue in complex cell biological system. On the other hand,
different body sites within one person is a unique our increased understanding of how androgens work
endocrinological paradox. The hair follicle has in the follicle has enabled the treatment of female
another exciting characteristic. It is the only tissue hirsutism with antiandrogens, such as cyproterone
in the adult body which can regenerate itself, often acetate, and the 5a-reductase type 2 inhibitor,
producing a new hair with different features. This is finasteride, developed to regulate prostate disorders,
how androgens can cause such major changes. is now available in many countries for use in male
Over the last 20 years, there has been much inter- pattern baldness. Greater understanding of hair fol-
est in the hair follicle, promoted by the discovery that licle biology may also enable the development of
the antihypertensive drug, minoxidil, could further approaches to treatment in the future.

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 Chapter 7: Androgens and hair

Long, thick Fig. 7.2 Androgens have paradoxically

(A) BEARD pigmented hair different effects on human hair follicles
Short, fine depending on their body site. (A) During
unpigmented and after puberty, androgens stimulate
hair the gradual transformation of small
+ follicles producing tiny, virtually colorless,
ANDROGENS vellus hairs, to terminal follicles producing
longer, thicker and more pigmented
hairs. These changes involve passing
through the hair cycle (see Fig. 7.3). (B) At
the same time, many follicles on the
scalp and eyelashes continue to produce
Vellus Terminal the same type of hairs, apparently
follicle follicle unaffected by androgens. (C) In complete
contrast, androgens may inhibit follicles
(B) NON-BALDING SCALP on specific areas of the scalp in
Androgen genetically susceptible individuals,
independent causing the reverse transformation of
terminal follicles to vellus ones, and
Long, thick
pigmented hair
androgenetic alopecia. (Diagram
reproduced from Randall 2000a.)
See plate section for color version.

+
ANDROGENS

blood
vessels

(C) BALDING SCALP

Androgen
sensitive
Long, thick
pigmented hair
Short, fine
unpigmented hair

+
ANDROGENS

Terminal Vellus
follicle follicle

People have been intrigued by the changes in

hair growth during a person’s life (see Fig. 7.1) for 7.2 Structure and function of the
thousands of years, with Aristotle first recognizing hair follicle
the connection between beard growth and the testes
(reviewed by Randall 2003). This chapter will cover 7.2.1 The roles of human hair
our current knowledge of the structure and function Hairs cover almost the entire body surface of human
of hair follicles, their responses to androgens, beings except for the soles of the feet, palms of the
the mechanism of action of androgens in the hands and the lips. They are fully keratinized tubes of
follicle, and current modes of controlling androgen- dead epithelial cells where they project outside the
potentiated hair disorders. skin. They taper to a point, but otherwise are

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 Chapter 7: Androgens and hair

BALDING SCALP: androgen sensitive

+ ANDROGENS + ANDROGENS

LONG, THICK
PIGMENTED
HAIR
New New
hair hair

Club Club
hair Sebaceous hair Sebaceous
gland gland
Hair Hair
germ Original germ Original
New New
hair Dermal hair
hair hair
Dermal papilla
papilla Dermal cells
cells papilla
Dermal
Dermal papilla
papilla
TERMINAL
FOLLICLE

Fig. 7.3 Androgen inhibition of hair size on the scalp leads to balding. Hair follicles pass through regular cycles of growth (anagen), regression
(catagen), rest (telogen) and hair shedding during which the lower part of the follicle is regenerated. This enables the follicle to produce a
different type of hair in response to hormonal stimuli to coordinate to changes in the body’s development, e.g. sexual maturity or seasonal
climate changes. Androgens inhibit follicles on specific areas of the scalp in genetically susceptible individuals, causing the regenerated follicles
to be smaller, protrude less into the dermis and produce smaller, less-pigmented hairs. Eventually the terminal hairs of childhood and early
adulthood are replaced by the vellus hairs of androgenetic alopecia, and the area appears bald. Follicles must pass through a full hair cycle,
probably a succession of cycles, to accomplish major changes. (Diagram reproduced from Randall 2010.) See plate section for color version.

extremely variable in length, thickness, color and Eyelashes and eyebrow hairs prevent substances
cross-sectional shape. These differences occur entering the eyes, and head hair protects the scalp
between individuals, e.g. blonde, red or dark haired and back of the neck from sun damage during our
people, and between specific body areas within one upright posture. During puberty the development of
individual, such as the long, thick scalp and beard axillary and pubic hair signals the beginning of sexual
hairs and the short, fine ones on the back of the hand. maturity in both sexes (Marshall and Tanner 1969;
Changes also occur in some areas within an individ- Winter and Faiman 1972; 1973), while a man’s beard
ual at different stages of their life; e.g. darker, thicker readily distinguishes the sexes (Jansen and Van Baalen
and longer beard hairs replace the fine, short, almost 2006), like the mane of the lion (Fig. 7.1).
colorless hairs on a boy’s face after puberty (Fig. 7.1).
The main functions of mammalian hair are insula- 7.2.2 Structure of the hair follicle
tion and camouflage. These are no longer necessary for Each hair is produced by a hair follicle; the biology of
the “naked ape,” although vestiges remain in the sea- the hair follicle was reviewed recently by Randall and
sonal patterns of our hair growth (Randall and Ebling Botchkareva (2009). Hair follicles are cylindrical, epi-
1991) and the erection of our body hairs when thelial down-growths from the epidermis into the
shivering with cold (goosebumps). Mammals often dermis and subcutaneous fat, which enlarge at the
have hairs specialized as neuroreceptors, e.g. whiskers, base into a hair bulb surrounding the tear-shaped,
and this remains, slightly, in human body hair, with its mesenchyme-derived dermal papilla (Fig. 7.3). The
good nerve supply. However, the main functions of dermal papilla, containing specialized fibroblast-like
human hair are protection and communication. cells in an extracellular matrix, regulates many aspects

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 Chapter 7: Androgens and hair

of hair growth (Reynolds and Jahoda 2004). Hairs are Hair follicle regeneration is characterized by dra-
produced by epithelial cell division in the hair bulb; matic changes in microanatomy and cellular activity
the keratinocytes move upwards, differentiating into which are still not fully understood. Hair follicle tran-
the various layers of the follicle. The central portion sition between the hair cycle stages is governed by
forms the hair itself, the color of which is produced by epithelial–mesenchymal interactions between the fol-
pigment donated by the follicular melanocytes in the licular keratinocytes and the dermal papilla cells. Cell
hair bulb. By the time it reaches the surface the cells fate during hair follicle growth and involution is
are fully keratinized and dead. Each hair is sur- controlled by numerous growth regulators. During
rounded by two multi-layered epithelial sheaths: active growth and hair production, factors promoting
the inner root sheath, which helps it move through proliferation, differentiation and survival predomin-
the skin and which disintegrates when level with the ate, including WNT5a, SCF, HGF, FGF7 and IGF-1,
sebaceous gland, and the outer root sheath, which while hair follicle regression is characterized by acti-
becomes continuous with the epidermis, completing vation of various signaling pathways that induce
the skin’s protective barrier (Fig. 7.3). Cell division apoptosis (Botchkareva and Kishimoto 2003; Botch-
continues until the hair reaches the appropriate kareva et al. 2006).
length for its body site. The epithelial stem cells necessary to synthesize a
new hair have been identified in the bulge region of
7.2.3 Changing the hair produced the outer root sheath below the sebaceous gland (Cot-
sarelis et al. 1990; Hsu et al. 2011). The bulge contains
by a follicle via the hair growth cycle stem cells with a wide potency, which are able to
To fulfill all its roles, the type of hair produced by a replace cells of the epidermis and sebaceous glands
follicle often needs to change. Follicles possess a as well as the hair follicle (Waters et al. 2007; Shimo-
unique mechanism for this: the hair growth cycle mura and Christiano 2010), and is also associated
(Kligman 1959; Fig. 7.3). This involves destruction with the melanocyte stem cells (Nishimura 2011)
of the original lower follicle and its regeneration to and nestin-expressing stem cells which can produce
form another which can produce a hair with different nerve cell lineages (Lui et al. 2011). Recently Rabbani
characteristics. Thus postnatal follicles retain the abil- et al. (2011) have shown coordinated activation of
ity to recapitulate the later stages of follicular epithelial and melanocyte stem cells in the bulge.
embryogenesis throughout life, a unique characteris- Our understanding of this aspect of hair follicle activ-
tic in adults. Exactly how differently sized a hair can ity has expanded dramatically and is the focus of
be to its immediate predecessor is currently unclear much attention with the aim of developing the hair
because many changes, like producing a full beard follicle as a stem cell source for regenerative medicine.
(Hamilton 1958) or androgenetic alopecia The processes of the hair growth cycle allow the
(Hamilton 1951a), take several years. follicle to replace the hair with a new one which may
Hairs are produced in anagen, the growth phase. resemble the original or may be larger, smaller and/or
Once a hair reaches its full length, a short apoptosis- a different color depending on the environment or
driven involution phase, catagen, occurs, where cell stage of a mammal’s maturity (Fig. 7.3). Changes in
division and pigmentation stops, and the hair hair length involve alterations in the length of anagen.
becomes fully keratinized with a swollen “club” end This can range from two to three years or more on the
and moves up in the skin with the regressed dermal head, to produce long scalp hair (Kligman 1959), to
papilla. After a period of rest, telogen, the dermal only about two months for the short hairs on the
papilla cells and associated keratinocyte stem cells finger (Saitoh and Sakamoto 1970). These changes
reactivate, and a new lower follicle develops down- are coordinated by the pineal-hypophysis-pituitary
wards, guided by the dermal sheath which sur- system (Ebling et al. 1991; Randall 2007). Coordin-
rounded the previous follicle. The new hair then ation to the environment is particularly important for
grows up into the original upper follicle (Fig. 7.3). some mammals, such as mountain hares, which need
The existing hair is generally lost; although previously a longer, warmer and white coat in the snowy winter,
believed due to the new hair’s upward movement, a but a shorter, brown coat in the summer to increase
further active shedding stage, exogen, is now recog- their chances of survival (Flux 1970). Human beings
nized (Higgins et al. 2009). from temperate regions also exhibit seasonal changes

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in both scalp (Orentreich 1969; Randall and Ebling such as Hairless and Tabby, plus transmembrane
1991; Courtois et al. 1996) and body hair (Randall molecules and extracellular matrix molecules have
and Ebling 1991), in line with seasonal changes in all been implicated in the mesenchymal–epithelial
melatonin, prolactin and cortisol secretion (Wehr interactions (Rendl et al. 2005).
1998; Wehr et al. 2001). The main change in human One of the first signs of puberty is the gradual
hair growth is the production of adult patterns of appearance of a few larger and more pigmented inter-
body hair growth after puberty, like the male lion’s mediate hairs, first in the pubic region and later in the
mane, in response to androgen (Fig. 7.2); some sea- axillae. Intermediate-sized hair follicles have recently
sonal fluctuations in human body hair growth may been characterized on the face (Miranda et al. 2010).
also coordinate at least in part to those of androgens These are replaced by longer and darker terminal
(Randall and Ebling 1991; Randall 2008). hairs (Fig. 7.2), and the area spreads. In boys, similar
These annual seasonal changes are important for changes occur gradually on the face starting above the
any investigations of androgen-dependent or scalp mouth and on the central chin, eventually generally
hair growth, particularly in individuals living in tem- spreading over the lower part of the face and parts of
perate zones. For example, scalp hair loss may be the neck, readily distinguishing the adult male (Mar-
exacerbated during the increased autumnal shedding shall and Tanner 1969; 1970). Adult men’s pubic hair
in both male and female patients. This has particu- distribution also differs from women’s, extending in a
larly important implications for any assessments of diamond shape up to the navel in contrast to women’s
new therapies or treatments to stimulate, inhibit or inverted triangle. Terminal hair on the chest and
remove hair; to be accurate, measurements need to be sometimes the back is also normally restricted to
carried out over a year to avoid natural seasonal men, though both sexes may also develop intermedi-
variations (Randall 2008). ate terminal hairs on their arms and legs, with ter-
minal hairs normally restricted to the lower limbs in
7.3 The paradoxical effects of women (Fig. 7.1). In all areas the responses are grad-
ual, often taking many years. Beard weight increases
androgens on human hair growth dramatically during puberty, but continues to rise
7.3.1 Human hair growth before until the mid-thirties (Hamilton 1958); while terminal
hair growth on the chest and in the external ear canal
and after puberty may be first seen many years after puberty (Hamilton
In utero the human body is covered with quite long, 1946).
colorless lanugo hairs. These are shed before birth and The amount of body hair is very variable and
at birth, or shortly after; babies normally exhibit differs both between families within one race and
pigmented, quite thick protective hairs on the eye- between races, with Caucasians generally exhibiting
brows and eyelashes and variable amounts on the more than Japanese (Hamilton 1958). This implicates
scalp, and by the age of three or four the scalp hair a genetically determined response to circulating trig-
is usually quite well developed, though it will not yet gers. The responses of the follicles themselves also
have reached its maximum length. These readily vis- vary, with female hormone levels being sufficient to
ible pigmented hairs are known as terminal hairs and stimulate terminal hair growth in the pubis and axil-
are formed by large deep terminal follicles (Fig. 7.2). lae, but male hormones being required for other
This emphasizes that terminal hair growth on the areas, such as the beard and chest. Beard hair growth
scalp, eyelashes and eyebrows is not androgen also remains high, even after 70, while axillary growth
dependent. The “hairless” rest of the body is normally is maximal in the mid-twenties and falls quite rapidly
covered with fine, short almost colorless vellus hairs then in both sexes (Hamilton 1958). This also seems
produced by small, short vellus follicles (Fig. 7.2). The paradoxical; markedly different responses in the two
molecular mechanisms involved in the distribution areas, although both respond to apparently similar
and formation of the different types of follicles during stimulation by androgens.
embryogenesis are not clear, but secreted signaling During early puberty the frontal hair line is
factors such as Sonic hedgehog, WNT and growth usually straight across the top of the forehead.
factors (e.g. the EGF and FGF families), nuclear With increasing age there is frequently a progressive
factors including various homeobox genes and others regression of the frontal hair line in a prescribed

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 Chapter 7: Androgens and hair

(A)

I II IIa III IIIa III-vertex

IV IVa V Va VI VII

(B)

Stage I II III
Fig. 7.4 Patterns of hair loss in androgenetic alopecia in men and women differ. Androgens cause a gradual inhibition of hair growth on the
scalp in genetically predisposed individuals. This is much more common in men than in women, and the pattern of the hair loss in men (A;
Hamilton 1951a) differs from that in women (B; Ludwig 1977). In men, the first signs are generally temporal regression, which spreads
backwards and joins thinning regions on the vertex to give a bald crown. In women, the front hairline is normally retained, and a general
thinning on the vertex gradually becomes more pronounced until the vertex becomes bald. It is also less clear whether androgens are actually
involved in women.

manner (described below in Section 7.5.1), accom- retained when follicles are transplanted to other skin
panied by progressive thinning of terminal hair on sites (Ebling and Johnson 1959), the basis of correct-
the vertex (Fig. 7.4). This is characterized by a gradual ive hair follicle transplant surgery (Orentreich and
inhibition of terminal follicles to smaller vellus fol- Durr 1982; Gokrem et al. 2008).
licles (Fig. 7.3), with the length of anagen decreasing
and that of telogen increasing. This is an example of a
much more dramatic biological paradox. How does 7.3.2 Evidence for the role of androgens
one hormone stimulate hair growth in many areas Although androgens are the clearest regulators of
such as the face, have no effect in others, e.g. eye- human hair growth unlike most other mammals
lashes, while inhibiting follicles on the scalp? These (Ebling et al. 1991), various other circulating factors
contrasts are presumably due to differential gene have an effect (reviewed in Randall 2007). These
expression within follicles from the various body sites. include adequate nutritional supplies, due to the fol-
The intrinsic response of individual follicles is licles’ high metabolic demands (Bradfield 1971), the

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hormones of pregnancy, which cause a prolonged ana- and female pattern pubic hair, but very little beard
gen resulting in a synchronized shedding of a propor- growth; they are also not reported to show male
tion of scalp hairs post-partum (Lynfield 1960), and pattern baldness (Griffin and Wilson 1989;
lack of thyroid hormone which restricts hair growth Fig. 7.3). Although the identification of two forms
(Jackson et al. 1972). Growth hormone is also neces- of 5a-reductase (type 1 and type 2) makes the situ-
sary in combination with androgens for normal body ation complex, all individuals with 5a-reductase
hair development in boys (Zachmann and Prader deficiency so far are deficient in 5a-reductase type 2,
1970; Zachmann et al. 1976). There is much evidence confirming its importance for much androgen-
supporting androgens’ importance, which fits in well dependent hair growth. A role for 5a-reductase in
with the concept of much terminal hair growth being a baldness is also supported by the ability of oral
secondary sexual characteristic. Terminal hair appear- finasteride, a 5a-reductase type 2 inhibitor (Kaufman
ance in puberty parallels the rise in circulating andro- et al. 1998; Shapiro and Kaufman 2003) and the dual
gen levels and occurs later in boys than girls (Marshall 5a-reductase inhibitor, dutasteride (Olsen et al.
and Tanner 1969; 1970; Winter and Faiman 1972; 2006), to promote hair regrowth. This suggests that
1973). Testosterone also stimulates beard growth in the formation of terminal pubic and axillary hair can
eunuchs and elderly men (Chieffi 1949). An extensive be mediated by testosterone itself, while that of the
US study also showed that castration before puberty secondary sexual hair of men requires the presence
prevented beard and axillary hair growth and after of 5a-dihydrotestosterone. This demonstrates a third
puberty reduced them (Hamilton 1951b; 1958). Never- paradox in androgen effects on hair follicles. Why
theless, the strongest evidence for the essential nature does the stimulation of increasing size in some
of androgens is the lack of any body hair, even the follicles like beard require 5a-dihydrotestosterone
female pubic and axillary pattern, or evidence of any formation, while follicles in the axillary and pubic
male pattern baldness, in adult XY androgen insensi- regions carry out the same changes in the absence of
tivity patients with absent or dysfunctional androgen 5a-dihydrotestosterone? Since androgens are stimu-
receptors, despite normal or raised circulating levels of lating the same transformation, presumably via the
androgens (Fig. 7.1, B) (see Chapter 3). same receptor, this is currently difficult to under-
stand, although it is further evidence of the intrinsic
7.4 The mechanism of androgen differences within hair follicles. It suggests that some
less well-known aspect of androgen action is
action in the hair follicle involved in hair follicles normally specific to men,
7.4.1 Hair growth in androgen which requires 5a-dihydrotestosterone, such as inter-
action with a specific transcription factor. Interest-
insufficiency syndromes ingly, androgen-dependent sebum production by
As described in Chapter 2 of this book, androgens the sebaceous glands attached to hair follicles is also
from the blood stream enter the cell and bind to normal in 5a-reductase deficiency type 2 (Imperato-
specific, intracellular androgen receptors, usually in McGinley et al. 1993).
the form of testosterone or its more potent metabol-
ite, 5a-dihydrotestosterone. The hormone-receptor
complex, generally in combination with transcrip- 7.4.2 The current model for androgen
tional regulators, then activates the appropriate gene
transcription for that cell type. Androgen insuffi- action in the hair follicle
ciency patients without functional androgen receptors 7.4.2.1 The role of the dermal papilla
demonstrate the absolute requirement for androgen The mesenchyme-derived dermal papilla plays a
receptors within hair follicles for the development of major role in determining the type of hair produced
the hair growth ascribed in Section 7.3.2 to androgens by a follicle, as shown by an elegant series of experi-
(see Chapter 3). These individuals produce no body ments involving the rat whisker by Oliver, Jahoda,
hair at puberty, even with high circulating androgen Reynolds and colleagues (Reynolds and Jahoda
levels, nor do they go bald (Fig. 7.1). 2004). Whisker dermal papillae transplanted into ear
Men with 5a-reductase deficiency also contribute or glabrous skin initiated the production of whisker
to our understanding because they exhibit axillary follicles, and hair growth could also be stimulated by

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 Chapter 7: Androgens and hair

Fig. 7.5 Current model of androgen

Hair action in the hair follicle: in the current,
well-accepted hypothesis, androgens
Hair bulb from the blood enter the hair follicle via
the dermal papilla’s blood supply. If
Basement membrane Melanocyte appropriate, they are metabolized to
(indirect target) 5a-dihydrotestosterone. They bind to
? androgen receptors in the key regulatory
? Extracellular matrix
cells of the follicle, the dermal papilla cells
Epithelial cells ? +T causing changes in their production of
(indirect target) +T ? regulatory paracrine factors; these then
+T Dermal papilla cells
(direct target)
alter the activity of dermal papilla cells,
? follicular keratinocytes and melanocytes.
? T = testosterone; ? = unknown paracrine
Blood capillary T
factors. (Modified from Randall 2000b.)
T See plate section for color version.
T
T CIRCULATING ANDROGENS T T

cultured dermal papilla cells reimplanted in vivo such as beard (Randall et al. 1992) and balding scalp
(Jahoda et al. 1984). (Hibberts et al. 1998) contain higher levels of specific,
In many embryonic steroid-regulated tissues, saturable androgen receptors than androgen-insensi-
including the prostate and the breast, steroids act via tive non-balding scalp in vitro; this has been con-
the mesenchyme (Thomson et al. 1997). Since hair firmed by studies using RT-PCR (reverse
follicles recapitulate the stages of embryogenesis transcription polymerase chain reaction) (Ando
during their growth cycles to reform a new lower hair et al. 1999). Most importantly, metabolism of testos-
follicle, they may behave like an embryonic tissue in terone by cultured dermal papilla cells also reflects
the adult. Studies on testosterone metabolism in vitro hair growth in 5a-reductase deficiency patients with
by plucked hair follicles, which leave the dermal beard, but not pubic or non-balding scalp, cells
papilla behind in the skin, from different body sites, forming 5a-dihydrotestosterone in vitro (Itami et al.
did not reflect the requirements for 5a-reductase in 1990; Thornton et al. 1993; Hamada et al. 1996);
vivo (reviewed in Randall 1994; Randall et al. 1991), similar results have been obtained examining gene
leading to the hypothesis that androgens would act on expression of 5a-reductase type 2 by RT-PCR (Ando
the other components of the hair follicle via the et al. 1999). This has led to wide acceptance of the
dermal papilla (Randall et al. 1991; Randall 2007). In hypothesis (Randall 2007; 2008).
this hypothesis androgens would alter the ability of However, some more recent observations suggest
the dermal papilla cells to synthesize, or release, con- minor modifications. The lower part of the connect-
trolling factors which would affect follicular keratino- ive tissue sheath, or dermal sheath, which surrounds
cytes, melanocytes and connective tissue sheath cells, the hair follicle and isolates it from the dermis, can
and also probably the dermal endothelial cells, to alter form a new dermal papilla and stimulate new human
the follicle’s blood supply in proportion to its change hair follicle development in another person (Reynolds
in size (Fig. 7.5). These factors could be growth et al. 1999). Cultured dermal sheath cells from beard
factors and/or extracellular matrix proteins. This follicles contain similar levels of androgen receptors
model would facilitate a mechanism for precise con- to beard dermal papilla cells (unpublished data: Mer-
trol during the complex changes needed to alter a rick AE, Randall VA, Messenger AG, Thornton MJ.
follicle’s size in response to androgens. Beard dermal sheath cells contain androgen receptors:
This hypothesis has now received a great deal of implications for future inductions of human hair
experimental support. Androgen receptors have been follicles.), and balding scalp dermal sheath expresses
localized by immunohistochemistry in the dermal the mRNA for 5a-reductase type 2 like the dermal
papilla and not the keratinocyte cells (Choudhry papilla (Asada et al. 2001), indicating that the
et al. 1992; Itami et al. 1995a). Cultured dermal dermal sheath can respond to androgens without
papilla cells derived from androgen-sensitive follicles the dermal papilla acting as an intermediary. Clearly

162
 Chapter 7: Androgens and hair

the dermal sheath also plays an important role in the et al. 1995a) and keratinocytes (Hibberts and Randall
hair follicle. This may be as a reserve to replace the 1996). In contrast, testosterone decreased the mito-
key inductive and controlling role of the dermal genic capacity of androgenetic alopecia dermal papilla
papilla cells if they are lost, to ensure follicles are cells from both men (Hibberts and Randall 1996) and
not lost. Alternatively, or in addition, the dermal stump-tailed macaques (Obana et al.1997). Interest-
sheath cells may respond directly to androgens to ingly, conditioned media from balding cells inhibited
facilitate the increase or decrease in size of the sheath not only the growth of other human dermal papilla
or even the dermal papilla in the development of a cells but also mouse hair growth in vivo (Hamada and
new anagen follicle; this would enable the new hair Randall 2006). This implies that an autocrine mech-
follicle to be larger or smaller depending on the fol- anism is involved in androgen-mediated hair follicle
licle’s specific response to androgens. changes; a view which is supported by the actual
In addition, studies on the beard hair medulla, a changes that occur in dermal papilla cell numbers
central structure only seen in the middle of large and size (Elliott et al. 1999). As well as supporting
human hairs, showed coexpression of a specialized the hypothesis for the mechanism of action, these
keratin, hHa7, and the androgen receptor (Jave- results demonstrate that the paradoxical effects of
Suarez et al. 2004). Since the hHa7 gene promoter androgen on hair follicles observed in vivo are
also contained sequences with high homology to the reflected in vitro, strengthening the use of cultured
androgen response element (ARE), keratin hHa7 dermal papilla cells as a model system for studying
expression may be androgen regulated. However, androgen action in vitro.
no stimulation occurred when the promoter was The main emphasis of research now lies in identi-
transfected into prostate cells, and keratin hHa7, with fying specific factors whose production by dermal
the same promoter, is also expressed in androgen- papilla cells is altered by androgens (reviewed by
insensitive body hairs of chimpanzees, making the Randall 2007). To date only insulin-like growth factor
significance unclear. Nevertheless, the current model (IGF-1), a potent mitogen, is identified as androgen-
needs modification to include possible specific, direct stimulated in beard cells in vitro (Itami et al. 1995b).
action of androgens on lower dermal sheath and DNA microarray methods also revealed that three
medulla cells. genes, SFRP2, MN1, and ATP1B1, were expressed at
significantly higher levels in beard than normal scalp
cells, but no changes were detected due to androgen in
7.4.2.2 Paracrine factors implicated in mesenchyme– vitro (Rutberg et al. 2006). However, stem cell factor
epithelial interactions in the hair follicle (SCF), the ligand for the melanocyte receptor c-kit, is
The production of growth factors by cultured dermal secreted in greater quantities by dermal papilla cells
papilla cells derived from human and rat hair follicles derived from beard hair follicles (with generally
has been investigated by several groups on the basis of darker hairs) than non-balding scalp cells (Hibberts
the primary role of the dermal papilla, its potential et al. 1996b), while cells from balding follicles (which
probable role in androgen action and the retention of have pale hairs) produce significantly less. However,
hair growth-promoting ability by cultured rat cells the concentration and distribution of the melanocytes
(discussed above). Cultured dermal papilla cells in the balding scalp follicles remain unchanged (Ran-
secrete both extracellular matrix factors and soluble, dall et al. 2008). Since SCF plays important roles in
proteinaceous growth factors (Randall 2007). Bio- hair pigmentation (reviewed in Randall et al. 2008),
assays demonstrate that human dermal papilla cells the dermal papilla probably provides local SCF for
secrete factors which stimulate the growth of other follicular melanocytes. Androgens in vivo appear to
dermal papilla cells (Randall et al. 1991; Thornton alter SCF expression by facial dermal papilla cells to
et al. 1998), outer root sheath cells (Itami et al. change melanocyte activity and thus hair color.
1995a), transformed epidermal keratinocytes (Hib- Androgens also inhibit balding dermal papilla
berts and Randall 1996) and endothelial cells (Hib- cells’ gene expression of protease nexin-1, a potent
berts et al. 1996a). Importantly, testosterone in vitro inhibitor of serine proteases which regulate cellular
stimulated greater mitogenic capacity of beard cells to growth and differentiation in many tissues (Sonoda
affect beard, but not scalp, dermal papilla cells et al. 1999). This may act by altering the amount of
(Thornton et al. 1998), outer root sheath cells (Itami extracellular matrix components produced and

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therefore the size of the follicle and hair produced androgenetic alopecia develops, anagen becomes
(Elliott et al. 1999).The inhibitory effects of media shorter, resulting in shorter hairs and an increasing
conditioned by balding dermal papilla cells on dermal percentage of hairs in telogen (see Section 7.2.3);
papilla cell growth in vitro and mouse hair growth in follicle miniaturization is also seen histologically,
vivo (Hamada and Randall 2006) suggest the active and the hairs become thinner (Braun-Falco and
secretion of an inhibitory factor(s). The recent dem- Christophers 1968; Kligman 1988; Rushton et al.
onstration that bald scalp from men with androge- 1991; Whiting 1993). The connective tissue sheath left
netic alopecia retains hair follicle stem cells but lacks in the dermis when the follicle becomes miniaturized
CD200-rich and CD34+ hair pigmentor cells also may become subject to chronic inflammation; this
suggests that inhibitory factors are involved (Garza may prevent terminal hair regrowth in long-term
et al. 2011). Androgens do stimulate the production baldness (Kligman 1988).
of transforming growth factor beta1 (TGF-b1) in Balding occurs in men in a precise pattern
balding dermal papilla cells with transfected androgen described by Hamilton (1951a), starting with regres-
receptors (Inui et al. 2002) and TGF-b2 (Hibino and sion of the frontal hairline in two wings and balding
Nishiyama 2004) in natural balding cells. Transform- in the center of the vertex. Hamilton graded this
ing growth factor beta is a strong candidate for an progression from type I, prepubertal scalp with ter-
inhibitor of keratinocyte activity in alopecia, as it minal hair on the forehead and all over the scalp,
inhibits hair follicle growth in vitro (Philpott 2000), through gradual regression of the frontal hairline
and a probable suppressor of TGF-b1 delayed catagen and thinning on the vertex, to type VII, where the
progression in mice in vivo (Tsuji et al. 2003), bald areas became fully coalesced to leave hair only
although TGF-b2 and TNF-a were actually slightly around the back and sides of the head (Fig. 7.4).
reduced in balding cells in a limited DNA macroarray Norwood modified Hamilton’s classification, includ-
analysis (Midorikawa et al. 2004). In addition, 5a- ing variations for the middle grades; this scale is used
dihydrotestosterone did increase the production of extensively during clinical trials (Norwood 1975). The
dickkopf 1 (DKK1), which stimulated apoptosis in physiology and pathophysiology of androgenetic alo-
keratinocytes (Kwack et al. 2008), and inhibited ker- pecia is reviewed more fully by Randall (2000b; 2005;
atinocyte growth by modifying WNT signaling in 2010), and an approach to its diagnosis was recently
balding dermal papilla cells (Kitagawa et al. 2009). reported by the European Consensus Group (Blume-
Thus, studying dermal papilla cells already impli- Peytavi et al. 2011a).
cates several factors: IGF-1 in enlargement; SCF in
altered pigmentation; and nexin-1, TGF-b, and DKK1 7.5.1.1 Incidence, role and consequences
in miniaturization. Alterations in several factors are The incidence of androgenetic alopecia in Caucasians
probably necessary to precisely control the major cell is high, with estimates varying widely, but progression
biological rearrangements required when follicles to type II is detected in 95% of men (Hamilton 1951a).
change size. Further study of this area should increase It is also seen in other primates, being well studied in
our understanding of the complex hair follicle and the stump-tailed macaque. This suggests a natural
lead to better treatments for hair follicle disorders. progression of a secondary sexual characteristic rather
than the malfunction of a disease. Marked androge-
netic alopecia would obviously highlight the surviving
7.5 Androgen-dependent hair older man as a leader, like the silver back of the chief
growth conditions male gorilla and the larger antlers of the mature deer
stags. Others have speculated that the flushed bald skin
7.5.1 Androgenetic alopecia in men would look aggressive to an opponent (Goodhart
A generalized loss of hair follicles from the scalp 1960) or mean there was less hair for the opposition
known as senescent balding has been reported in both to pull (Ebling 1985), giving the bald man important
sexes by the seventh or eighth decade (Kligman 1988; advantages. The lower incidence of androgenetic
Courtois et al. 1995). This differs from the progressive alopecia amongst men from African races (Setty
baldness seen in androgenetic alopecia, also known as 1970) suggests that any advantages did not outweigh
male pattern baldness, male pattern alopecia, common the evolutionary survival advantages of the hairs’ pro-
baldness or androgen-dependent alopecia. As tection of the scalp from the hot tropical sun.

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In the current youth-orientated culture of indus- (Ellis and Harrap 2001). Interestingly, a very strong
trialized societies, the association of increasing hair correlation in incidence was found in 54 sets of sons
loss with age combined with the major role of hair in and fathers, with 81.5% of balding sons having
human communication means that androgenetic alo- balding fathers (Hamilton–Norwood scale III or
pecia has strong negative connotations. It often causes higher) (Ellis and Harrap 2001; Ellis et al. 2001a).
well-documented psychological distress and reduc- This is greater than expected from an autosomal
tion in the quality of life, even though it is not life- dominant inheritance and could imply a paternally
threatening or physically painful, in both men (e.g. inherited gene, e.g. on the Y chromosome, or the
Franzoi et al. 1990; Girman et al. 1998) and women involvement of a gene that is capable of being pater-
(Van der Donk et al.1991; Cash 1993). Other people nally imprinted (i.e. preferentially inactivated by
perceive men with visible hair loss as older, less phys- methylation of DNA, etc.).
ically and socially attractive, weaker and duller. In Several genes have been investigated for associ-
parallel, people with androgenetic alopecia have a ation with androgenetic alopecia. No association was
poor self-image, feel older and are lacking in self- detected with neutral polymorphic markers for either
confidence, even those who seem accepting of their type 1 (SRD5A1) or type 2 (SRD5A2) 5a-reductase
condition and have never sought treatment (Girman genes in case–control association studies of Austra-
et al.1998), and this has recently been shown to apply lian (Ellis et al. 1998) or Korean (Asian) men (Ha
to men from many countries (Cash 2009). Male pat- et al. 2003). A later study found an association with a
tern baldness primarily causes concern amongst those mutant allele (A49T) of 5a-reductase type 2, but this
who develop marked loss before their forties, and decreased the incidence of alopecia, although increas-
early balding has been linked to myocardial infarction ing that of prostate cancer (Hayes et al. 2006)!
(Lesko et al. 1993). Whether this indicates a dual end- Known dimorphic and polymorphic markers within
organ sensitivity or reflects the psychological stress the androgen receptor gene are more linked to
early balding induces in the youth-orientated Ameri- balding in Caucasian men (Ellis et al. 2001b). The
can culture is unknown. No relationship between the Stu I restriction fragment length polymorphism
incidence of balding and prostatic carcinoma was (RFLP) in exon 1 was present in 98% of 54 young
detected in men aged between 50 and 70 by balding men and 92% of 392 older balding men, but
Demark-Wahnefried et al. (1997), while others report was also found in 77% of their older, non-balding
both an increased (Giles et al. 2002; Yassa et al. 2011) controls. Analysis of triplet repeat polymorphisms,
and a reduced relative risk (Wright et al. 2010). Since CAG and GAC, revealed significantly higher inci-
both conditions have very high incidence in Cauca- dence of short/short polymorphic CAG/GGC haplo-
sians, it would be unlikely that there would be a types in balding subjects and lower short/long,
specific clear-cut relationship that could be useful although no significance was provided. Interestingly,
clinically to predict cancer risk from hair loss. shorter triplet repeat lengths are associated with
precocious puberty, i.e. appearance of pubic hair
7.5.1.2 Roles of androgens and genes before age eight (Hoffmann and Happle 2000) and
Male pattern baldness is androgen dependent, since it androgen-dependent prostate cancer (Stanford et al.
does not occur in castrates, unless they are given 1997). Whether this has functional significance, such
testosterone (Hamilton 1942), nor in XY individuals as increased androgen sensitivity, or simply reflects
with androgen insensitivity due to non-functional linkage disequilibrium with a causative mutation, is
androgen receptors (see Chapter 3). The genetic not clear. However, when the binding capacity for a
involvement in androgenetic alopecia is also pro- range of steroids was compared between androgen
nounced. It runs in families, there are racial differ- receptors from balding and non-balding follicle
ences, and androgen replacement stimulated balding dermal papilla cells, no differences were detected
only in castrated men with a family history (Hamilton (Hibberts et al. 1998), and no link was seen with
1942). Although androgenetic alopecia has historic- increased copy number variations of the androgen
ally been accepted as an autosomal dominant trait receptor gene (Cobb et al. 2009).
with variable penetrance (Bergfeld 1955), this is based Recently, genetic variability in a 1 Mb region
on a familial analysis in 1916 (Osbourn 1916), and a within and centromeric to the androgen receptor gene
more complex, polygenic inheritance is more likely was found associated with androgenetic alopecia

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(Hillmer et al. 2008), and the strongest risk was abnormality (reviewed by Cousen and Messenger
associated with a variant in the flanking ectodyspla- 2010). Recent report of an XY individual with com-
sin A2 receptor gene (EDA2R) (Hillmer et al. 2009). plete androgen insensitivity and no other androgen-
Links with a locus on chromosome 20 (20 pll) have dependent characteristics who exhibits female pat-
also been reported in several populations (Hillmer tern hair loss (Cousen and Messenger 2010) does
et al. 2008; Richards et al. 2008). Other genes have suggest that sometimes at least there may be an
also been implicated, including a link to one allele of androgen-independent, or androgen receptor-inde-
the steroid metabolism gene, CYP17, to both women pendent, mechanism. Overall, there is some debate
with polycystic ovaries and their brothers with early about whether androgen is essential for this hair loss
onset androgenetic alopecia (Carey et al. 1993). An in women (Birch et al. 2002), though this is still
interesting connection is severe, early onset androge- generally assumed. If, as occurs in men, the changes
netic alopecia in men with the X-linked gene for develop due to the genetically influenced, specific
adrenoleukodystrophy, who tend to have low testos- follicular responses within the scalp follicles them-
terone levels (Konig et al. 2000). The gene for hair- selves, it is not surprising that circulating androgen
less, which results in a complete loss of hair (Ahmad abnormalities are often absent.
et al. 1998), also showed a marginally significant
correlation with androgenic alopecia with two muta-
tions, but these became insignificant after correction 7.5.3 Hirsutism
for multiple testing (Hillmer et al. 2002). The situ- Hirsutism is the development of male pattern body
ation is still not fully clear, but is moving forward hair growth in women. This normally benign con-
rapidly. dition causes marked psychological distress because
the person erroneously feels that they are changing
sex. The extent of body hair growth which causes a
7.5.2 Androgenetic alopecia in women problem varies and depends on the amount of
Androgenetic alopecia has also been described in normal body hair amongst her race or subgroup.
women, but the pattern of expression is normally Normally hirsutism would include terminal hair on
different and the incidence less. Post-pubertal reces- the face, chest or back. Ferriman and Gallwey
sion to type II was found in about 25% of Caucasian (1961) introduced a scale for grading hirsutism
women by age 50 (Hamilton 1951a), although this which is widely used, especially to monitor hirsut-
did not develop further. Although women can ism progression with, or without, treatment. An
exhibit the “male” pattern, they generally do not approach for the evaluation of hirsutism has
show the frontal recession and usually exhibit a recently been established as a European consensus
different pattern, retaining the frontal hair line but (Blume-Peytavi et al. 2009).
having a progressive diffuse loss or thinning on the Hirsutism is often associated with an endocrine
vertex which may lead to balding (Ludwig 1977) abnormality of the adrenal or ovary which causes
(Fig. 7.4). This type of balding is frequently termed raised androgens and is very frequently (over 70%
female pattern hair loss (FPHL) rather than andro- of cases) associated with polycystic ovarian syn-
genetic alopecia. Venning and Dawber (1988) found drome (PCOS). It can also be caused by Cushing
that 80% of premenopausal women had thinning in syndrome, acromegaly, hyperprolactinemia and
Ludwig stages I–III; while 13% had Hamilton types drugs (Azziz 2003; Alsantali and Shapiro 2009).
II–IV. After the menopause, 37% exhibited the Some women have no obvious underlying clinical
“male” pattern with some showing marked templar or biochemical disorder and are termed “idio-
M-shaped recession, although not progressing pathic.” The proportion of these is larger in older
beyond Hamilton stage IV. papers as modern methods increase the range of
The progression of balding in women is normally abnormalities that can be detected, e.g. low SHBG.
slow, and a full endocrinological investigation is The assumption that idiopathic hirsutism is due to
generally recommended if a rapid onset is seen. a greater sensitivity of the follicles to normal andro-
Although female pattern hair loss is seen frequently gens is given credence by hirsutism occurring asym-
in association with hyperandrogenism, other women metrically on only one side of a woman (Jenkins
frequently have no other symptoms of androgen and Ash 1973).

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7.6 Treatment of androgen- 25 years. However, its mechanism of action has been
very uncertain (Messenger and Rundegren 2004).
potentiated hair disorders Recent detection of appropriate ATP-sensitive potas-
7.6.1 Androgenetic alopecia sium (KATP) channels in the dermal papilla of human
hair follicles, and appropriate responses in human
Mainly because the pathogenic mechanisms of andro-
hair follicles in organ culture (Shorter et al. 2008)
genetic alopecia are not fully understood, the treat-
has confirmed a probable action via these channels.
ments available are limited and vary in effectiveness.
Minoxidil stimulates regrowth in up to 30%, with
Over the centuries, a wide range of remedies has been
only about 10% obtaining complete regrowth; most
suggested (Lambert 1961), and current treatments
success occurs with younger men and with the early
include wigs and hairpieces, surgery and medical
stages of balding, i.e. Hamilton stage V or less (Daw-
therapies including hormone action modifiers and
ber and Van Neste 1995). A stronger topical applica-
non-hormonal therapy (Ross and Shapiro 2005;
tion of a 5% solution is now licensed for use in men in
Rogers and Avram 2008). Several of these are based
many countries (Olsen et al. 2002), and recently a
on our understanding of the mechanisms of androgen
more acceptable, user-friendly, foam-based applica-
action within the follicle. Recently some investigators
tion has been developed (Blume-Peytavi 2011b).
have also started looking into the application of lasers
Recently, prostaglandin F2a (PGF2a) analogs, such
for androgenetic alopecia based on the low levels of
as latanoprost and bimatoprost, used as eye drops to
visible or near infrared light used to reduce inflam-
reduce intraocular pressure in glaucoma, have been
mation etc. (Leavitt et al. 2009; Kim et al. 2011).
reported to stimulate eyelashes to lengthen, thicken
and darken (Curran 2009). Bimatoprost (Latisse), a
7.6.1.1 Surgery prostamide F2a analog, was licensed for the treatment
All surgical methods capitalize on the different intrin- of hypotrichosis of the eyelashes by the FDA in
sic responses to androgens by spreading “non- December 2008 (NDA 022369). No other drugs have
balding,” i.e. occipital and parietal, terminal follicles caused such a dramatic stimulation of hair growth
over the androgen-sensitive scalp regions (Orentreich after a local application as these prostaglandin analogs
and Durr 1982). Originally involving the transplant of have on eyelashes; minoxidil’s effect topically is much
small biopsies with several follicles, this usually now less than via the original oral ingestion (Messenger
involves micro-grafts with one or two follicles. Once and Rundegren 2004). The eyelashes are highly spe-
established, these expensive and painful treatments cialized, short hairs which have evolved to protect the
are long-lasting; however, the effect can be marred eyes from foreign objects. They have marked differ-
by the continual natural progression of balding, ences to scalp hairs, and their follicles lack the normal
which may well require further transplants to avoid arrector pili muscle found in scalp follicles (Thibaut
isolation of the transplanted region. Future modifica- et al. 2009). Although specialized, eyelashes are pro-
tions may include culturing dermal papilla cells to duced by hair follicles and are replaced regularly via
expand the non-balding follicular material before the hair cycle (Thibaut et al. 2009), like all other hair
replanting into balding regions (Randall 2010; Aoi follicles. However, human hair follicles also exhibit
et al. 2012). markedly different behaviors depending on their body
site, including the major differences in response to
7.6.1.2 Non-hormonal therapy androgens discussed above, and hair graying with age
The ideal treatment for alopecia is an externally occurs first above the ears before gradually spreading
applied (topical) substance which would act locally over the scalp (Keogh and Walsh 1965). We have
to stimulate hair growth only in specific target areas, carried out a range of studies on scalp hair follicles
with no side-effects. Minoxidil, a vasodilator used for and shown that bimatoprost can stimulate hair follicle
hypertension, stimulated excessive hair growth as a growth in organ culture and that scalp follicles con-
side-effect. This provoked major interest in hair fol- tain appropriate receptors to respond in vivo (unpub-
licle biology because it demonstrated that vellus fol- lished data: Khidhir KG, Woodward DF, Farjo NP,
licles could be stimulated to form terminal hairs. Farjo BK, Tang ES, Wang JW, Picksley SM, Randall
Topical application of minoxidil has been used in VA. A prostaglandin-related glaucoma therapy offers
both male and female androgenetic alopecia for over a novel approach for treating alopecia). Based on this,

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clinical trials of bimatoprost applied topically in showed similar, possibly better effects than finasteride
both men and women are now beginning in the in men (Olsen et al. 2006).
USA and Germany. A short study of another glau- Although a range of treatments is now available,
coma drug, latanoprost, a PGF2a analog, has reported all medications need to be used continually because
some effects on androgenetic alopecia in men they are opposing a natural process which, if treat-
(Blume-Peytavi et al. 2011c). ment is discontinued, retains all the components to
continue to progress.
7.6.1.3 Endocrine-based treatments
Antiandrogen therapy is not a practical option for
men due to the side-effects, but cyproterone acetate,
7.6.2 Hirsutism
in combination with estrogen to ensure contraception Once a serious underlying pathology has been elimin-
and prevent potential feminization of a male fetus, ated, a range of treatments is available for hirsutism
has been used in women. It increased the percentage (Azziz 2003; Martin et al. 2008; Alsantali and
of hair follicles in anagen and may cause some Shapiro 2009; Lapidoth et al. 2010). These range
regrowth, but is probably most effective in preventing from simple cosmetic treatments to oral pharma-
further progression (Dawber and Van Neste 1995; ceutical medication.
Vexiau et al. 2002). Since cyproterone acetate is
unavailable in the USA, spironolactone and high- 7.6.2.1 Non-hormonal approaches
dose cimetidine have been used as alternative Cosmetic treatments such as bleaching and depilatory
antiandrogens. measures, such as shaving, waxing or depilatory
Finasteride, a 5a-reductase type 2 inhibitor, was creams, are common, but only remove hair or reduce
developed to treat androgen-potentiated prostate dis- the amount or appearance of hair temporarily. Elec-
orders and is now available as an oral treatment for trolysis, with the aim of permanent removal by killing
androgenetic alopecia in men in many countries at a the dermal papilla and germinative epithelium/stem
lower dose of 1 mg/d. Clinical trials demonstrated cells is the most established long-lasting treatment,
significant effects on stimulating hair regrowth in but it is expensive, time consuming and may cause
younger men with mild to moderate hair loss (Kauf- scarring. Photoepilation, using laser or intense pulse
man et al. 1998). More recently effects have also been light (IPL) treatment, is a more recently introduced
seen in older men (Kaufman et al. 2008a; 2008b). alternative to electrolysis (Sanchez et al. 2002; Alsan-
Even if hair did not regrow, balding progression was tali and Shapiro 2009). A Cochrane review of photo-
frequently halted and no significant adverse effects epilation found that alexandrite and diode lasers were
have been reported. Unfortunately, no effects of finas- more useful, while there was little evidence of effect-
teride have been seen in postmenopausal women with iveness with IPL, longer wavelength (Nd:YAG) or
androgenetic alopecia (Price et al. 2000); use in pre- ruby lasers (Haedersdal and Gotzsche 2006).
menopausal women requires ensuring against contra- A hair growth inhibitor, eflornithine
ception as for antiandrogens. Topical routes of hydrochloride, is available by prescription as a topical
application of finasteride in liposomes have also been cream as Vaniqa®, or under other names around the
studied but are not yet available clinically (Kumar world. It is an irreversible inhibitor of the enzyme
et al. 2007). Interestingly, response to finasteride in ornithine decarboxylase which is approved by the
women has recently been shown to depend on genetic FDA (USA) for the reduction of unwanted facial hair
variations in the androgen receptor gene, bringing in women. It is used alone or as an adjuvant to laser
in a whole new area of epigenetics to alopecia therapy (Lapidoth et al. 2010).
treatment (Keene and Goren 2011). Previously, Tang
et al. (2003) reported that response to finasteride in 7.6.2.2 Endocrine-based treatments
men was correlated to the ability of their follicle Oral contraceptives are generally considered the first-
dermal papilla cells to produce IGF-1. Both these line therapy for hirsutism in premenopausal women
results show how important it is to understand the (Martin et al. 2008), in the form of an estrogen,
mechanism of androgen action in hair follicles to frequently ethinyl estradiol, in combination with
develop new treatments. A short trial of dutasteride, a progestin. The progestin used should not have
a dual inhibitor of both 5a-reductase types 1 and 2 androgenic properties, and a combination with an

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antiandrogenic form, which should compete for the contact with the blood or is specific for hair follicles
androgen receptor in the follicle, such as cyproterone is not yet available. Further research on the biology of
acetate or drospirenone, is recommended (Alsantali androgen action in the hair follicle may facilitate its
and Shapiro 2009). Oral contraceptives act by sup- development.
pressing luteinizing hormone secretion and thereby
inhibiting ovarian androgen biosynthesis, increasing 7.7 Key messages
SHBG production (which decreases serum free  Androgens are the main regulator of human hair
androgens), and causing some reduction in androgen growth and responsible for initiating clinical
synthesis by the adrenals. conditions including androgenetic alopecia and
If the oral contraceptives are insufficient, anti- hirsutism.
androgens are recommended (Martin et al. 2008).  Androgens have paradoxically different effects
on hair follicles depending on their body site.
The most common antiandrogen treatment, outside
They can stimulate the formation of large hairs,
the USA, is cyproterone acetate, given with estrogen e.g. beard, axilla; have no effect, e.g. eyelashes; or
if the woman is premenopausal. It is used at higher inhibit follicles on the scalp.
doses, but must still be balanced with estrogens if  All effects are gradual.
pregnancy is a possibility. Spironolactone, an aldos-  Common androgen-potentiated disorders of hair
terone antagonist, known to have antiandrogen growth, including hirsutism in women and
activity, or flutamide, a pure non-steroidal antian- androgenetic alopecia in both sexes, particularly in
drogen, can be used as alternatives (Swiglo et al. men, cause widespread psychological distress due
2008); flutamide is not recommended as a front-line to the importance of hair in human
therapy due to hepatotoxicity (Martin et al. 2008; communication.
Alsantali and Shapiro 2009). Patients have to be  Androgen receptors are necessary for all
androgen-dependent growth and 5a-reductase
well motivated because hair growth on the face
type 2 for most hair, except for female patterns of
generally takes at least nine months before a notice- axillary and pubic hair, even in men.
able effect occurs, although any acne will be cleared  The action of androgens on human hair follicles
in a couple of months and effects on thigh hair demonstrates several paradoxes: contrasting
growth will be seen in four to six months (Sawers effects in different sites; major differences in the
et al. 1982). Facial responses are seen first on the persistence of stimulatory effects depending on
sides of the face and last on the upper lip, in reverse body region; a varying requirement for the
order to the appearance of facial hair in men formation of 5a-dihydrotestosterone even
(personal observations). amongst follicles exhibiting increased growth.
Finasteride (see Section 7.6.2.1) has also been used Since these are all site-related and retained on
transplantation, these indicate intrinsic
for hirsutism with some success (Lakryc et al. 2003;
differences within follicles, presumably
Alsantali and Shapiro 2009). This seems logical, as
determined during embryonic development.
5a-reductase type 2 is necessary for male pattern body  The current model for androgen action in the hair
hair growth (see Section 7.4.1). Contraception is still follicle proposes that androgens act via the cells of
required, as with all endocrine treatments, due to the the dermal papilla, altering their production of
potential to affect the development of a male fetus. regulatory paracrine factors such as growth
Metformin, insulin-sensitizing therapy, aimed factors, which then influence the activity of other
at altering the insulin resistance and hence the follicular components, e.g. keratinocytes,
hyperandrogenism often associated with polycystic melanocytes and endothelial cells. The dermal
ovarian disease, has been used clinically (Harborne sheath may also play a role as a direct androgen
et al. 2003). However, insulin-sensitizing drugs target.
including the thiazolidinediones (e.g. rosiglitazone  Treatment for androgen-dependent hair
disorders involves cosmetic, surgical, endocrine
and pioglitazone) do not appear effective (Cosma
and non-endocrine related therapies.
et al. 2008).  A 5a-reductase type 2 inhibitor, finasteride,
Overall, there have been major changes in the and antiandrogens, generally cyproterone
treatment of androgen-potentiated disorders over acetate, are being used to control androgenetic
the last 10 years. The ideal therapy of a uniformly alopecia and hirsutism. Such treatments of
effective, topical treatment which is inactivated on

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 Chapter 7: Androgens and hair

premenopausal women require  Further understanding of the mechanism of

combination with estrogens to ensure androgens in the hair follicle is necessary to
contraception to avoid possible feminization of a enable the development of better treatments,
male fetus. preferably working topically and specific to the
 Treatments may need several months to hair follicle.
show their effects and will need to be used
continually as long as the source of androgens is
present.
 Non-endocrine treatments for hair loss include
Acknowledgements
minoxidil; prostaglandin-related glaucoma drugs I should like to acknowledge the assistance in prepar-
are under investigation. ation of this manuscript by Lucy Scott, and Chris
Bowers and Jenny Braithwaite for the figures.

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