MECHANISMS OF DISEASE
Volume 341Number 7
R eview A rticles
Mechanisms of Disease
From the Department of Dermatology, University Hospital Eppendorf,
University of Hamburg, Hamburg, Germany (R.P.); and the Department
of Dermatology, University of Pennsylvania Medical Center, Philadelphia
(G.C.). Address reprint requests to Dr. Paus at the Department of Dermatol-
ogy, University Hospital Eppendorf, University of Hamburg, Martinstr. 52,
D-20246 Hamburg, Germany, or at email@example.com.
©1999, Massachusetts Medical Society.
AIR has many useful biologic functions, in-
cluding protection from the elements and
dispersion of sweat-gland products (e.g.,
pheromones). It also has psychosocial importance in
our society, and patients with hair loss (alopecia)
(Table 1) or excessive hair growth often suffer tre-
mendously. Not surprisingly, the demand for drugs
that alter hair growth and appearance has led to a
multibillion-dollar industry, yet few drugs that are
effective for these purposes are available. However,
recent progress in our understanding of the biology
and pathology of hair follicles should lead to more
effective therapies for disorders of hair growth.
STRUCTURE AND FUNCTION OF HAIR
Hair follicles vary considerably in size and shape,
depending on their location, but they all have the
same basic structure (Fig. 1 and 2). Rapidly prolif-
erating matrix cells in the hair bulb (Fig. 1A) pro-
duce the hair shaft, whose bulk — the cortex — is
composed of hair-specific intermediate filaments and
associated proteins. Pigment in the hair shaft is pro-
duced by melanocytes interspersed among the ma-
trix cells. As the matrix cells differentiate and move
upward, they are compressed and funneled into their
final shape by the rigid inner-root sheath, whose di-
mensions and curvature largely determine the shape
of the hair. The dermal papilla, which is composed
of specialized fibroblasts located at the base of the
follicle (Fig. 1 and 2), is thought to control the num-
ber of matrix cells and thus the size of hair.
Abnormal hair loss
Baldness caused by miniaturization of genetical-
ly predisposed follicles in the male pattern
(frontal recession and thinning at the vertex)
or the female pattern (loss of hair primarily
over the crown, with sparing of frontal hair)
Hair loss in patches, thought to be caused by an
autoimmune response to hair follicles in the
anagen stage; extensive forms of the disorder
are called alopecia areata totalis (hair loss over
the entire scalp) and alopecia areata universa-
lis (hair loss over the entire body)
Caused by destruction of hair follicles as a result
of inflammation, trauma, fibrosis, or un-
known causes; examples include lichen pla-
nopilaris and discoid lupus erythematosus
Growth stage of the hair-follicle cycle
Abrupt shedding of hair caused by interruption
of active hair-follicle growth (e.g., in patients
Lowermost portion of the hair follicle, contain-
ing rapidly proliferating matrix cells that pro-
duce the hair
Portion of the outer-root sheath of the hair fol-
licle, located at the region of the insertion of
the arrector pili muscle; thought to contain
epithelial stem cells responsible for regenerat-
ing follicles in the anagen stage
Stage of the hair cycle characterized by regres-
sion and involution of the follicle
Fully keratinized, dead hair — the final product
of a follicle in the telogen stage; 50 to 150
club hairs are shed daily from a normal scalp
Excessive hair growth in androgen-dependent
areas in women
Excessive hair growth (usually diffuse) beyond
that considered normal according to age,
race, sex, and skin region
Fine hair on the body of the fetus, usually shed
in utero or within weeks after birth
Primary pathological process in androgenetic
alopecia, resulting in conversion of large (ter-
minal) hairs into small (vellus) hairs
Resting stage of the hair cycle; club hair is the
final product and is eventually shed
Excessive shedding of hair caused by an in-
creased proportion of follicles entering the
telogen stage; common causes include drugs
Large, usually pigmented hairs on scalp and
Very short, nonpigmented hairs (e.g., those
found diffusely over nonbeard area of face
and bald scalp as a result of miniaturization of
August 12, 1999
The New England Journal of Medicine
agen, and Telogen Stages of Cycling (Hematoxylin and Eosin).
Panel A (a high-magnification view of the bracketed portion of
Panel B) shows a hair bulb during the anagen (growth) stage
(¬100), Panel B shows a scalp-hair follicle during the anagen
stage (¬25), Panel C shows a scalp-hair follicle during the cat-
agen (involutional) stage (¬40), and Panel D shows a scalp-hair
follicle during the telogen (resting) stage (¬25). In these panels,
apm denotes arrector pili muscle, bg bulge, cl club hair, Cr cor-
tex, cts connective-tissue sheath, Cu cuticle, dp dermal papilla,
drm dermis, epi epidermis, hs hair shaft, iec involuting epithe-
lial column, irs inner-root sheath, m matrix cells, ors outer-root
sheath, sc subcutaneous fat, and sg sebaceous gland.
Structure of Hair Follicles during the Anagen, Cat-
Normal development and cycling of hair follicles
depend on the interaction of the follicular epitheli-
um with the adjacent mesenchymal dermal papilla
(Fig. 2). The dermal papilla induces hair-follicle
formation from the overlying epithelium during fe-
tal development, and at the onset of each new fol-
licular cycle in adults the dermal papilla interacts
with secondary germ cells in the hair-follicle bulge
to regenerate the lower follicle.
of a cluster of biochemically distinct cells in the out-
er-root sheath (Fig. 1D), which are located near the
insertion of the arrector pili muscle. These cells have
the characteristic properties of epithelial stem cells:
they are the slowest-cycling and longest-lived epi-
thelial cells within the hair follicle.
Epithelial stem cells in the bulge portion of the
outer-root sheath may also serve as a reservoir for epi-
dermal and sebaceous-gland cells.
root sheath normally express an array of keratins,
adhesion molecules, cytokines, and growth factor re-
The bulge consists
Cells in the outer-
ceptors that are distinct from those expressed by epi-
They migrate out of the follicle and
regenerate the epidermis after injury or loss. In hy-
perproliferative states such as psoriasis and during
wound healing, epidermal cells produce keratins 6, 16,
and 17, which are normally found only in the outer-
root sheath of hair follicles
the close relation between the epidermis and the hair
The outer-root sheath of the hair follicle also con-
tains melanocytes, Langerhans’ cells (dendritic anti-
gen-presenting cells), and Merkel cells (specialized
neurosecretory cells). All these cells repopulate the
epidermis after injury, and they also play a part in
certain functions of the hair follicle. For example,
the hair follicle acts as a sensory organ and immuno-
logic sentinel for the skin. Hairs detect mechanical
stimuli above the surface of the skin, and the slight-
est bend in a hair activates neuroreceptors in the fol-
licle, relaying important sensory information to the
nervous system. The Langerhans’ cells at the opening
of the follicle detect surface pathogens and activate
the immune system. The hair follicle has a complex
immunologic profile, with immunologically “privi-
leged” matrix cells (lacking major-histocompatibility-
complex class I expression) at its base, and a com-
plement of perifollicular macrophages, mast cells,
and other immunocytes that act as the effector arm
of the immune system.
— further evidence of
MORPHOGENESIS OF HAIR FOLLICLES
In utero, the epithelium and underlying mesen-
chyma interact to form hair follicles.
this time, the precise distribution of hair follicles over
the surface of the body is established and the future
phenotype of each hair (e.g., long scalp hair and short
eyebrow hair) is determined. Many of the molecular
signals that control these events were first discovered
in drosophila (fruit flies). For example, the mamma-
lian counterparts of the
— all necessary for the normal development of dro-
sophila — are critical for the normal formation of
hair follicles as well.
Roughly 5 million hair follicles cover the human
body at birth. No additional follicles are formed af-
ter birth, although the size of the follicles and hairs
can change with time, primarily under the influence
of androgens (see below). The precise spacing and
distribution of the follicles are established by genes
that are expressed very early in the morphogenesis
of the follicles. For example, lymphoid-enhanc-
er factor 1, bone morphogenetic protein 4, and the
type II receptor for transforming growth factor
all expressed before there is any morphologic evi-
dence of hair-follicle formation.
development, cells containing the protein products
of homeobox genes, including
and other genes
Slightly later in
genes, appear in
MECHANISMS OF DISEASE
Volume 341Number 7
Selected stages of the morphogenesis of hair follicles and the three stages of follicular cycling (anagen, catagen, and telogen) are
shown. The roman numerals indicate morphologic substages of anagen and catagen. The pie chart shows the proportion of time
the hair follicle spends in each stage.
Development and Cycling of Hair Follicles.
August 12, 1999
The New England Journal of Medicine
*Information is from Orfanos and Hertel,
Paus, Stenn et al., and Dawber.
AndrogensPromote miniaturization of follicles and
shorten duration of the anagen stage in an-
drogen-sensitive areas of scalp; enlarge fol-
licles in androgen-dependent areas (e.g.,
male beard) during adolescence
Prolong the anagen stage; postpartum reduc-
tion in estrogen secretion causes telogen
Acts synergistically with androgen during
virilization in adolescence
Can induce hirsutism
Low levels cause telogen effluvium; high lev-
els may have a similar effect
Anabolic steroidsSame actions as those of androgens; acceler-
ate androgenetic alopecia and aggravate
-Adrenergic antagonists Can cause telogen effluvium
Prolong duration of the anagen stage, coun-
teracting telogen effluvium and androgenic
turization, and prolongs the anagen stage
in androgen-dependent scalp follicles; con-
verts vellus follicles to terminal follicles
Minoxidil Induces and prolongs the anagen stage and
converts vellus follicles to terminal follicles
Oral contraceptivesCessation may cause telogen effluvium
RetinoidsCan cause premature onset of the catagen
stage or premature loss of club hair, mani-
fested as telogen effluvium
-reductase type II, inhibits minia-
the precise locations where the hair follicles will form.
The protein products of several of these genes are
also present at different times during the hair cycle
in adults, suggesting that they are important not only
for the normal distribution and development of fol-
licles but also for their continued growth.
Once the distribution of the follicles has been es-
tablished, subsequent molecular events in the devel-
oping follicle determine the future phenotype of each
hair.Morphogens such as sonic hedgehog and
wnt, together with intracellular signaling molecules
-catenin and lymphoid-enhancer factor 1, in-
fluence the maturation of the new hair follicles.
Each hair follicle perpetually goes through three
stages: growth (anagen), involution (catagen), and rest
(telogen) (Table 1 and Fig. 1 and 2). Determining
the molecular signals that orchestrate the follicle’s
transit between these stages is one of the key chal-
lenges of hair research. Although most of our cur-
rent knowledge of the substances that modulate hair
growth in humans is derived from clinical observa-
tions (Table 2), studies in mice have identified some
of the molecular events associated with hair-follicle
cycling. Numerous growth factors and
growth factor receptors are critical for normal hair-
follicle development and cycling, but no single
growth factor appears to exert ultimate control over
The onset of the anagen stage recapitulates hair-
follicle development, since the formation of the new
lower hair follicle begins with the proliferation of
secondary germ cells in the bulge (Fig. 1A and 2).
Whether the same proteins and signaling pathways
are responsible for both folliculogenesis in utero and
the onset of anagen in adults is not known. However,
interactions between the dermal papilla and the
overlying follicular epithelium are critical for both
Two secreted molecules that have important roles
in hair-follicle development and cycling are insulin-
like growth factor 1 and fibroblast growth factor 7.
Both are produced by the dermal papilla, and their
receptors are found predominantly in the overlying
matrix cells. Mice that lack insulin-like growth fac-
tor 1 or its receptor have poorly developed hair fol-
licles. Insulin-like growth factor 1 maintains and in-
creases follicle growth in vitro.
fibroblast growth factor 7 have relatively normal hair
follicles, but disruption of the receptor for fibro-
blast growth factor 7, which is also the receptor for
fibroblast growth factor 2, causes markedly reduced
and aberrant hair-follicle formation.
Hair follicles in different areas of the body pro-
duce hairs of different lengths, with the length pro-
Mice that lack
portional to the duration of the anagen cycle. For
example, scalp hair follicles stay in the anagen stage for
two to eight years and produce long hairs, whereas
eyebrow hair follicles do so for only two to three
months and produce short hairs. The cessation of the
anagen stage is controlled by fibroblast growth fac-
tor 5, which is first expressed in the follicle just be-
fore the end of this stage.
growth factor 5 have an extended anagen stage, re-
sulting in the “angora” phenotype, with hair that is 50
percent longer than normal.
the follicle still eventually enters the catagen stage,
suggesting that other signaling pathways are also im-
portant for the induction of this stage. Indeed, the
system of epidermal growth factor receptors also con-
trols this transition, because in mice without epider-
mal growth factor receptors or with nonfunctional
receptors, the anagen stage is prolonged,
ogenous epidermal growth factor terminates the ana-
gen stage in sheep and delays its initiation in mice.
Mice that lack fibroblast
Even in these mice,
MECHANISMS OF DISEASE
Volume 341Number 7
During the catagen stage, hair follicles go through
a highly controlled process of involution (Fig. 1C
and 2) that largely reflects a burst of programmed
cell death (apoptosis) in the majority of follicular ke-
ratinocytes. Follicular melanogenesis also ceases
during this stage, and some follicular melanocytes
undergo apoptosis as well. Toward the end of the
catagen stage, the dermal papilla condenses and moves
upward, coming to rest underneath the hair-follicle
bulge (Fig. 1 and 2). If the dermal papilla fails to reach
the bulge during the catagen stage, the follicle stops
cycling and the hair is lost, as observed in both hu-
mans and mice with mutations of the
This gene encodes for a transcription factor whose
disruption prevents the dermal papilla from ascend-
ing and interacting with the stem cells of the bulge,
resulting in permanent alopecia.
catagen stage in mice, a few hair follicles are also
destroyed by an inflammatory-cell infiltrate, in an
apparently physiologic process of “programmed or-
gan deletion.” Aberrant programmed organ dele-
tion may account for certain permanent forms of
During the telogen stage, the hair shaft matures
into a club hair, which is eventually shed from the fol-
licle, usually during combing or washing. It is unclear
whether shedding is an active, regulated process
a passive event that occurs at the onset of the anagen
stage, as the new hair grows in. Most people lose 50
to 150 scalp hairs per day. The telogen stage typically
lasts for two to three months before the scalp follicles
reenter the anagen stage and the cycle is repeated.
The percentage of follicles in the telogen stage
varies substantially according to the region of the
body (e.g., 5 to 15 percent of scalp follicles are in the
telogen stage at any one time, as compared with 40
to 50 percent of follicles on the trunk).
in the percentage of scalp follicles in the telogen
stage leads to excessive shedding. Therefore, drugs
that maintained or reduced the percentage of follicles
in this stage would be valuable in treating hair loss.
HORMONAL AND NEURAL FACTORS
CONTROLLING HAIR GROWTH
Estrogens, thyroid hormones, glucocorticoids, ret-
inoids, prolactin, and growth hormone all modulate
hair growth (Table 2). The hormones with the most
dramatic effects are androgens. Testosterone and its
active metabolite, dihydrotestosterone, act through
androgen receptors in the dermal papilla.
hormones increase the size of hair follicles in andro-
gen-dependent areas such as the beard area during
adolescence, yet later in life they can cause miniatur-
ization of follicles in the scalp (resulting in androge-
Hair follicles in balding skin differ from those in
nonbalding skin with respect to the metabolism of
androgen, the numbers of androgen receptors
in the dermal papilla, and the secretory responses
of the cells in the dermal papilla.
pillae secrete mitogens after androgenic stimulation,
thus increasing hair growth, whereas others synthe-
size inhibitory factors, thus reducing hair growth.
These paradoxical effects of androgens on hair growth
may be explained by genetically determined differ-
ences in the end-organ response of individual hair
Skin cells contain both isoenzymes of 5
(types I and II), the enzyme that catalyzes the con-
version of testosterone to the more potent dihy-
drotestosterone. The type I enzyme is found pre-
dominantly in sebaceous glands, and the type II
enzyme is found in hair follicles (and the prostate
gland). Androgenetic alopecia does not develop in
men with a congenital absence of 5
type II, and finasteride, which inhibits 5
type II, slows or reverses the progression of andro-
The hair follicles are the most richly innervated
parts of the skin, and constant remodeling of this in-
nervation occurs throughout the normal hair-follicle
and in alopecia. The bulge region of the
hair follicle is especially rich in nerve endings47 and
Merkel cells,10 the neurosecretory cells that produce
nerve growth factor or other neuropeptides that may
control the proliferation of follicles. Several neu-
rotrophins that inhibit hair growth and their recep-
tors are found in hair follicles during the catagen
stage.49 Other peptides, such as substance P and cor-
ticotropin, which can be produced in the skin, and
neuropeptide-depleting agents, such as capsaicin, in-
duce the onset of the anagen stage in mice.12,25
Some dermal pa-
PATHOBIOLOGY OF DISORDERS
OF HAIR GROWTH
Except for rare congenital hair defects, caused by
mutations in keratins or other structural proteins,
and “scarring” alopecias, hair loss and unwanted hair
growth reflect aberrations of hair-follicle cycling.
Thus, in principle, they are reversible phenomena.25
For example, the transient shedding of hair — telo-
gen effluvium — that is associated with drugs, fever,
endocrine abnormalities, parturition, anemia, and
malnutrition occurs when an increased number of
hair follicles prematurely enter the telogen stage and
then shed their hair shafts. Transient shedding typi-
cally begins two to four months after the inciting
event and lasts for several months.23,27 Regrowth rou-
tinely follows, barring any metabolic or nutritional
Androgenetic alopecia is due to the progressive
shortening of successive anagen cycles and is com-
monly manifested as telogen effluvium. Along with
August 12, 1999
The New England Journal of Medicine
the shortening of the anagen stage, genetically pre-
disposed follicles are gradually miniaturized in the
presence of androgens, and large, pigmented hairs
(terminal hairs) are replaced by barely visible, depig-
mented hairs (vellus hairs) (Table 1).40 Nonetheless,
hair follicles are still present and cycling, even in
bald scalps; therefore, androgenetic alopecia is often
classified as reversible.24,27 However, simply remov-
ing androgens does not usually result in the conver-
sion of miniaturized follicles to terminal ones; thus,
current treatments for advanced androgenetic alope-
cia, including minoxidil and finasteride, are usually
ineffective. Since the volume of the dermal papilla
determines the diameter of the hair shaft and may
determine the duration of the anagen stage,27,50 ab-
normalities of the dermal papilla may underlie andro-
In contrast to androgenetic alopecia, hirsutism and
hypertrichosis result from an extended anagen stage
with an abnormal enlargement of hair follicles. Small
vellus hairs are transformed into large, terminal hairs.
Depilatory creams and waxes, the usual treatments,
alleviate the problem only temporarily, because irri-
tation or plucking rapidly induces the anagen stage
and hair-follicle growth.25,27 Electrolysis and selec-
tive photothermolysis with the use of lasers destroy
the hair shaft, outer root sheath, bulge, and dermal
papilla of the hair follicles.51 The extent of the de-
struction determines whether the follicle regenerates.
Antineoplastic drugs disrupt the rapidly prolifer-
ating bulb matrix cells. As a result, hair production
ceases, and the hair shaft becomes narrower, with
subsequent breakage and loss of the hair. Because
the hairs that are lost are those in the anagen stage,
this phenomenon is called anagen effluvium.34 The
stem cells of the hair follicles are spared,52 presum-
ably because of their slow cycling,4 and they sub-
sequently generate a new hair bulb. Radiation ther-
apy can also result in reversible anagen effluvium.27
However, high doses of radiation (50 to 60 Gy) typ-
ically cause permanent alopecia,27 probably because
of the destruction of the epithelial stem cells or the
Some types of inflammatory alopecias (such as
those caused by lichen planopilaris and discoid lupus
erythematosus) are scarring and permanent, whereas
others (such as alopecia areata) are nonscarring and
reversible.24,27,39 In scarring alopecias, the inflamma-
tion usually involves the superficial portion of the
follicle, including the bulge area, suggesting that the
stem cells necessary for the regeneration of the fol-
licle are irreversibly damaged. In contrast, the acute
follicular inflammation in alopecia areata attacks the
hair bulb in the subcutaneous fat.24,27 This inflam-
mation terminates the anagen stage, forcing the fol-
licles into the catagen stage. However, because the
bulge area is spared, a new hair bulb and hair shaft
grow at the start of the anagen stage, once the in-
flammation has subsided or has been blunted with
In graft-versus-host disease27,53 and androgenetic
alopecia,54 inflammation surrounds the bulge area of
the outer-root sheath. Over time, the inflammation
may irreparably damage the follicle stem cells, ac-
counting for the decrease in hair-follicle density that
often occurs in androgenetic alopecia. (Rare cases of
scarring alopecia have been noted in women with
severe androgenetic alopecia.27)
Two drugs have been approved by the Food and
Drug Administration for the treatment of hair loss
due to androgenetic alopecia: topical minoxidil solu-
tion and oral finasteride. Minoxidil prolongs the
anagen stage, causes follicles at rest to grow, and en-
larges the follicles (although the drug’s exact mech-
anism of action at the cellular level is not known).
Thus, treatment with minoxidil lengthens and en-
larges the small vellus hairs and decreases shedding.
Unfortunately, these effects are variable and occur in
only a minority of patients, making it difficult to
predict the efficacy of treatment on an individual
Finasteride blocks 5a-reductase type II and de-
creases both serum and cutaneous dihydrotestos-
terone concentrations; it thus inhibits androgen-
dependent miniaturization of hair follicles.40,46 In
well-designed clinical trials involving men between
the ages of 18 and 41 years, finasteride prevented hair
loss or increased hair growth in the majority of the
men.46 However, at least 17 percent of the men con-
tinued to lose hair while taking finasteride,46 suggest-
ing that pathways of androgen metabolism other
than that involving 5a-reductase type II probably
also contribute to miniaturization.41 Finasteride is
also beneficial in women with hirsutism, but the drug
should be used very cautiously in women because of
its potential feminizing effects on male fetuses.
Additional therapies for hair loss will almost cer-
tainly become available in the future (e.g., topically
effective androgen-receptor antagonists). A better
understanding of the pathophysiology of alopecias
should lead to more successful treatments involving
the use of drugs that specifically alter hair-follicle cy-
cling or that protect hair follicles from immune at-
tack.25 The development of drugs that shield rapidly
proliferating bulb cells from chemotherapeutic dam-
age or that protect stem cells from irreversible dam-
age by autoimmune inflammatory-cell infiltrates or
ionizing radiation would also be valuable. Once the
genes that confer a predisposition to alopecia have
been identified, gene therapy may be a useful alter-
native approach. Given the accessibility of the follicle
and the availability of liposome preparations that tar-
get the follicle, the topical introduction of genes seems
MECHANISMS OF DISEASE Download full-text
Volume 341Number 7
We are indebted to Mr. Murat Ünalan and Ms. Carina van der
Veen for assistance in the preparation of the manuscript.
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