Retinoids in Hair Disorders

Abstract

Vitamin A has been shown to have an essential role in the differentiation, growth and regulation of the human hair cycle. The use of both systemic and topical retinoids is implicated in both the pathogenesis and treatment of various hair disorders. Of particular importance is the direct impact that retinoids have in the dynamic hair growth cycle. Retinoic acid has been shown to directly affect the anagen initiation phase of the hair cycle and direct the differentiation of embryonic and induced pluripotent stem cells into keratinocytes to produce normal hair follicles. Retinoids also have a critical role in the up- or down-regulation of protein pathways depending on their mode of transmission. Systemic retinoids have been shown to cause hair disorders including acute telogen effluvium, alopecia areata and acquired progressive kinking of the hair. Conversely, the use of topical retinoid agents has been reported as an effective treatment option for androgenetic alopecia and alopecia areata, whilst systemic retinoid agents have been reported as an effective option for frontal fibrosing alopecia and monilethrix.

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129
Introduction
Early observations have shown that vitamin A deciency can
induce epidermal hyperkeratosis, squamous metaplasia of
mucous membranes, various keratinization disorders, and cer-
tain precancerous conditions (1). Conversely, vitamin A has been
shown to induce robust immune responses and aids in the dif-
ferentiation and growth of skin, hair, and other tissues (2). These
ndings suggest that vitamin A is implicated in both the patho-
genesis and treatment of various hair disorders.
Retinoids are derivatives of vitamin A, or all-trans retinol,
or synthetic compounds that share structural and/or functional
similarities with the vitamin. Retinoids function by binding to
nuclear receptors, which in turn interact with other transcrip-
tion factors to coordinate gene expression. The regulation of the
retinoid signaling pathway is complex, and retinoids can have
numerous effects on multiple tissues in a dose-dependent manner.
For decades, dermatologists have used vitamin A and related
compounds (retinoids) to treat a wide range of cutaneous disor-
ders, including psoriasis, acne, and cutaneous T-cell lymphoma.
More recently, evidence has emerged for the use of retinoids both
as a causative agent in some hair disorders as well as a therapeu-
tic option for treatment of specic hair disorders.
Retinoids and Hair Cycle
Hair growth involves complex interactions of genes, signal-
ing factors, cell-to-cell interactions, and complex proteins and
hormones. Retinoids have a direct impact on these interactions
by altering the dynamic hair growth cycle. The cycle of hair
growth comprises four main stages, including anagen (growth
and differentiation), catagen (regression and apoptosis), telo-
gen (inactivity), and exogen (the shedding of old hair follicles)
(Figure22.1) (3). This cycle results in the replacement of every
hair on the scalp every 3–5 years, with individual follicles
undergoing 10–30 such cycles in a lifetime (4). On average, a
normal scalp has 100,000 hairs, with approximately 86% being
in anagen, 1% in catagen, and 13% in telogen (5). The variation
in hair cycle length is attributable to the length of the anagen
phase, which is unique to the individual (6). As hair is produced
solely in anagen, this phase also determines the physical length
of the hair.
The regeneration of hair is dependent on the recycling of the
anagen terminal follicle. The primary follicle stem cells are at
the site of contact of the external root sheath and the erector pili
muscle, with a secondary site of regeneration located at the ana-
gen bulb (6). Hair follicle induction and growth is also dependent
on interactions between the external environment, the epider-
mis. and underlying mesenchyme. Several pathways, such as the
Wnt, sonic hedgehog, bone morphogenetic protein, and broblast
growth factor intracellular pathways are essential in these recip-
rocal signaling events necessary for hair follicle morphogenesis
and differentiation (7).
Studies with transgenic mice support a role for retinoic acid
in the hair follicle (8). It was found that blocking of the retinoic
acid−signaling pathways resulted in a delay in anagen initiation
while increasing retinol and all-trans-retinoic acid (tretinoin) (8).
Exogenous tretinoin was also shown to induce catagen in cul-
tured hair follicles (9). In addition, exogenous tretinoin with bone
morphogenetic protein directed the differentiation of embryonic
and induced pluripotent stem cells into keratinocytes that when
grafted into nude mice produced normal epidermis, hair folli-
cles, and sebaceous glands (10). There was upregulation of sig-
naling proteins with the addition of retinoic acid, peaking during
mid-anagen through to early catagen (8). The results suggest that
retinoic acid can alter differentiation and the hair growth cycle to
regulate both the telogen-to-anagen and anagen-to-catagen tran-
sitions and assist in lipid metabolism for maintenance of epider-
mal barrier function.
It has also been shown that retinoic acid plays an impor-
tant role in hair follicle formation and patterning through the
homeobox gene proteins Hox C8 and Hox C6 (11). Retinoic acid
appears to up- and downregulate the homeobox genes, which
consequently inuences hair follicle generation, initiation, dif-
ferentiation, and even inhibition (11). Retinoic acid receptor
(RAR) and retinoid X receptor (RXR) genes have been identi-
ed in almost every portion of the hair follicle. The RARs and
RXRs differ depending on the specic portion of the hair fol-
licle (12). This gene arrangement also provides validation of the
complex interaction that exists between protein synthesis, cell
turnover, and the activation of cellular retinoic acid-binding
protein from retinoic acid within the nucleus (12). The local-
ized components that are involved in the signaling to the hair
follicle by retinoic acid have been hypothesized in many reports
(13–15). There is still much that is unknown regarding the exact
mechanism of retinoic acid’s function within the hair follicle,
22
Retinoids in Hair Disorders
Brent J. Doolan and Rodney Sinclair
9781138314771_C022.indb 129 09-08-2019 21:16:44

130 Retinoids in Dermatology
and future studies are required to determine the mechanism of
retinoic acid differentiation within the hair follicle.
Retinoid-Induced Hair Disorders
Acute Telogen Effluvium
Acute telogen efuvium (ATE) is a self-limiting, non-scarring,
diffuse loss of club (telogen) hair in disease states of the fol-
licle that usually occurs 3–4 months after a triggering event
(Figure 22.2) (16). The exact prevalence of ATE is not known,
but among those seeking treatment, women are overrepresented,
probably due to unawareness or underreporting in males. It can
occur in people of any age, any gender, and any racial background
and can be triggered by metabolic stress, hormonal changes, or
medications, including retinoids (17). ATE is usually a reactive
and self-limiting condition.
The condition can be assessed and monitored using the hair
pull test (Figure 22.3), where the clinician applies traction to
a bundle of scalp hairs. If more than 10% of the hairs in each
bundle are removed from the scalp area, the hair pull test is con-
sidered positive.
Removal of the inciting factor will usually lead to spontaneous
improvement (16). In general, reassurance about the reversibil-
ity of the hair loss is sufcient to alleviate the patient’s concern.
Dose reduction or cessation of therapy may be necessary in more
severe cases. In some cases, telogen efuvium may not sponta-
neously resolve when the inciting trigger is removed. Chronic
telogen efuvium is a diffuse hair loss of the scalp that persists
longer than 6 months. It is characterized by abrupt, diffuse shed-
ding of hair that runs a uctuating course over several years (18).
Patients receiving systemic treatment with synthetic retinoids
often suffer from substantial retinoid-induced ATE. This is one of
the most frequent and psychologically distressing adverse effects
of retinoid therapy, which results in premature termination of a
clinically desired and often highly effective systemic therapy
with retinoids (19). The risk of ATE due to the systemic retinoids
has been reported to vary over a range of 10%–75% (20). The
risk is greater for acitretin than for etretinate therapy and is much
less common with isotretinoin and bexarotene. Hair loss is a
dose-related effect and is reversible starting 2 months after either
discontinuation of therapy or a signicant dose reduction. Hair
loss may affect body hair also, with mild hair loss involving the
pubic, axillary, and vellus hairs. Increased hair fragility may also
be observed. As with telogen efuvium of other causes, women
report more noticeable hair loss than men, and the condition may
make underlying mild androgenic alopecia more obvious.
The administration of systemic retinoids can induce a large
number of hair follicles in the growing (anagen) phase to shift
to the telogen phase. It is estimated that approximately 7%−35%
of the follicles may shift to this state (17). Growth of the telogen
hairs ceases for 1−6 months (on average 3 months), though this
cessation of growth is not noticed by the patient. When the hairs
FIGURE 22.1 Human ha ir growth cycle dynam ics.
Q4
FIGURE 22.2 Acute telogen efuvium.
9781138314771_C022.indb 130 09-08-2019 21:16:45
Updated Figure 22.1 Attached.

131Retinoids in Hair Disorders
re-enter the growth phase (anagen), the hairs that had been sus-
pended in the resting phase (telogen) are extruded from the fol-
licle, and hair shedding is observed. A small proportion of ATE
cases may experience persistent, episodic shedding, as some fol-
licles may not revert to an asynchronous growth pattern (18).
The exact mechanism by which systemic retinoids induce
ATE has not been established, but it has been hypothesized that
it is due to defective anchoring of the hair shaft during telogen
(21). It has also been postulated that ATE may in part be due to
upregulation of transforming growth factor-beta 2, which is a key
inducer of catagen and has been shown to have signicant upreg-
ulation of transcripts with retinoic acid treated hair bulbs (9).
Alopecia Areata
Alopecia areata (AA) is an autoimmune, non-scarring alopecia
that is mediated by CD8+ T-cell attack on the lower cycling
hair follicle and a loss of immune privilege in the hair follicle
(Figure 22.4) (22). Lesions of AA often resolve spontaneously,
but the disease may progress to loss of all scalp hair (alopecia
totalis) or to total loss of scalp and body hair (alopecia univer-
salis). AA is a common disease, affecting about 0.2% of the
population (22). Males and females are affected equally, and
the prevalence is almost the same for all ethnic groups. Studies
suggest AA is a complex polygenetic disease that also involves
exogenous, environmental factors (23). It has been suggested that
vitamin A may play a role in the formation of AA, with vitamin
A toxicity leading to the establishment of AA (24).
It has been reported that the expression of retinoid synthesis
enzymes and binding proteins are increased in human patients
with AA, as well as in rodent models (25). It was noted that
feeding mice high levels of dietary vitamin A combined with
increased retinoic acid synthesis accelerated the onset of AA (25).
Furthermore, in mice with excess retinol and all-trans-retinoic
acid within the basal epidermis and outer root sheath, progressive
cyclical alopecia with accelerated telogen to anagen transition was
noted. In contrast, a severe reduction in dietary vitamin A intake
resulted in a reduction in alopecia-related anagen induction.
Vitamin A also directly regulates the immune response, hav-
ing been shown to increase T-helper 2 and reduce T-helper 1 cyto-
kines (26). Vitamin A also reduces levels of interferon gamma,
which has been shown to play a key role in the etiology of AA
(26). It has been suggested that vitamin A may promote the ini-
tiation of the anagen hair cycle, which likely increases follicle
susceptibility to autoimmune destruction (27). Together, these
reports implicate retinoids in the pathogenesis of AA, although
the precise mechanism behind these effects remains unclear and
requires further investigation.
Miscellaneous
It has been noted that acquired progressive kinking of the hair
was present in a case series of three patients who were prescribed
Q1
FIGURE 22.3 The ha ir pull test—Around 10–20 hairs are grasped rmly at the scalp between the thumb and index nger, and traction is applied as the
hairs a re pulled along their length.
FIGURE 22.4 Alopecia areata with a close-up examination of scalp hair
follicles.
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132 Retinoids in Dermatology
long- term oral etretinate at 50 mg/day or more (28). Kinking of
the hair was noticed 3–12 months after starting treatment and
coincides with the normal anagen cycle of hair growth. This nd-
ing suggests that systemic retinoid treatment at high doses may
have a dynamic effect on the inner root sheath or may represent
a pre-alopecia phase of hair loss.
There have also been case reports that have documented hair
color lightening and darkening while during oral etretinate
treatment for psoriasis (29) and pityriasis rubra pilaris (30).
Repigmentation of white hair and change of hair texture after
6 months of oral acitretin (25 mg/day) for treatment of psoriasis
has also been reported (31).
Retinoids for Treatment of Hair Disorders
Frontal Fibrosing Alopecia
Frontal brosing alopecia (FFA) is a primary lymphocytic
scarring alopecia with a distinctive clinical pattern of pro-
gressive frontotemporal hairline recession and eyebrow loss
that mainly affects postmenopausal women (Figure 22.5) (32).
Histopathology from affected regions shows an immune-medi-
ated inammatory inltrate of lymphocytes surrounding the
bulge region of the hair follicle. Inammation of the bulge area
destroys the hair follicle stem cells, preventing hair regenera-
tion (32). Hair follicles are permanently replaced by a scar-like
brous tissue. It has been hypothesized that loss of the follicu-
lar immune privilege and a peroxisome proliferator-activated
receptor-γ deciency may enable the inammatory process
to attack the stem cells in the bulge region and permanently
destroy them (33).
A recent study assessing the efcacy of oral isotretinoin and
acitretin in treatment of FFA showed success with this treatment
modality (34). The investigators reported an arrest of disease pro-
gression in the majority of patients using oral isotretinoin 20 mg/
day and in those treated with acitretin 20 mg/day. Furthermore,
results were superior to the control group treated with nasteride
5 mg/day. Notably, in contrast to all other drugs used to treat
FFA, this study noted no disease progression after discontinua-
tion of treatment. The mechanism of action of retinoids in FFA
is not fully understood but may represent an anti-inammatory
effect that contributes to normalizing of the antigen expression of
the hair follicle keratinocytes.
Androgenetic Alopecia
Unlike AA, which is caused by an autoimmune reaction at the
hair follicle, androgenetic alopecia (AGA) (commonly referred to
as male- or female-pattern baldness) is caused by the heightened
sensitivity of scalp follicles to dihydrotestosterone. In men, hair
loss typically involves the temporal and vertex region while spar-
ing the occipital region: the characteristic “horseshoe” pattern
(35). AGA features a progressive miniaturization of the hair fol-
licle leading to vellus transformation of terminal hair. This results
from an alteration in hair cycle dynamics: anagen phase duration
gradually decreases and the telogen phase increases. As the ana-
gen phase duration determines hair length, the new anagen hair
becomes shorter, eventually leading to bald appearance (35).
Data on the use of topical retinoids to treat AGA was rst
described in 1986, within a cohort of 56 subjects (36). Results
showed that after 1 year of combination treatment involving the
use of topical tretinoin with 0.5% minoxidil, there was termi-
nal hair regrowth in 66% of the subjects (36). Treatment with
tretinoin monotherapy was also shown to stimulate some hair
regrowth in approximately 58% of patients.
It has been documented that the percutaneous absorption of 2%
minoxidil is increased nearly threefold by the addition of 0.05%
tretinoin, which increases the permeability of the stratum cor-
neum (37). When minoxidil combined with tretinoin is applied
only once daily, the urinary excretion of minoxidil was found to
be signicantly higher than that of minoxidil alone applied twice
daily. Moreover, 0.5% minoxidil plus 0.025% tretinoin (95%
alcohol plus 5% propylene glycol vehicle) applied twice daily to
the affected scalp area was reported to prolong the anagen hair
ratio and induce new hair regrowth (37).
These ndings prompted further studies into the efcacy of
combined retinoids. One study assessed the efcacy of 5% topi-
cal minoxidil solution with the use of 0.01% tretinoin (38). The
efcacy and safety of therapy was compared using a combined
solution of 5% minoxidil and 0.01% tretinoin once daily with
that of conventional 5% topical minoxidil therapy applied twice
daily for treatment of AGA. No statistical differences were found
between the two treatment groups, therefore validating the use of
daily treatment including the use of 0.01% tretinoin, instead of
twice-daily treatment with minoxidil monotherapy.
Alopecia Areata
Although systemic retinoid therapy has been shown to induce
hair loss in some patients, approaches involving the use of topi-
cal retinoids have shown promising results as therapeutic options
for treatment of AA. This difference in mode of administration
most likely represents targeted growth and differentiation from
topical retinoid application versus a complete systemic response
that may recruit a multitude of other biochemical pathways that
possibly result in unwanted side effects such as AA.
In a phase I/II randomized, half-head trial reviewing the ef-
cacy of 1% bexarotene gel for management of treatment refrac-
tory AA, general improvement in hair regrowth was found
FIGURE 22.5 Frontal brosing alopecia.
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133Retinoids in Hair Disorders
within a cohort of 42 patients over 24 weeks (39). Five of 42
(12%) had 50% or more partial hair regrowth on the treated side,
and 6 of 42 (14%) on both sides, including 3 complete responders.
Side effects included mild scalp irritation in 31/42 patients, with
4 patients having grade-3 irritation.
Topical tretinoin (0.05%) cream was also compared to topical
betamethasone dipropionate, dithranol paste (0.25%), and white
soft petroleum jelly in a cohort study of 80 patients with AA
(40). Medications were applied to the patients twice daily for 3
months. Assessment at the 3-month time interval showed good
regrowth in 55% of patients using tretinoin versus 70%, 35%, and
20% of those who used topical steroids, dithranol paste, or white
soft petroleum jelly respectively.
In a more recent study, the effectiveness of adapalene in com-
bination with steroids has been assessed for treatment of AA.
The researchers compared the efcacy of topical mometasone
furoate 0.1% cream monotherapy versus mometasone furoate
0.1% cream plus adapalene 0.1% gel in the treatment of AA (41).
Over a 12-week study period, mean regrowth scores were higher
in patients who were exposed to combination therapy. Mean per-
centages of hair regrowth in the combination group were statisti-
cally higher than monotherapy group for the fourth (50.2% vs.
23.5%), eighth (78.5% vs. 50.7%), and twelfth week (90.5% vs.
71%). This new approach has potential as a future therapeutic
modality in the treatment of AA.
Monilethrix
Monilethrix presents clinically with hair that tends to be normal
at birth but becomes short, fragile, and brittle within months.
This results in hypotrichosis, particularly on the occipital scalp
(42). It is characterized by regular, periodic thinning of hair
shafts, giving them a beaded appearance. Although the occipital
scalp is most commonly affected, the eyebrows and eyelashes
can be involved, as well as the nails. Three genes have been
associated with monilethrix (KRT81, KRT83, and KRT86),
which are responsible for the autosomal dominant form of the
disease (43).
Systemic retinoids have been reported as potential therapeutic
options for the treatment of monilethrix. A single case of child-
hood monilethrix showed increased hair length with loss of bead-
ing along the hair shaft with a dose of 0.5 mg/kg of etretinate
over 6 months (44). During treatment, the scalp appearance of
keratosis pilaris persisted, suggesting that the beading alone was
inuenced by etretinate. A second case report found cosmetic
and clinical improvement with the use of 0.5 mg/kg of acitretin
in a 7-year-old girl over a 12-month period, but clinical symp-
toms recurred within 4 months of therapy discontinuation (45).
Conclusions
Retinoids are implicated in the pathogenesis and treatment of
various hair disorders. Vitamin A and retinoids play an important
role in hair follicle transformation and the hair cycle. Therefore,
their use may interrupt the normal hair cycle and can cause a dif-
fuse hair loss that presents as a telogen efuvium. They may also
be responsible for changes in hair texture and color. Generally,
hair loss due to retinoids is reversible with the medication’s
withdrawal, and the overall prognosis is favorable. Conversely,
there is emerging evidence that retinoids are effective treatments
for various hair disorders, including frontal brosing alopecia,
alopecia areata, androgenetic alopecia, and monilethrix.
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