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Prostaglandin-Induced Hair Growth

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Latanoprost, used clinically in the treatment of glaucoma, induces growth of lashes and ancillary hairs around the eyelids. Manifestations include greater thickness and length of lashes, additional lash rows, conversion of vellus to terminal hairs in canthal areas as well as in regions adjacent to lash rows. In conjunction with increased growth, increased pigmentation occurs. Vellus hairs of the lower eyelids also undergo increased growth and pigmentation. Brief latanoprost therapy for 2-17 days (3-25.5 microg total dosage) induced findings comparable to chronic therapy in five patients. Latanoprost reversed alopecia of the eyelashes in one patient. Laboratory experiments with latanoprost have demonstrated stimulation of hair growth in mice and in the balding scalp of the stumptailed macaque, a primate that demonstrates androgenetic alopecia. The increased number of visible lashes is consistent with the ability of latanoprost to induce anagen (the growth phase) in telogen (resting) follicles while inducing hypertrophic changes in the involved follicles. The increased length of lashes is consistent with the ability of latanoprost to prolong the anagen phase of the hair cycle. Correlation with laboratory studies suggests that initiation and completion of latanoprost hair growth effects occur very early in anagen and the likely target is the dermal papilla.
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S185
SURVEY OF OPHTHALMOLOGY
VOLUME 47
SUPPLEMENT 1
AUGUST 2002
© 2002 by Elsevier Science Inc. 0039-6257/02/$–see front matter
All rights reserved. PII S0039-6257(02)00307-7
Prostaglandin-Induced Hair Growth
Murray A. Johnstone, MD,
1
and Daniel M. Albert, MD, MS
2
1
Glaucoma Consultants Northwest, Swedish Medical Center, Seattle, Washington, and
2
University of Wisconsin,
Madison, Wisconsin, USA
Abstract.
Latanoprost, used clinically in the treatment of glaucoma, induces growth of lashes and
ancillary hairs around the eyelids. Manifestations include greater thickness and length of lashes, addi-
tional lash rows, conversion of vellus to terminal hairs in canthal areas as well as in regions adjacent to
lash rows. In conjunction with increased growth, increased pigmentation occurs. Vellus hairs of the
lower eyelids also undergo increased growth and pigmentation. Brief latanoprost therapy for 2–17 days
(3–25.5
g total dosage) induced findings comparable to chronic therapy in five patients. Latanoprost
reversed alopecia of the eyelashes in one patient. Laboratory experiments with latanoprost have dem-
onstrated stimulation of hair growth in mice and in the balding scalp of the stumptailed macaque, a
primate that demonstrates androgenetic alopecia. The increased number of visible lashes is consistent
with the ability of latanoprost to induce anagen (the growth phase) in telogen (resting) follicles while
inducing hypertrophic changes in the involved follicles. The increased length of lashes is consistent
with the ability of latanoprost to prolong the anagen phase of the hair cycle. Correlation with labora-
tory studies suggests that initiation and completion of latanoprost hair growth effects occur very early in
anagen and the likely target is the dermal papilla. (
Surv Ophthalmol 47(Suppl 1)
:S185–S202,
2002. © 2002 by Elsevier Science Inc. All rights reserved.)
Key words.
alopecia anagen eyelash hair hair follicle hair
growth • hypertrichosis • glaucoma • latanoprost • prostaglandin
Latanoprost, a prostaglandin analog, is an effec-
tive
15
and widely used medication in the treatment of
open-angle glaucoma.
15
Recently, latanoprost has
been recognized as a drug capable of regularly in-
ducing hypertrichosis involving eyelashes, adjacent
adnexal hair, and vellus hair of the skin.
46,121
The
purpose of the present article is to reconcile latano-
prost-induced hypertrichosis with what is known
about hair characteristics and hair follicle behavior.
Hair follicles are a complex structure that undergo
recurring cycles of involution and growth. The fac-
tors regulating the transition between the three
stages of the hair cycle are critical to understanding
hair follicle behavior, but those factors are not well
understood. Studying the response of hair follicles
to latanoprost may offer some additional insights
into mechanisms modulating follicle behavior.
For descriptive purposes, hair is typically charac-
terized as having three different types: vellus, inter-
mediate, and terminal. Vellus hair is soft, unmedul-
lated, short, and unpigmented. Terminal hair is
coarse, medullated, longer, and pigmented. The ap-
pearance of intermediate hair is between that of vel-
lus and terminal, and presents a spectrum of appear-
ances. Approximately five million hair follicles cover
the human body at birth and no additional follicles
are formed after birth.
92
However, the type of hair
produced by a given follicle can change, as exempli-
fied in changes in hair follicle behavior at puberty.
Hairs of the eyelashes and those that form the eye-
S186 Surv Ophthalmol 47 (Suppl 1) August 2002
JOHNSTONE AND ALBERT
brows are the first terminal hairs to appear during
development.
48
Eyelashes have the widest diameter
of body hairs, are the most highly pigmented of the
terminal hairs,
8
and generally do not become gray
with age.
61
Hair Cycle
EMBRYOGENESIS AND CYCLING
A unique feature of hair follicles is their cyclical
behavior, which at each hair cycle recapitulates em-
bryologic development. During embryogenesis, in-
ducing signals from the dermal papilla,
125,128
originat-
ing from the mesoderm, cause epithelial elements in
the ectoderm to proliferate, differentiate, and mi-
grate downward into the dermis, culminating in de-
velopment of a mature hair follicle. Hair follicles
then begin to undergo cyclic behavior.
CATAGEN AND TELOGEN
Cyclic behavior leads to an involutional stage (
cat-
agen
) during which epithelial elements undergo
apoptosis
124
by a programmed dedifferentiation.
52
The
epithelial elements migrate toward the surface, and
by late catagen leave only secondary epithelial hair
germ cells in an area called the bulge, which is located
at the level of the arrector pili muscle (Fig. 1). A de-
crease to one-third of the hair follicle’s former
length occurs during the upward migration.
62
Asso-
ciated with the upward migration and dedifferen-
tiation, the residual epithelial stalk becomes sur-
rounded by a greatly thickened and corrugated
“glassy” basement membrane zone; the perifollicular
connective tissue also becomes wrinkled and folded
during late catagen, culminating in development of
a club follicle surrounded by a club hair (Fig. 1).
The club follicle thus finally matures to leave a club
hair during the resting stage (
telogen
). Telogen then
persists until the next anagen phase.
ANAGEN
In response to a stimulus of unknown origin from
the dermal papilla, the secondary epithelial germ in
the bulge
19
initiates a new growth phase of the hair
follicle, namely,
anagen
. During mid anagen, the
newly formed hair then dislodges the old club hair
that still lies in the follicular canal. The germinative
epithelial cells in the bulge are of a population
unique from other follicular epidermis. When anagen
is triggered, embryologic events are recapitulated
and a new hair follicle is formed during early
Fig.
1
.Ha
i
r
f
oll
i
cle cycle.
Af
ter
i
n
i
t
i
al
morphogenesis culminating in a mature
follicle, the hair follicle undergoes an in
-
volutional phase (catagen) followed by
a
resting phase (telogen). A new growth
phase (anagen) then ensues in response
to signals from the dermal papilla, thus
initiating a recurring cycle. Elucidation o
f
the constellation of molecular signals tha
t
orchestrate the transition between the
phases of the hair cycle is a central focus
of hair research.
PROSTAGLANDIN-INDUCED HAIR GROWTH
S
187
anagen. The dermal papilla is necessary to both in-
duce and maintain the hair follicle.
6,53,125
The vol-
ume of the dermal papilla, which is determined by
controlling the number of matrix cells in the hair
bulb, determines the diameter of the induced hair
shaft and may also determine the duration of
anagen.
41,92
SYNCHRONY AND DURATION
Although the hair cycle in many animals is syn-
chronous, in humans it is asynchronous. The entire
cycle varies in length depending on location in the
body. On the scalp vertex, hair grows at a rate of 0.40
mm per day,
62
and scalp hair may grow for as long as
6 years.
92
Of the 100,000 hairs on the scalp,
76
approx-
imately 84% are in anagen stage, 2% in catagen,
14% in telogen,
62
and about 70–100 are shed daily.
76
A much shorter anagen phase and relatively longer
telogen phase characterize eyelashes and eyebrows
compared to scalp hair, and they have the lowest ra-
tio of anagen to telogen follicles. Eyelashes grow for
approximately 30 days, undergo quiescence for 15
days, and remain dormant for about 100 days.
48
The
total length of the cycle is reported to be 5 months.
61
The growth phase of the cycle in eyebrows is approx-
imately 6 months with an equal period of rest.
76,116
Hair Structure
To fully appreciate the myriad molecular signals
that must be implicated in maintenance of the con-
tinuous cycling of the hair follicle, it is useful to re-
view the numerous cellular and structural elements
comprising the follicle. Anatomically, the hair folli-
cle unit consists of a fibrous connective tissue
sheath, an outer root sheath, an inner root sheath.
and the hair shaft. A sebaceous gland and an arrector
pili muscle complete the follicle unit (Figs. 1 and 2).
The eyelashes are uniquely distinguished by the ab-
sence of an arrector pili muscle.
61
The entire follicle
in the anagen phase may extend to a depth in the
Fig.
2
.Ha
i
r structure
d
ur
i
ng the late
anagen phase of the hair cycle. The il
-
lustration emphasizes the highly differ
-
entiated concentric layers of the folli
-
cle, each with their respective cell type
and protein products. Components o
f
the hair shaft undergo programmed in
-
volution and harden or cornify by
a
process of keratinization as they move
upward within the inner root sheath. The
inner root sheath and hair shaft move
upward as a unit sliding past the oute
r
root sheath.
S188 Surv Ophthalmol 47 (Suppl 1) August 2002
JOHNSTONE AND ALBERT
dermis three times that of the distance from the sur-
face to the arrector pili muscle. The section of the
follicle below the arrector pili is transitory in the
sense that it disappears during catagen and reforms
during anagen.
FIBROUS SHEATH, BASEMENT MEMBRANE
(VITREOUS MEMBRANE) AND OUTER
ROOT SHEATH
The fibrous sheath surrounding the follicle is
composed of thick collagen bundles. Beneath the fi-
brous sheath is a glassy or vitreous membrane simi-
lar to a subepidermal basement membrane but
thicker. The outer root sheath of the hair follicle is
continuous with cells lining the epidermis. In addi-
tion to epithelial cells, the outer root sheath con-
tains amelanotic melanocytes,
109
Langerhan’s cells,
29
and Merkel neurosecretory cells.
50
INNER ROOT SHEATH
Moving inward, the next layer is the inner root
sheath, which is composed of three separate cell
types. The first is Henley’s layer, containing a single
layer of cells; the second is Huxley’s layer, which is
composed of two concentric rows of specialized cells
containing trichohyalin granules; and the third is
the cuticle of the inner root sheath, a single layer of
flattened squamous cells with atrophic nuclei.
HAIR SHAFT
Moving further inward, the three layers of the hair
shaft are encountered. They consist of the cuticle of
the hair shaft, which surrounds the hair as it
emerges from the surface of the skin. The hair shaft
cuticle surrounds the cortex, which in turn sur-
rounds the medulla. Cuticle cells of the hair become
imbricated with their free ends directed upward, en-
abling them to interlock with the cells of the cuticle
of the inner root sheath with their free ends directed
downward. The inner root sheath and hair shaft
move upward together gliding over the relatively
more stationary outer root sheath.
76
HAIR BULB AND MATRIX CELLS
The hair bulb is the thickest part of the follicle at
the lower end. The bulb contains a proliferative
zone composed of a germinative matrix of undiffer-
entiated pluripotent polygonal cells capping the der-
mal papilla. These matrix cells of ectodermal origin
give rise to the seven epithelial cell types that make
up the layers of the follicle
125
(Fig. 2). The matrix
cells of the bulb are involved in intense metabolic ac-
tivity with a complete replication cycle in the human
scalp of about 39 hours, which may be greater than
that of any other tissue with the exception of bone
marrow.
76
Matrix cells that differentiate into medulla and
cortical fibers of the hair shaft move upward where
they are shaped and compressed into their final
form by the rigid inner-root sheath, which kerati-
nizes before the hair shaft.
62
The dimensions and
curvature of the inner root sheath thus determine
the thickness and curvature of the hair. Once the di-
mensions of the rigid inner root sheath are estab-
lished, further changes in shape do not easily occur,
suggesting that the size and shape of the follicle is
determined early in anagen when cells of the inner
root sheath begin to differentiate. The length of hair
is directly proportional to the duration of anagen.
92
The dermal papilla contains specialized fibroblasts
that control the number of matrix cells in the hair
bulb and may by this means control the thickness of
the resulting hair.
92
MATRIX CELL DIFFERENTIATION AND
KERATINIZATION DURING ANAGEN
Differentiation begins above the hair bulb, lead-
ing to formation of the concentric highly differenti-
ated epithelial layers of the follicle. During anagen,
programmed involution of the cortex and medulla
cells begins above the hair bulb, ultimately leading
to completion of keratinization and cornification
(hardening) about half way up the shaft.
7
This re-
gion is defined as the keratogenous zone. The cells
of the inner root sheath also undergo programmed
involution during anagen as they reach the region of
the arrector pili muscle and do not contribute to the
emerging hair.
91
MELANOCYTES AND MELANOGENESIS
Numerous large melanocytes, with well formed
dendritic processes, are located over the apex of the
papilla in the region of the superior hair bulb (Fig.
2) and divide infrequently.
52
The melanocytes are in-
volved in intense melanin synthesis and their den-
dritic processes contain a dense accumulation of me-
lanosomes. Melanin is actively transferred to the
medullary and cortical cells of the hair follicle by
phagocytosis of the melanosome-rich dendritic pro-
cesses of the melanocytes.
8,104
Pigment production
and transfer only occur during anagen. At the onset
of catagen, melanocytes undergo involution, mela-
nin synthesis ceases, the dendrites are resorbed, and
the melanocytes undergo programmed dedifferenti-
ation to take on the appearance of undifferentiated
epithelial germ cells.
52
Anagen-associated melanogenesis and the cyclic
production of a pigmented hair shaft result from
programmed and tightly coordinated epithelial,
mesenchymal, and neuroectodermal interactions.
107
A phagocytic mechanism involving uptake of mela-
nosomes from the dendritic processes of melano-
PROSTAGLANDIN-INDUCED HAIR GROWTH
S
189
cytes also occurs in the cells of the epidermis that
are constantly dividing but are not involved in cycli-
cal growth and involution. Iris melanocytes in con-
trast are thought to be continent with no pigment
transfer to the surrounding iris stromal cells.
Three types of melanosomes are present in hair.
Eryrthromelanin granules, seen in red hair, are poly-
morphous and have an irregular internal structure.
Homogenous eumalanin granules are seen in dark
hair and lamellated pheomelanin granules predomi-
nate in light hair.
62,66
In gray and white hair melano-
somes are reduced or absent.
66
THE DERMAL PAPILLA
The dermal papilla is a connective tissue compo-
nent inside the anagen hair bulb (Fig 2). The papilla
contains specialized fibroblasts, histiocytes, mel-
anophages, mast cells, Langerhans’ granule-contain-
ing cells, ground substance, and collagen fibers. A
profuse system of small blood vessels supplies the
dermal papilla. A stalk connects the underlying con-
nective tissue to the papilla and a basement mem-
brane separates it from the matrix cells of the bulb.
7
During catagen the dermal papilla migrates upward
with the hair bulb to lie beneath the residual second-
ary epithelial germ cells at the bulge.
BLOOD SUPPLY AND INNERVATION
There is a rich blood supply to the follicular unit
with the greatest concentration of vessels in areas of
greatest metabolic activity. The vascular supply un-
dergoes active remodeling during the hair follicle
cycle with a marked diminution of the blood supply
of the lower portion of the telogen follicle.
18,59
It is
hypothesized that the actively growing follicular unit
is the primary stimulus determining the blood sup-
ply of the structure, with the blood supply largely a
reflection of the growth needs of the follicle.
18
Hair
follicles are the most richly innervated part of the
skin and active remodeling of hair follicle innerva-
tion occurs throughout the normal hair-follicle cy-
cle.
12
Furthermore, neurotrophins play an active
role in modulating the phases of the hair cycle.
11
INTEGRATION OF THE HAIR CYCLE WITH
CELLULAR AND STRUCTURAL RELATIONSHIPS
Active features of the hair cycle thus include pro-
liferation, differentiation into multiple epithelial
cell types, migration, angiogenesis, and pro-
grammed dedifferentiation. Cellular elements in-
volved in cyclical behavior include fibroblasts of the
connective tissue sheath; epithelial cells, melano-
cytes, and Merkel cells (assumed to be touch recep-
tors) of the outer root sheath; seven different deriva-
tives of the germinal epithelial cells; melanocytes of
the bulb; dermal papilla fibroblasts and melano-
cytes; vascular endothelial cells; and nerve fibers.
Synchronization of a remarkable number of cellular
processes and cell types is thus essential for proper
maintenance of the hair cycle. Once a phase of the
hair cycle is initiated, ensuing events in the follicular
tissue are highly regulated and tightly coupled. By
contrast, initiation of the various cycle phases is re-
sponsive to a variety of stimuli. A multiplicity of sig-
nals is known to be involved in controlling initiation
of the phases during cycling, but their attributes and
relative contributions remain to be clarified.
125
Prostaglandin-Induced Hair Growth—
Human Studies
ADVERSE EVENTS AND CASE REPORTS
In three phase III multicenter latanoprost clinical
trials in Europe, Scandinavia, and Japan involving
829 patients,
4
one case of darker eyelashes
5
was re-
ported with no cases of hypertrichosis seen.
5
A subse-
quent case report in a unilaterally treated eye re-
ported hyperpigmentation of the lashes and also
noted that the lashes appeared to be greater in
density and thickness. Treatment later applied to
the fellow eye caused a similar appearance.
121
Re-
cently, in a case report latanoprost reversed alopecia
of the eyelashes.
68
PATIENT SERIES
The paucity of reports of hypertrichosis following
latanoprost therapy suggested that this finding
might be spurious or represent a rare or idiosyn-
cratic event. However, hypertrichosis was indepen-
dently identified by a prospective study initiated in a
series of 43 patients who were unilaterally treated
with latanoprost.
46
Careful comparison of latano-
prost-treated and control eyes demonstrated that a
number of different manifestations of hypertrichosis
were regularly seen in the latanoprost-treated eye
(LTE) of these patients. A mean increase in lash
length of 19% (range 0–36%) was found in the LTE.
Lashes were regularly thicker in the LTE; a finding
illustrated in Figs. 3 and 4. The two patients who had
no measurable lash length change exhibited in-
creased numbers of lashes.
The types of manifestations also included in-
creased numbers of lashes in preexisting lash rows as
illustrated in Figs. 4, 5, and 6. In the areas of transi-
tion between the terminal lashes along the lash line
and the vellus hair of the skin, hair in the control
eye was a mixture of vellus and intermediate types, as
illustrated in Figs 5b, 5d, and 5f. Hair in the same
transition areas in the LTE had a more robust ap-
pearance, was longer, thicker, more heavily pig-
mented, and arose at a more acute angle from the
skin than in the control eye as illustrated in Figs. 5a,
S190 Surv Ophthalmol 47 (Suppl 1) August 2002
JOHNSTONE AND ALBERT
5c, and 5e. The increased number of terminal versus
vellus and intermediate hairs at times produced the
appearance of partial new rows of terminal lashes
(Figs. 5a, 5c, and 5e).
In the medial and lateral canthal area, where vellus
and intermediate hairs were present in the control
eye, a number of patients had a greater abundance of
thicker, longer, and more pigmented terminal hairs
in the same area of the LTE, a finding illustrated in
Figs. 6a and 6b. Pigmentation of the eyelashes and as-
sociated intermediate hairs was regularly greater in
the LTE than in the control eye. The increase in pig-
mentation was more notable in patients who initially
had darker lashes (Fig. 3). Several patients had a strik-
ing curling of the lashes (Fig. 6c). Although usually
not grossly visible, with slit-lamp examination the vel-
lus hair of the skin of the lateral portion of the lower
lid often appeared more abundant, longer, thicker,
and darker in the LTE. The most obvious eyelid hy-
pertrichosis observed clinically resolved following dis-
continuation of latanoprost (Fig. 7).
The findings pointed not only to a greater fre-
quency of terminal lashes but also lash hypertrophy
and hyperpigmention. In addition, altered differenti-
ation occurred in intermediate hairs adjacent to the
lash line and in regional adnexal and vellus hairs.
The diffuse occurrence of manifestations (Table 1)
of hypertrichosis observed in a study of 43 patients
46
provided evidence that hypertrichosis in response to
latanoprost was a generalized phenomenon rather
than a rare or idiosyncratic one.
More recently, in a prospective study, lash length
was assessed in 14 eyes of 7 patients using a digital im-
aging technique after latanoprost treatment for a
minimum of 5 months. Longer lashes (0.75 mm)
were observed in two eyes of one patient (14% of to-
tal patients) following treatment. In the same pa-
tients, lash thickness was assessed subjectively. Ten of
14 eyes (71%) were judged to have thicker lashes.
82
In a subsequent report, 100% of treated eyes had in-
creased eyelash lengths.
81
Follicle counts and sophis-
ticated techniques for measurement of hair growth
currently used on the scalp have not been applied to
the eyelashes. Such techniques may in the future pro-
vide more sensitive tools for assessment of the hair
growth-inducing effects of prostaglandins.
F
ig. 3.a: Eyelashes of upper eyelid of latanoprost-treated eye (LTE), and b: control non-treated eye (NTE) of 71-year
-
old Caucasian man. c: Lashes of lower eyelids of LTE and d: NTE of 52-year-old Caucasian man. In the LTE in both pa
-
tients eyelashes are longer and thicker (trichomegaly) as well as more numerous (polytrichia). In addition, lashes are
more pigmented in the LTE. The pigmentation increase is more striking in the initially more darkly pigmented eyelashes
of the patient in a and b.
PROSTAGLANDIN-INDUCED HAIR GROWTH
S
191
Lash growth has been reported following installa-
tion of two topical prostaglandin eye drops recently
introduced for pressure control in glaucoma. After
taking travoprost 0.004% for 12 months, changes in
eyelashes, including increased length, thickness,
density, and color, were reported in 57% of pa-
tients.
79
In patients taking bimatoprost 0.03% for 3
months, eyelash growth was reported in 12%.
27
EFFECTS OF BRIEF, LOW-DOSE
LATANOPROST TREATMENT
A subsequent study
45
was initiated to determine
the minimum interval of latanoprost exposure neces-
sary to cause hypertrichosis of eyelashes and to exam-
ine the duration of the resulting effect. Records and
photographs of 89 glaucoma patients with hypertri-
chosis following unilateral treatment with topical la-
tanoprost were reviewed. Five patients had taken top-
ical latanoprost for a brief interval (
21 days); male:
female ratio, 2:3; all Caucasian; average age 72. Treat-
ment duration was 2, 3, 5, 12, and 17 days. In each of
these patients, latanoprost was stopped because of is-
sues of intolerance or allergy. Follow-up listed in or-
der determined by the previously described treat-
ment duration was 13, 14, 5, 6, and 4 months. Brief
treatment findings (
21 days) were compared with
sustained (
21 days) treatment findings.
In the 5 patients treated briefly,
45
increased num-
ber, length, thickness, and pigmentation of lashes oc-
curred (Fig. 6c) and findings were similar in magni-
tude to those following unilateral sustained treatment.
There was no obvious correlation between appear-
ance and duration of treatment except in three pa-
tients who took latanoprost for
5 days. Each had
marked curling of lashes (Fig. 6c) that was non-uni-
form in direction and degree, in contrast to the occa-
sional more modest uniform curling seen with sus-
tained treatment. Within a few months following
cessation of latanoprost therapy, polytrichia was no
longer obvious. In contrast to patients treated chroni-
cally (
21 days), in each patient treated briefly (
21
days), trichomegaly persisted to some degree through-
out the duration of the follow-up interval.
IMPLICATIONS OF HAIR GROWTH INDUCED BY
BRIEF TREATMENT
It is extremely unusual for a 2-day course of treat-
ment to have manifestations up to 14 months later
F
ig. 4. 76-year-old Caucasian male. Eyelashes of upper eyelid of latanoprost-treated eye (LTE) (a) compared with con
-
trol non-treated eye (NTE) (b). Eyelashes of lateral portion of lower lid of LTE (c) and NTE (d). Trichomegaly, polytri
-
chia, and hyperpigmentation are apparent in the eyelashes of the LTE. Note the marked differences in the eyelash ap
-
pearance in the lateral portion of the lower lids, a location where the latanoprost-associated eyelash differences were
often most striking and easily appreciated.
S192 Surv Ophthalmol 47 (Suppl 1) August 2002
JOHNSTONE AND ALBERT
and such observations deserve further consider-
ation. Initiation of anagen following very low doses
and brief exposure times to latanoprost is surprising
but may have a rational explanation. Mutual induc-
tive influences between the ectodermal and meso-
dermal elements initiate a programmed develop-
ment of the follicle.
6,26
The type and duration of the
inductive influences necessary to initiate and sustain
the hair cycle are unknown.
26
However, very brief ex-
posure to inductive stimuli during embryogenesis is
capable of establishing a developmental path by
means of tightly linked successive or sequential in-
duction programs.
3
For example, some signaling
ligand responses can begin abruptly as the concen-
tration of ligand increases, providing a molecular basis
for steep or even switch-like signals.
2
Once a cell has
been directed into a particular path of differentiation,
it may begin to secrete autocrine-signaling mole-
cules that then reinforce a developmental decision.
3
The very brief stimulus required to initiate in-
creased growth and altered differentiation of hair
follicles as observed in the study
45
suggests that a
program is initiated to trigger the anagen phase of
the hair cycle in the follicles of eyelashes and that
this program is able to proceed in the absence of an
ongoing stimulus. Whether a similar brief stimulus is
required to initiate anagen in other hair types has
not been studied.
Increased hair length as observed in the latano-
prost-induced eyelash growth studies is associated
with an increase in the duration of the anagen
phase. The increased anagen duration has been hy-
pothesized to be determined at the initiation of the
anagen phase and is probably controlled by the der-
mal papilla.
92
The increased pigmentation in the
eyelashes is different than that in the iris because the
pigmentation in eyelashes is associated with melano-
cyte differentiation and the associated melanogene-
sis is tightly coupled to the process of differentiation.
A brief low total dosage, (
3
g) administered
over 2 days may cause the picture of polytrichia, tri-
chomegaly, and hyperpigmentation.
45
Marked irreg-
ular lash curling was observed following 5 days of la-
tanoprost treatment
45
and may result from a lack of
uniform penetration into the hair follicle leading to
slightly asymmetric development of the follicle and
inner root sheath. Evidence of unilaterally greater
lash thickness, length, curling, and pigmentation fol-
lowing brief treatment persisted for up to 14
months.
45
However, this retrospective study ended at
14 months. Whether the duration of trichomegaly
may persist for a longer time has not been studied.
Because the number of follicles remains constant
throughout life, findings of polytrichia suggest that
the ratio of anagen to telogen follicles (about 50:50
in eyelashes) is shifted to an increased percent of the
F
ig. 5. Eyelashes of lower eyelid of 77-year-old Caucasian man: latanoprost-treated eye (LTE) (a), control non-treated
eye (NTE) (b). Eyelashes of lower eyelid of 65-year-old African-American male LTE (c), NTE (d). Eyelashes of lower eyelid
of 83-year-old Asian woman LTE (e), NTE (f). In all three racial groups, note apparent polytrichia, trichomegaly, and hy
-
perpigmention. Note also development of partial additional row of eyelashes below the primary lash line in the LTE vs.
the NTE in each patient.
PROSTAGLANDIN-INDUCED HAIR GROWTH S193
follicles entering the anagen phase. Without a per-
sistent stimulus the ratio of anagen to telogen folli-
cles eventually return to pretreatment levels.
The persistent trichomegaly following brief latano-
prost therapy suggests either that some follicles have a
prolongation of the anagen phase, that the data re-
lated to the normal length of the hair cycle in the folli-
cles may be longer than the reported 6 months, or
that there is an alteration in the developmental pro-
gram carried by the germinative epithelium that then
persists from one cycle to the next. Such changes in
the developmental program can occur in adults as il-
lustrated by androgenetic alopecia. For example, a
gradual alteration in the developmental program is
thought to occur in hair follicles during androgenetic
alopecia. There is a progressive shortening of succes-
sive anagen cycles, miniaturization of the follicles, and
an eventual change in the differentiation pattern to
produce vellus rather than terminal hair. The observa-
tion that a trophic change in the developmental pro-
gram may be carried by the germinative epithelium
from one cycle to the next in response to a therapeu-
tic agent is heartening and warrants further study.
A possible explanation for the difference in a pat-
tern of persistence of trichomegaly in patients with
chronic latanoprost therapy in contrast to those with
brief therapy is that inhibitory effects or downregula-
tion may occur in response to a greater cumulative
dosage used in chronic therapy. A relevant example
of such dose-dependent inhibitory behavior on cell
proliferation in hair follicles is illustrated by minoxi-
dil. Minoxidil increases DNA synthesis in both der-
mal papilla and follicular germ cells, but at higher
concentrations suppressed DNA synthesis.55 Further-
more, a similar increase in DNA synthesis has been
found in skin cells treated with minoxidil, but cytotoxic
effects occurred at higher concentrations, with a nar-
row margin between proliferation and cytotoxicity.95
Such observations with minoxidil, coupled with
clinical observations following brief versus chronic
latanoprost usage, are intriguing because they sug-
gest that there may be a very narrow dose and dura-
tion-dependent therapeutic window for optimizing
the effects of these hair growth agents. Scalp hair
with an approximate 7-year growth cycle does not
provide a convenient clinical model for studying the
effects of hair growth-inducing agents. Because of
their bilateral symmetry, their relatively short growth
cycle, their normally well-defined length, and their
normally high ratio of telogen to anagen follicles,
F
ig. 6. In a 49-year-old Caucasian man, note the altered lash development in lateral canthal area in latanoprost-treated
eye (LTE) (a) compared with control non-treated eye (NTE) (b). The altered development includes increased numbers of
terminal lashes in the region as well as increased pigmentation. Photographs in 6c (LTE) and 6d (NTE) are of the eyelashes
of a 79-year-old Caucasian woman taken 7 months following brief (2 days), low total dose (3 g) latanoprost instillation.
Lashes remain increased in number, are longer, thicker, more pigmented, and also more curled than in the fellow eye.
S194 Surv Ophthalmol 47 (Suppl 1) August 2002 JOHNSTONE AND ALBERT
lash growth responses may represent a unique model
for unlocking the mysteries of subtle but potentially
extremely important dose-dependent responses of
follicles exposed to hair growth agents.
PATIENT EXPECTATIONS AND EDUCATION
Clinical implications of the latanoprost-induced
hair growth phenomenon relate primarily to cos-
metic issues. One might advise patients as follows
prior to starting the agent: An increase in apparent
number, length, and thickness of lashes is likely fol-
lowing initiation of treatment. The increase in lash
length and thickness is likely to be no more than
about 20% and will reach its maximum in about 3
months. When administered bilaterally, the lash
growth effects often go unnoticed by patients and
their families. When lash growth is noticed, the
growth generally is modest enough to not be of cos-
metic concern and is often welcomed by women tak-
ing the agent. When administered unilaterally, the
lash appearance is generally not a cosmetic concern,
but occasionally may be moderately troublesome.
The above explanation is probably adequate for
most patients.
For patients wanting to know more detail the fol-
lowing may be useful: The apparent increase in lash
numbers is a result of two things. Latanoprost stimu-
lates resting lash follicles to grow, thus initially
changing the ratio of growing follicles to those nor-
mally at rest. In addition, some lashes along the lid
margin that are generally small may become en-
larged. Over time the number of apparent increased
numbers of lashes will likely diminish as the ratio of
growing to resting lashes returns to equilibrium.
The apparent increase in lash length and thickness
is likely to persist while taking the agent. Following
discontinuation of latanoprost, the increased length
and thickness of lashes may persist for a period of
F
ig. 7. Hypertrichosis of lower eyelids (a and b) following 4 months of latanoprost therapy in 80-year-old Caucasian fe
-
male. Complete resolution of hypertrichosis occurred within several months following discontinuance of latanoprost. Pho
-
tos c and d were taken 3 years following discontinuation of latanoprost therapy.
PROSTAGLANDIN-INDUCED HAIR GROWTH S195
months or longer. There may be some slight increase
in growth of hair on the eyelids but it is extremely
rare for the growth to be noticeable to patients or
their families. Following the use of latanoprost in
chronic therapy, latanoprost-induced growth of hair
on the lids appears to be reversible (Fig. 7).
Latanoprost-Induced Hair
Growth—Animal Studies
The underlying mechanism of latanoprost-associ-
ated hair growth is poorly understood at the present
time. Preliminary experiments were carried out in
the mouse and macaque to determine if these ani-
mals show a hair growth response to latanoprost and
can serve as models for studying the mechanism of
action.
MURINE MODEL
Using the C57 BL/6 mouse as a model of anagen
induction on the normal hair-growth cycle, studies
were designed to determine if latanoprost influences
the timing or onset of anagen cycling in normal hair
(Voss et al, in preparation). Previous studies have re-
ported that hair growth in this mouse strain is in-
duced by treatment with cyclosporin A.69,94 Truncal
skin pigmentation is also dependent on the melano-
cytes present in the hair follicles rather than epider-
mal pigmentation.69 Mature melanocytes are not
present in the telogen phase of the C57 BL/6 mouse
hair cycle, causing the skin to be pink/white in
color. The number of melanocytes in each follicle
increases as anagen is initiated, causing skin pigmen-
tation to turn gray/black in color. In addition to the
gross observations of pigmentation changes, the
mouse skin demonstrates thickening as the hair cy-
cle progresses from telogen to anagen.
Paus et al reported that topical application of cy-
closporin A, an immunosuppressant known for its
hypertrichotic effects, induced anagen in 75% of
treated mice within a 10-day period in the C57 BL/6
strain.94 They also observed that this drug induced
more complete hair growth when compared to con-
trols.94 Maurer et al have reported responses of
100% in experimental mice within a 15-day period
using cyclosporin A and 90% in 17 days using FD
306, another immunosuppressant.69 Preliminary stud-
ies with latanoprost applied topically to the C57 BL/6
model indicate that latanoprost promotes rapid in-
duction of the hair growth cycle into anagen phase
when compared to vehicle-treated mice. These changes
can be observed grossly by skin pigmentation and
microscopically by measuring skin thickness (Voss et
al, in preparation).
PRIMATE MODEL
Using the primate model of androgenetic alopecia
(male pattern baldness), the stumptailed macaque
(Macaca arctoides), studies were done to determine
whether latanoprost influenced hair type and thickness
(Uno et al, in presss: Acta Dermato-Venereologica).
These monkeys develop frontal alopecia and have
been utilized for screening of several hair growth
agents, including minoxidil and finasteride.100,117,118
Analysis of the hair in the scalp of the stumptailed
monkeys included grading of hair growth in sequential
global photographs and phototrichographic analysis
of vellus, intermediary, and terminal hairs as de-
scribed in previous studies.119,120 Preliminary experi-
ments suggested that latanoprost increased hair den-
sity and converted vellus hair to intermediary hair
type (Uno et al, in press: Acta Dermato-Venereologica.)
Hair Growth Changes Induced
by Other Prostaglandins
PGE2- AND PGF2-MURINE STUDIES
Prior to the introduction of latanoprost, hair
growth modulation by prostaglandins had been in-
vestigated. Houssay examined the effect of PGE2 and
PGF2 on the diffuse hair wave in mice. The prostag-
landins were administered intraperitoneally twice a
day.37 After a 22-day period of treatment a marked
inhibition of hair growth was noted in the prosta-
glandin-treated mice. PGE2 analogs have been inves-
tigated as agents against radiation- or doxorubicin-
induced alopecia in a murine model of hair injury.
The extent of hair loss and regrowth was evaluated.
Both systemic and topical application of a PGE2
analog resulted in a significant degree of protec-
tion against radiation-induced28,32,67 or doxorubicin-
induced67 alopecia.
TABLE 1
Latanoprost-Induced Hair Growth Manifestations
Lashes
Increased lash numbers in lash row
Additional lash rows
Increased lash length
Increased lash thickness
Increased lash curling
Steeper lash angulation from follicle
Increased pigmentation
Medial and Lateral Canthal Hair
Increased number of visible hairs
Vellus and intermediate hair develops into terminal hair
Increased pigmentation
Skin of Lid
Vellus hair
Thicker
Longer
Increased pigmentation
S196 Surv Ophthalmol 47 (Suppl 1) August 2002 JOHNSTONE AND ALBERT
Arachadonic acid metabolism in dermal papilla
cells was stimulated by the calcium ion ionophore
A23187 to produce large amounts of PG6ketoF1 al-
pha, PGE2 and leukotriene B4. High concentrations
of VEGF also induced production of the above me-
tabolites. Low concentrations of minoxidil inhibited
PG6KF1 alpha production but stimulated produc-
tion of PGE2 and LTB4, thus implicating VEGF and
minoxidil in the modulation of eicosanoid produc-
tion by dermal papilla cells.57
Growth effects were absent in skin keratinocytes
after treatment with PGE1 or PGF210 in one study.
However, another study found that prostaglandin E
receptor EP2 and EP3 subtypes have real effects on
the rate of proliferation of keratinocytes.54 Prosta-
glandin endoperoxide synthase-1 is present in the
dermal papilla from human hair follicles, and mi-
noxidil is an activator of the enzyme as evidenced by
its ability to cause increased PGE2 production by
murine 3T3 fibroblasts.70 However, minoxidil had
no effect on PGE2 or PGF2 production in kerati-
nocytes.56 In melanocytes of anagen hair bulbs,
arachidonate may, through production of endoge-
nous prostaglandins, stimulate dispersion of mela-
nosomes into the dendritic processes. This was dem-
onstrated by a series of cellular events characterized
by peripheral orientation of microfilaments in the
dendritic processes and by associated complexing of
melanosomes.103
SELECTIVE PROSTANOID RECEPTOR AGONIST
ACTIVITY-MURINE STUDIES
Regrowth of fur in adult CBA-J mice was assessed
following treatment with DP, EP1, EP2, EP3, FP, IP,
and TP receptor agonists. Fur regrowth was signifi-
cantly different from the control group only follow-
ing application of the FP receptor agonist flupros-
tenol (p 0.01).113
PGE2 ANALOG-HUMAN STUDIES
Viprostol, a PGE2 analog, is an effective antihyper-
tensive agent in oral, intravenous, and even trans-
dermal forms. It reduces blood pressure by direct re-
laxation of arteriole smooth muscle and has an
established transdermal delivery system with marked
follicular penetration and high perifollicular con-
centrations. In fact, mean percutaneous absorption
of viprostol is approximately 40–60% with an elimi-
nation half-life of 4–6 days.80 Because of evidence of
reduced scalp blood flow in male pattern baldness,
this drug was felt to be promising as a treatment for
androgenetic alopecia. A randomized prospective
controlled trial in 57 men was undertaken but dem-
onstrated that hair counts declined in the treatment
groups at the end of a 6-month study.80 In another
study viprostol administration led to human scalp
hair growth providing an argument that the E series
prostaglandins may have an effect on hair growth al-
though to a lesser extent than the F series.101
Hair Growth Changes Induced by
Non-Prostaglandin Drugs
Other drugs which have an impact in modulating
hair growth are of interest because examination of
their behavior may shed some light on the mecha-
nism by which latanoprost induces changes in mod-
ulation of hair growth and cycling. Drug-induced
hair loss generally affects the follicles in the anagen
phase through two main modalities.
HAIR LOSS (ANAGEN EFFLUVIUM)
The first modality of drug-induced hair loss,
anagen effluvium, involves abrupt cessation of mi-
totic activity in rapidly dividing hair matrix cells and
the second (telogen effluvium) precipitates the folli-
cles into premature rest. In response to anagen ef-
fluvium, hair loss usually occurs within days to weeks
of drug administration.22,23 Anagen effluvium is the
typical adverse effect of antineoplastic drugs. Re-
gions of the body with the highest percentage of
anagen follicles, such as the scalp and beard, are
most severely affected by these insults, while those
with the lowest percentage of anagen follicles, such
as eyebrows and eyelashes, are least affected.
HAIR LOSS (TELOGEN EFFLUVIUM)
The second modality, telogen effluvium, may be
caused by a large number of agents, including antico-
agulants, interferons, retinoids, and antihyperlipi-
demic drugs. Drugs, in fact, are the least frequent
cause of telogen effluvium; post-natal, post-febrile,
weight loss, and psychogenic states are other frequent
causes. Some agents only occasionally cause hair ab-
normalities whereas others cause hair loss in most pa-
tients. In telogen effluvium, hair loss becomes appar-
ent 2–4 months following treatment.99 Hair loss is
usually reversible after interruption of treatment.
HAIR GROWTH
Hirsutism and hypertrichosis may be associated
with a number of drugs. Hirsutism is defined as the
growth of terminal hair with masculine characteristics
and pattern in women, whereas hypertrichosis de-
scribes the growth of terminal from vellus hair. Drugs
that induce hair growth include cyclosporin (30–
60% of patients following organ transplantation9,16),
minoxidil (80% with systemic therapy84), diazoxide
(almost 100% in children for hypoglycemia,116 1% in
adults for hypertension14), erythropoietin (13% of
patients51), calcium-channel blockers, benoxapro-
fen, and tretinoin.
PROSTAGLANDIN-INDUCED HAIR GROWTH S197
Basic Mechanisms Involved in the
Regulation of Hair Growth
MOLECULAR SIGNALS RELATED TO ONTOGENY
Review of the factors known to be involved in reg-
ulation of hair growth may provide insights into
mechanisms through which latanoprost modulates
hair growth. Molecular signals that control normal
hair distribution and follicle formation originally
were identified as the signals controlling ontogeny in
drosophila and include the mammalian counterpart
of genes such as hedgehog, patched, wnt, dishev-
eled, armadillo, engrailed, and notch.72,73,108 Protein
products of homeobox genes also appear at the loca-
tion where dermal appendages will form.85 Because
several of these gene products are present during
the hair cycle in adults they appear to be important
not only to embryogenesis but also to maintenance
of the cyclical growth pattern.30,73,93 Subsequent mat-
uration of the hair follicle also involves morphogens
such as sonic hedgehog and wnt.73,108
GROWTH FACTORS
Cytokine gene expression profiles identified dur-
ing the anagen phase include insulin-like growth fac-
tor 1, transforming growth factor beta 1, tumor ne-
crosis factor, and basic fibroblast growth factor.65
Insulin-like growth factor 1 and fibroblast growth
factor 7 are produced by the dermal papilla and cor-
responding receptors are found predominantly in
the overlying matrix cells of the bulb.20 Insulin-like
growth factor 1 maintains and increases follicle
growth in vivo.20,110 Hepatocyte growth factor is a
multifunctional polypeptide, which acts as mitogen,
motogen, or morphogen and stimulates the growth
of a variety of epithelial cells, and melanocytes.106
Human dermal papilla cells express hepatocyte
growth factor and stimulate DNA synthesis with
elongation of the hair shaft.44,106
Cessation of anagen is controlled by fibroblast
growth factor 5,102 and absence of the factor results
in persistence of anagen with an associated increase
in length of hair.36 Epithelial growth factor retards
hair growth74 and the receptor is involved in termi-
nating the anagen stage.31,78 Protein kinase C is a
negative regulator of hair growth and may play a
role in growth inhibitory signals.34 A transcription
factor encoded by the hairless gene is essential for
the dermal papilla to ascend and interact with the
stem cells of the bulge. If the dermal papilla does
not properly ascend to reach the bulge, for example,
when the hairless gene is defective, the follicle stops
cycling and permanent alopecia results.90
Dermal papilla cells synthesize and release vascular
endothelial growth factor.59 Dermal papilla cells also
bind vascular endothelial growth factor resulting in
subsequent proliferation and migration.60 Several
studies suggest the growing hair follicle has the abil-
ity to stimulate its own blood supply.111
HORMONES
Hair growth-regulating hormones include growth
hormone, thyroid hormones, glucocorticoids, estro-
gens, and androgens. Estrogen receptors are present
in the dermal papilla and 17-beta estradiol arrests
the follicles in telogen while an estrogen receptor
antagonist causes exit from telogen.87 Androgens act
through androgenetic receptors in the dermal pa-
pilla and have the most striking effects. During ado-
lescence, they cause vellus hair to differentiate into
terminal hair in androgen-dependent areas. In older
adults, this same androgen stimulation causes loss of
hair in areas susceptible to androgenetic alopecia.
Some dermal papillae secrete mitogens after andro-
genetic stimulation whereas others synthesize inhibi-
tory factors, which could result from genetically de-
termined differences in end organ responses of the
different follicles.
Consideration of Basic Mechanisms
Related to Latanoprost-induced
Hair Growth
TRANSITION FROM TELOGEN TO
ANAGEN FOLLICLES
Recently observed findings of hypertrichosis fol-
lowing latanoprost therapy suggest the induction of
the anagen phase in telogen follicles. The findings
following latanoprost treatment can be compared
with what is known from the literature about signals
that orchestrate the follicle transition from telogen
to the anagen stage. Because the total number of
lash follicles does not change, the ability of latano-
prost to increase the number of lashes is consistent
with the initiation of anagen in follicles normally in
telogen. The proportion of follicles in telogen is
normally higher in eyelashes (50%) than in hair
elsewhere (e.g., scalp 14%). Many eyelash follicles
are thus available to undergo transition from telo-
gen to anagen. In addition, the bilateral presence of
eyelashes provides a readily available control popula-
tion. The large telogen population and bilaterality
provide a uniquely sensitive and easily studied
model to assess drug-induced hair growth.
FOLLICULAR HYPERTROPHY DETERMINATION
EARLY IN ANAGEN
A stimulus from the dermal papilla determines
the course of differentiation of the matrix cells41,92
and the number of matrix cells that differentiate to
form the bulb determines the follicle size.92 After the
rigid internal root sheath has formed, enlargement of
S198 Surv Ophthalmol 47 (Suppl 1) August 2002 JOHNSTONE AND ALBERT
the follicle is not feasible,62 further supporting the
concept that hair follicle size is determined very
early in anagen. The follicular hypertrophy observed
with latanoprost is thus likely to result from a stimu-
lus very early in anagen and the dermal papilla may
be considered as a target tissue. Altered differentia-
tion of follicles from vellus and transitional to termi-
nal hair must also occur very early in the anagen cy-
cle for similar reasons.
DETERMINATION OF ANAGEN DURATION AND
HAIR LENGTH
An increase in hair length results when there is a
delay in cessation of anagen. Stimuli occurring dur-
ing anagen may initiate its cessation, an extreme ex-
ample of which occurs with telogen effluvium result-
ing from drug exposures. Delayed cessation of anagen
may also result from a stimulus in early anagen that in
part determines the duration of anagen for that hair
follicle cycle.41,92 One might postulate that increased
length of hair follicles observed following chronic la-
tanoprost therapy46 was associated with a delay in on-
set of catagen and determined by chronic exposure
to the agent. However, increased hair length that oc-
curred following very brief latanoprost exposure45
indicates that the continuous presence of the agent
is not required to cause increased duration of
anagen and increased hair length associated with la-
tanoprost treatment.
VASCULAR ISSUES
The actual mechanism by which latanoprost exerts
its action on hair follicles is unknown. PGF2, the
naturally occurring prostanoid from which latanoprost
was derived, causes vasodilatation; therefore, a vascular
stimulus could be postulated. However, studies with
viprostol, an active vasodilator, caused reduced hair
growth in one study. In addition, an exhaustive study
demonstrated a striking lack of vasoactive behavior
of latanoprost.112 Finally, the follicle is thought to
initiate a stimulus to recruit its blood supply rather
than vice versa.18 These combined observations make
a vascular mechanism seem less likely.
MITOGENIC ISSUES
A mitogenic stimulus must be required to trigger
cell division at the initiation of the anagen. More-
over, an ongoing mitogenic stimulus is also required
to facilitate continued division of matrix cells of the
anagen follicle.76 Furthermore, minoxidil behaves as
a mitogen in the hair follicle.55,75,95 PGF2, the par-
ent compound of latanoprost, has been shown to be
capable of inducing mitosis in aneuploid, immortal
murine 3T3 cells,25,43,122,123 endometrial cells,88,89 and
hepatocytes.44,106 Although such a stimulus occurs in
those unique cell systems, PGF2 has not been dem-
onstrated to be mitogenic in hair follicles. In the
eye, latanoprost and PGF2 did not enhance the mi-
totic index of human uveal or cutaneous melanoma
lines, measured by thymidine uptake, although both
drugs increased the mitotic index of one murine cu-
taneous line.24
CELL ADHESION MOLECULES
Rapid remodeling and downward migration is a
salient behavior of the hair follicle. The develop-
ment of hair results from reciprocal interactions
between epidermal and mesenchymal tissues and is
influenced by cell adhesion molecules and compo-
nents of the extracellular matrix. In fact, one of the
main roles of cell adhesion molecules is to mold the
follicle by relaxing or reinforcing cell contacts in ar-
eas of increased morphogenetic activity.33 Adhesion
molecules involved in hair follicle development
include tenascin, neural cell adhesion molecule
(NCAM), E-cadherin, intercellular adhesion mole-
cule 1 (ICAM-1)47,77 and integrins.17 Prostaglandins
may be involved in regulation of integrin mRNA ex-
pression.71 PGF2 has also been shown to upregu-
late ICAM-1 production.83
PROTEASES
Enlargement and downward migration of the hair
follicle require rapid remodeling of the extracellular
matrix surrounding and preceding the advancing folli-
cle. In fact, extracellular matrix remodeling is a central
feature of hair formation.6,17,64,105,129 Hair follicle epithe-
lial cells interact with dermal papilla cells to release ma-
trix-remodeling proteases105,129 that are crucial to con-
trolled follicle development.129 Latanoprost has been
shown to induce nuclear transcription factors leading
to increased synthesis of proteases86 which alter the ex-
tracellular matrix environment.63,86,114,115 These studies
have demonstrated that proteases induced by latano-
prost reduce the extracellular matrix material sur-
rounding cells. Reduction of the extracellular matrix
material may influence the behavior of the hair follicle
by the following three mechanisms.21,38–40 The first
mechanism is by enhancement of the normal remodel-
ing of the extracellular matrix by proteases at the lead-
ing edge of the expanding and downward migrating
follicular unit. Extracellular matrix remodeling is es-
sential to permit cell proliferation, hair bulb enlarge-
ment, and downward migration of the entire follicle
unit that occurs during the initiation of anagen. En-
hancement of the remodeling process by prostaglan-
dins may lead to a larger more robust follicle. Second,
extracellular matrix remodeling is known to initiate
signals that alter differentiation decisions. Extracellular
matrix induced alterations in differentiation decisions
may explain the clinically observed prostaglandin-in-
duced change of follicles from vellus to terminal hairs.
PROSTAGLANDIN-INDUCED HAIR GROWTH S199
A third mechanism may take place at the cusp of the
transition between anagen and catagen. Alterations in
the extracellular matrix environment are capable of
delaying apoptosis thus increasing the length of the
cell cycle. Extracellular matrix alterations induced by
prostaglandins may be similarly cytoprotective and pro-
long the cell cycle in the hair follicle leading to an in-
crease in the duration of anagen and thus the length of
the hair shaft.
TROPHIC STIMULAE
Latanoprost is selective for the FP receptor on the
cell surface, which acts to cause release of Ca to
the cytosol and stimulates protein kinase activity. Both
of these actions result in trophic metabolic activity
fundamental to cell growth and proliferation,2 which
may explain the observed behavior of latanoprost.
Therapeutic Agents Currently Used
in Hair Growth
ANDROGENETIC ALOPECIA
Androgenetic alopecia occurs as a result of pro-
gressive shortening of successive anagen cycles with
gradual miniaturization of hair follicles, during
which large, pigmented terminal hairs are gradually
replaced by fine, unpigmented vellus hairs.49 This
form of alopecia requires the presence of andro-
gens. Hair follicles are still present and cycling so
the process is theoretically reversible.92 There is a
physiologic process of programmed organ deletion
in murine models; in which a few hair follicles are
normally destroyed by inflammatory cell infiltrates.1
However, in androgenetic alopecia, inflammation
regularly surrounds the bulge area of the follicle and
may result in irreparable damage to the follicle stem
cells, leading to irreversible hair loss.42
MINOXIDIL (ROGAINE)
Minoxidil and finasteride are the two drugs ap-
proved by the FDA for treatment of hair loss. Minoxidil
prolongs the anagen phase of hair growth; causes
follicles in telogen to enter the anagen phase,75 and
enlarges the hair follicle.92 The most probable site of
action of minoxidil is the specialized mesenchymal
cells of the dermal papilla.35 The mechanism of action
of minoxidil has been reported to be related to its ef-
fects on potassium channels.13 Minoxidil is a potassium-
channel opener that causes vasorelaxation127 and
stimulates cutaneous blood flow to the scalp.126 Minoxi-
dil sulfate, a metabolite of minoxidil, is a potent va-
sodilator. Uptake and conversion from minoxidil to
minoxidil sulfate occurs within the hair follicle sug-
gesting a direct action on the follicle.117
There is a mitogenic effect of minoxidil in murine
3T3 cells,117 and minoxidil increased DNA synthesis
in both dermal papilla and follicular germ cells,55
but at higher concentrations suppressed DNA syn-
thesis. A similar increase in DNA synthesis has been
found in skin cells treated with minoxidil; however
cytotoxic effects occured higher concentrations,95
with a narrow margin between proliferation and cy-
totoxicity. A marked inhibition of collagen synthesis
has been found in the presence of minoxidil,58 sug-
gesting modification of the extracellular matrix envi-
ronment as another possible mode of action.
FINASTERIDE (PROPECIA)
Finasteride inhibits 5-reductase type II, which
converts testosterone to dihydrotestosterone, the ac-
tive factor in determining hair follicle responses to
androgens. The enzyme 5-reductase type II has
been shown to be essential to male-pattern hair
growth and alopecia because these conditions do
not develop in men who have an absence of the en-
zyme.96 Finasteride, as a specific inhibitor of 5 re-
ductase, slows or reverses the progression of andro-
genetic alopecia. The dermal papilla is the likely
target of finasteride because it contains androgen re-
ceptors, which are increased in the papillae of the
beard and androgenetic alopecia prone scalp ar-
eas.98 Finasteride is not effective in treating androge-
netic alopecia in women. Interestingly, androgens
have no effect on eyelashes.97
LATANOPROST
Recently, latanoprost has been found to reverse
alopecia of the eyelashes, suggesting the possibility
of a therapeutic role.68 Although latanoprost is capable
of inducing increased growth of healthy lashes and
adnexal hairs, a role in reversing androgenetic alope-
cia has not been systematically assessed. The scalp
follicles are a different type than those in the lash re-
gion and the scalp follicles involved in androgenetic
alopecia also have a poorly understood underlying
pathology. It remains to be determined whether
there could be a useful clinical effect from treatment
with latanoprost or another prostaglandin analog.
Summary
Latanoprost has recently been reported to alter
lash and adjacent adnexal hair growth. This drug
also stimulates hair growth in mice and in the bald-
ing scalp of stumptailed macaques. Hair follicles rep-
resent a complex microorgan system characterized
by constant cycling behavior involving growth, quies-
cence, and involution. Hair growth and cycling are
under the influence of a number of gene products
and growth factors. Latanoprost appears to be a
stimulus altering growth and differentiation patterns
as well as the transition between phases of the hair
cycle. Mechanisms by which latanoprost might influ-
S200 Surv Ophthalmol 47 (Suppl 1) August 2002 JOHNSTONE AND ALBERT
ence cells in the hair follicle include altering pro-
duction of regulatory substances such as morpho-
gens, growth factors, or gene products involved in
the modulation of extracellular matrix components
and cell membrane associated adhesion molecules.
The mechanisms by which latanoprost triggers hair
cycle changes are not clear and warrant further study.
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The authors wish to acknowledge grant support provided by
Pharmacia Corporation for research involving the monkey and
mouse models of latanoprost-induced hair growth discussed in
this article. They would also like to thank Pharmacia Corpora-
tion for support in preparation of illustrations and figures in-
cluded in the manuscript and Don Anderson, MD, for providing
the photographs in Figure 7. Dr. Johnstone has a proprietary in-
terest in the development of prostaglandins and their derivatives
for use in hair and eyelash growth as a result of a relevant patent
application.
Reprint address: Murray Johnstone, MD, Arnold Medical Pa-
vilion, 1221 Madison #1124, Seattle, WA 98104.
... [7] PAP affects patient care in many ways, such as cosmetic concerns, difficulty in IOP measurement, and intraoperative difficulty. [2,8] Hypertrichosis has been linked to the ability of FP agonists to prolong anagen in resting hair follicles while inducing hypertrophic changes in the involved follicles [9] and elongated eyelashes by changing the hair follicle cycles. [9] The mechanisms of prostaglandin-associated periocular skin pigmentation has not been explored fully; however, the FP-agonists' effects on melanogenesis [10] and melanocyte proliferation [11] are considered the key events. ...
... [2,8] Hypertrichosis has been linked to the ability of FP agonists to prolong anagen in resting hair follicles while inducing hypertrophic changes in the involved follicles [9] and elongated eyelashes by changing the hair follicle cycles. [9] The mechanisms of prostaglandin-associated periocular skin pigmentation has not been explored fully; however, the FP-agonists' effects on melanogenesis [10] and melanocyte proliferation [11] are considered the key events. On the other hand, DUES resulting from current antiglaucoma FP agonists likely follows inhibition of adipogenesis around the eyelid followed by atrophy of orbital fat. ...
... With this grading system, the cosmetic aspects of PAP were classified as superficial or deep based on the differences in the underlying pathogenesis. [9][10][11][12][13][14][15][16][17] Previously, grading or subjective measurement of PAP had been attempted in each PAP component such as conjunctival hyperemia (0 to 3), [21] eyelash changes, [22] DUES (0 to 4), [7] dermatochalasis (À3 to +2), steatoblepharon (À1 to +2), marginal reflex distance (0 to 4), and levator muscle excursion (0 to 4). [5] Rabinowitz et al published an objective PAP grading system for monocular FP agonist users in a prospective study. ...
Article
The distribution of prostaglandin-associated periorbitopathy (PAP) graded using the Shimane University PAP Grading System (SU-PAP) among glaucoma/ocular hypertension subjects using a topical FP or EP2 receptor agonist was reported. A 460 consecutive 460 Japanese subjects (211 men, 249 women; mean age ± standard deviation, 69.9 ± 14.5 years) who had used either a FP agonist (0.005% latanoprost, 0.0015% tafluprost, 0.004% travoprost, 0.03% bimatoprost, or fixed combinations of these) or EP2-agonist (0.002% omidenepag isopropyl) for more than 3 months in at least 1 eye were retrospectively enrolled. Age, sex, prostaglandin, intraocular pressure (IOP) measured by Goldmann applanation tonometry (IOPGAT) and iCare rebound tonometry (IOPRBT), difference between IOPGAT and IOPRBT (IOPGAT-RBT), PAP grade, and PAP grading items were compared among groups stratified by PAP grade or prostaglandins. Of the study patients, 114 (25%) had grade 0 (no PAP), 174 (38%) grade 1 (superficial cosmetic PAP), 141 (31%) grade 2 (deep cosmetic PAP), and 31 (7%) grade 3 (tonometric PAP). The IOPGAT was significantly higher in grade 3 (17.5 ± 5.4 mm Hg) than grades 0 (15.0 ± 5.1 mm Hg, P = .032) and 1 (14.5 ± 4.2 mm Hg, P = .008), and the IOPGAT-RBT was significantly higher in grade 3 (5.8 ± 3.2 mm Hg) than the other 3 grades (1.3-1.9 mm Hg, P < .001 for all comparisons); the IOPRBT was equivalent among the 4 grades. The PAP grade was significantly higher associated with travoprost (2.0 ± 0.8) and bimatoprost (2.0 ± 0.7) than latanoprost (1.0 ± 0.8, P < .001 for both comparisons) and tafluprost (1.0 ± 0.7, P < .001 for both comparisons), but significantly lower associated with omidenepag (0.0 ± 0.0, P < .001 for all comparisons) than the other 4 prostaglandins. Multivariate analyses showed older age (standard β = 0.11), travoprost (0.53, referenced by latanoprost) and bimatoprost (0.65) were associated with higher PAP grades, while tafluprost (-0.18) and omidenepag (-0.73) were associated with lower PAP grades. The PAP graded using SU-PAP reflects the degree of overestimation of the IOPGAT and different severities of PAP among the different prostaglandins. SU-PAP, the grade system constructed based on the underlining mechanisms of PAP, is a simple grading system for PAP that is feasible for use in a real-world clinical situation.
... Latanoprost is a prostaglandin F2 alpha analog that, like minoxidil, was initially developed to treat other conditions (glaucoma in this case) but later repositioned for the topical treatment of alopecia [13][14][15]. ...
... The latanoprost's mechanism of action is not fully elucidated; however, it is suggested that the drug induces hair follicle transition from the telogen to the anagen phase, which is the active growth phase of the hair [13]. Accumulating evidence also indicates that endogenous prostaglandin F2 alpha analogs promote vasodilation in the dermis, suggesting that latanoprost can increase blood flow in the vessels, improving hair follicle nutrition [16]. ...
Article
Alopecia is a condition associated with different etiologies, ranging from hormonal changes to chemotherapy, that affects over 80 million people in the USA. Nevertheless, there are currently few FDA-approved drugs for topical treatment, and existing formulations still present skin irritation issues, compromising treatment adherence. This work aimed to develop a safe formulation based on nanostructured lipid carriers (NLC) that entrap an association of minoxidil and latanoprost and target drug delivery to the hair follicles. To do so, thermal techniques combined with FTIR were used to assess the chemical compatibility of the proposed drug association. Then, NLC with 393.5 ± 36.0 nm (PdI<0.4) and +22.5 ± 0.2 mV zeta potential were produced and shown to entrap 86.9% of minoxidil and 99.9% of latanoprost efficiently. In vitro, the free drug combination was indicated to exert positive effects over human primary epidermal keratinocytes, supporting cell proliferation, migration and inducing the mRNA expression of MKI67 proliferation marker and VEGF – a possible effector for minoxidil-mediated hair growth. Interestingly, such a favorable drug combination profile was optimized when delivered using our NLC. Furthermore, according to the HET-CAM and reconstructed human epidermis assays, the nanoformulation was well tolerated. Finally, drug penetration was evaluated in vitro using porcine skin. Such experiments indicated that the NLC could be deposited preferentially into the hair follicles, causing a considerable increase in the penetration of the two drugs in such structures, compared to the control (composed of the free compounds) and generating a target-effect of approximately 50% for both drugs. In summary, present results suggest that hair follicle-targeted delivery of the minoxidil and latanoprost combination is a promising alternative to treat alopecia.
... Latanoprost is a prostaglandin F2 alpha analog that, like minoxidil, was initially developed to treat other conditions (glaucoma in this case) but later repositioned for the topical treatment of alopecia [13][14][15]. ...
... The latanoprost's mechanism of action is not fully elucidated; however, it is suggested that the drug induces hair follicle transition from the telogen to the anagen phase, which is the active growth phase of the hair [13]. Accumulating evidence also indicates that endogenous prostaglandin F2 alpha analogs promote vasodilation in the dermis, suggesting that latanoprost can increase blood flow in the vessels, improving hair follicle nutrition [16]. ...
... The exact mechanism is unknown; however, it promotes telogen follicles to grow into the anagen phase by acting on prostanoid receptors in the hair follicle (HF). Prostaglandin analogues may also extend the anagen phase of eyelashes, resulting in increased lash length (39)(40)(41)(42). Bim also appears to improve eyelash thickness by increasing the size of the dermal papilla (DP) and hair bulb (43,44), Bim also appears to increase melanogenesis, which accounts for hair darkening after treatment (45). ...
Article
Background: Since medication absorption through the skin and eye tissue seems similar, commercially available eye-drops could be used to treat skin diseases when topical therapies are unavailable or unaffordable. The FDA-approved and off-label applications of various eye drops used as topical treatments in dermatological clinical practice were highlighted in this review.Methodology: A thorough PubMed and Google Scholar library search using various combinations of the keywords (Eye drop, ocular solution, conjunctival installation, and skin diseases, topical, local, beta-blockers, prostaglandin, cyclosporin, apraclonidine, atropine, oxymetazoline).Results and conclusions: Based on the findings of the studies reviewed, timolol is highly recommended for infantile hemangioma and other vascular skin conditions such as angiomas, Kaposi sarcoma, acne, rosacea, and wound healing. Bimatoprost is a drug that can be used to treat hypotrichosis of any kind, as well as mild localized alopecia areata and leukoderma. Oxymetazoline ispromising for treating facial erythema. We recommend apraclonidine for mild upper eyelid ptosis induced botulinum neurotoxin. We don't recommend atropine for hyperhidrosis, although it can help with hydrocystomas and pruritis produced by syringomas. Tobramycin will need to be tested in RCTs before it can be confirmed as a viable alternative to systemic treatments for treating green nail syndrome.
... 177 It was used for scalp alopecia as latanoprost prolongs the anagen phase of the hair cycle. 178 Sixteen men with mild AGA (Hamilton II-III) enrolled in a double-blinded, placebo-controlled clinical to evaluate the effects of daily application of latanoprost 0.1%. An increase in hair density was noted in the treatment group. ...
Article
Full-text available
Background Androgenetic alopecia (AGA) is the most common form of hair loss consisting of a characteristic receding frontal hairline in men and diffuse hair thinning in women, with frontal hairline retention, and can impact an individual's quality of life. The condition is primarily mediated by 5-alpha-reductase and dihydrotestosterone (DHT) which causes hair follicles to undergo miniaturization and shortening of successive anagen cycles. Although a variety of medical, surgical, light-based and nutraceutical treatment options are available to slow or reverse the progression of AGA, it can be challenging to select appropriate therapies for this chronic condition. Aims To highlight treatment options for androgenetic alopecia taking into consideration the efficacy, side effect profiles, practicality of treatment (compliance), and costs to help clinicians offer ethically appropriate treatment regimens to their patients. Materials and Methods A literature search was conducted using electronic databases (Medline, PubMed, Embase, CINAHL, EBSCO) and textbooks, in addition to the authors' and other practitioners' clinical experiences in treating androgenetic alopecia, and the findings are presented here. Results Although topical minoxidil, oral finasteride, and low-level light therapy are the only FDA-approved therapies to treat AGA, they are just a fraction of the treatment options available, including other oral and topical modalities, hormonal therapies, nutraceuticals, PRP and exosome treatments, and hair transplantation. Discussion Androgenetic alopecia therapy remains challenging as treatment selection involves ethical, evidence-based decision-making and consideration of each individual patient's needs, compliance, budget, extent of hair loss, and aesthetic goals, independent of potential financial benefits to the practitioners.
... 1,11 For example, the prostaglandin and prostaglandin-ethanolamide analogs latanoprost and bimatoprost, respectively, stimulate hair growth in vitro (eg, human tissue explants) and in vivo (eg, mouse and humans). [12][13][14][15] In contrast, prostaglandin D 2 (PGD 2 ), a known proinflammatory mediator, 16 and its receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2; also known as G-protein-coupled receptor 44 [GPR44] or PGD 2 receptor-2 [DP 2 ]), inhibit hair lengthening 17 and follicle regeneration after wounding 18 in vitro (eg, human tissue explants) and in vivo (mouse models). ...
Article
Full-text available
Purpose: To evaluate oral setipiprant versus placebo for scalp hair growth in men with androgenetic alopecia (AGA). Patients and methods: Males aged 18 to 49 years with AGA were enrolled in a double-blind, multicenter, 32-week, phase 2a trial; randomized to twice-daily (BID) 1000-mg (2×500 mg for a total daily dose of 2000 mg) setipiprant tablets or placebo for 24 weeks; and assessed at weeks 4, 8, 16, and 24, with a week 32 follow-up. The study initially included a finasteride 1-mg once-daily group, removed by protocol amendment. Changes from baseline to week 24 in target area hair count (TAHC) and blinded Subject Self-Assessment (SSA) of target area photographs were coprimary efficacy endpoints. Hair growth was also evaluated using blinded Investigator Global Assessment (IGA). Safety assessments included adverse events (AEs) and clinical laboratory tests. Analysis of covariance models were used to test statistical significance for TAHC, SSA, and IGA. Data were summarized without statistical analysis for finasteride. Results: Randomized subjects (N=169) included 74 placebo, 83 setipiprant, and 12 finasteride subjects; 117 (69.2%) and 113 (66.9%) subjects completed week 24 and 32 visits, respectively. Treatment groups had similar baseline characteristics. Neither coprimary efficacy endpoint was met. At week 24, TAHC and SSA findings indicated no hair growth improvements with setipiprant versus placebo. Setipiprant also did not improve hair growth versus placebo per the IGA. Treatment-related AEs, all mild or moderate in severity, occurred in 12.3%, 25.9%, and 25.0% of the placebo, setipiprant, and finasteride groups, respectively. Two treatment-emergent serious AEs (TESAEs), cellulitis and multiple sclerosis, were reported in the placebo group, both unrelated to treatment. No TESAEs were reported with setipiprant or finasteride. Conclusion: Setipiprant 1000 mg BID was safe and well tolerated but did not demonstrate efficacy versus placebo for scalp hair growth in men with AGA.
Article
Introduction: Glaucoma is a progressive optic neuropathy and the leading cause of irreversible vision loss. By 2040, the number of individuals with glaucoma is expected to nearly double. The only known modifiable risk factor for glaucoma is intraocular pressure. Topical medications are often used as first line therapies. Although there are numerous available treatments, there continues to be a need for the development of new medical therapies due to variable response, intolerable side-effect profiles in some patients, and elevated intraocular pressure refractory to other treatments. Areas covered: This review will cover glaucoma medications currently undergoing phase II and III of drug development. Expert opinion: There are numerous drugs currently in development that have demonstrated significant and clinically relevant reduction of intraocular pressure. Differentiating factors include improved tolerability, novel mechanisms of action, multiple mechanisms of action, or superior IOP reduction. However, the availability of generic prostaglandin analogs may limit adoption of these novel compounds as first line agents, except for certain subgroups of glaucoma patients. Use as adjuvant or second line therapy appears more likely for the majority of glaucoma patients.
Article
Hair is a deeply rooted component of identity and culture. Recent articles in this series have focused on scientific evidence relating to hair growth and new insights into the pathogenesis and mechanism of hair loss. This article reviews emerging evidence that has advanced our understanding of hair growth in both of these areas to provide a context for outlining current and emerging therapies. These include finasteride, minoxidil, topical prostaglandins, natural supplements, microneedling, low-level laser light, platelet-rich plasma, fractional lasers, cellular therapy, Wnt activators and SFRP1 antagonism.
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Background: Topical prostaglandin analogs (PGAs) are widely approved and preferred first-line options for glaucoma and elevated intraocular pressure (IOP). However, prostaglandin-associated periorbitopathy syndrome (PAPS) is now a well-recognized clinical and cosmetic concern for patients receiving PGAs, especially during long-term and unilateral therapy. PGA-associated periocular changes occur in a substantial proportion of patients, with older patients (>60 years) at greater risk of clinical presentation. PAPS may hinder long-term management of glaucoma, including treatment adherence, ophthalmic surgery outcomes, and reliable IOP measurements. Recommendation: New therapeutic approaches may address this unmet clinical need. Omidenepag isopropyl (OMDI) is a novel, non-prostaglandin, selective EP2 receptor agonist in ongoing development, which provides a unique pharmacological mechanism of action. OMDI appears to provide IOP reductions comparable to PGAs, but without PAPS-related undesirable effects. OMDI may offer a suitable long-term option for patients who demonstrate decreased efficacy, or failure, of PGAs, plus patients with significant PAPS, while fulfilling international guidelines.
Article
In the quiescent mouse BP-A31 fibroblasts, prostaglandin F2 alpha (PGF2 alpha) induces the expression of cell cycle-related genes c-fos, c-jun, and c-myc, and after a delay of approximately 12 h the entry into the phase of DNA replication. A weaker mitogenic effect was produced by certain other PGs (F1 alpha > D2), whereas the effects of PGs E and I were marginal or absent. The mitogenic effects of PGF2 alpha as well as of 12-O-tetradecanoyl phorbol 13-acetate (TPA; activator of protein kinase C) but not those of insulin (acting via the insulin-like growth factor 1 receptor) were abolished by a low concentration (7.5 nM) of staurosporine (inhibitor of protein kinase C). Moreover, long-time (24 h) preincubation with phorbol dibutyrate reduced the mitogenic effects of a subsequent exposure either TPA or PGF2 alpha. These observations favor the involvement of protein kinase C in the PGF2 alpha-dependent intracellular signal transduction. However, simultaneous stimulation of the quiescent cells with saturatin...
Article
The aims of this study were to investigate: (1) the production of all arachidonic acid metabolites in hair dermal, papilla cells (DPC) and (2) the effects of minoxidil and vascular endothelial growth factor (VEGF) on this production. Eicosanoid synthesis was evaluated in culture medium after incorporation of tritiated arachidonic acid into DPC membrane phospholipids. Compared to controls, exposure of DPC to 1 μM 12-O-tetradecanoyl phorbol 13-acetate did not stimulate arachidonic acid metabolism, however exposure to calcium ionophore A23187, produced large amounts of eicosanoids, consisting mainly of 273% PG6KF(1α), 176% of PGE2 and 68% LTB4. A good correlation was found with ELISA and radioassay techniques for total synthesis of major metabolites. The ELISA technique was also used to investigate the effects of minoxidil and VEGF on DPC production of three arachidonic acid metabolites: prostaglandins 6KF(1α), E2 and leukotriene B4, before and after stimulation with A23187. High concentrations of VEGF induced an activation of the production of these metabolites, and a low concentration of minoxidil (12 μM) inhibited PG6KF(1α), production but stimulated that of PGE2 and LTB4. These data confirm the implication of VEGF and minoxidil in the modulation of eicosanoid production by hair, dermal papilla cells.