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Journal of Dermatological Treatment. 2010; Early Online, 1–10
REVIEW ARTICLE
Hair growth and rejuvenation: An overview
MONA SEMALTY
1
, AJAY SEMALTY
1
, GEETA PANT JOSHI
2
&
MOHAN SINGH MANIYARI RAWAT
2
1
Department of Pharmaceutical Sciences, and
2
Department of Chemistry, HNB Garhwal University Srinagar (Garhwal),
Uttarakhand, India
Abstract
Hair has psychological and sociological importance throughout the ages in framing the personality and general appearance of
an individual. Significant progress is being made on discovering an effective and safe drug for hair growth. Angiogenesis, androgen
antagonism, vasodilation, potassium channel opening and 5-alpha reductase inhibition are the major non-surgical therapeutic
strategies of hair growth promotion. In spite of a flood of drugs claiming to be useful as hair growth promoters, more rational
strategies, which can target the problem areas or stages of the hair growth cycle effectively, are still awaited. This article highlights
the developments in hair rejuvenation strategies and reviews the potential of herbal drugs as safer and effective alternatives.
Key words: alopecia, baldness, hair growth, hair loss, herbal drugs, minoxidil
Introduction
Hair has been a sign of beauty and a contribution to an
individual’s personality since time immemorial. Alo-
pecia (baldness), a dermatological disorder, is a com-
mon problem of cosmetology as well as primary
health practice. It is common throughout the world
and has been estimated to affect between 0.2% and
2% of the world’s population (1–3). The clinical
severity of alopecia in a patient may not be a good
indicator of a subsequent downturn in quality of life
or psychological well-being of the patient.
Drugs which claim to treat hair loss target a steadily
growing, multi-billion dollar market worldwide.
Great expectations are associated with pharmaceuti-
cal hair loss management, but still there is no radical
improvement in the availability of more precise ther-
apies (4). Much of that disappointment appears to
result from unrealistic expectations, ill-targeted (and
therefore inefficient) drug therapy and insufficient
industrial interest in dissecting the basic mechanisms
by which hair loss occurs and by which human hair
growth promoters exert their effects.
Over the past several years about 300 000 products
have claimed to help hair regrowth. With the excep-
tion of minoxidil and finasteride, none of them was
found to be effective in hair growth promotion.
Minoxidil, a synthetic (cardiovascular) drug, was
scientifically proved to help the treatment of alopecia.
The hair growth activity of minoxidil is actually the
side effect of this cardiovascular drug (5). Currently,
minoxidil (useful in both male and female pattern
baldness) and finasteride (useful in male pattern
baldness) are two US FDA-approved synthetic drugs
finding concomitant use for treatment of androgenic
alopecia, but their side effects have reduced their
usage (6,7). Moreover, both the drugs are the result
of serendipity, not of rational hair drug design.
Therefore, to search for more precise therapies for
alopecia, newer synthetic drugs or drugs of plant
origin need to be explored. Herbal drugs have
been widely used for hair growth promotion since
ancient times in Ayurveda, Chinese and Unani sys-
tems of medicine. Natural products are very popular
and well accepted in the cosmetic and hair care
industries (8,9).
Correspondence: Mona Semalty, Department of Pharmaceutical Sciences, PB No.-32, HNB Garhwal University Srinagar (Garhwal)-246174, India.
Fax: 91 1346 252174. E-mail: monasemalty@gmail.com
(Received 26 September 2009; accepted 21 December 2009)
ISSN 0954-6634 print/ISSN 1471-1753 online 2010 Informa UK Ltd.
DOI: 10.3109/09546630903578574
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The goal of the present article is to provide an
overview of available hair loss treatment alternatives.
The article provides a brief review of the hair growth
cycle and different causes of hair loss, followed by
focuses on the various types of drugs available for
alopecia. The article reviews various studies show-
ing hair growth-promotion efficacy of modern and
herbal drugs.
Hair growth cycle
Hair is the cumulative, physical result of a coordi-
nated process of cellular proliferation and differ-
entiation within a hair follicle. Hair follicles are
epidermally derived appendages which arise as a
result of inductive events between specialized dermal
fibroblasts acting on bipotential epithelial stem cells.
The stem cells which commit to a hair follicle fate
enter a period of massive proliferation that culminates
in the formation of a mature hair follicle (10).
The hair follicle cycle is a complex process and
entails involvement of cell differentiation, epithelial–
mesenchymal interactions, stem cell augmentation,
pattern formation, apoptosis (programmed cell death),
cell and organ growth cycles, and pigmentation.
The most important reason for studying the cycling of
the hair follicle is that the follicle is a regenerating
system (Figure 1). By traversing the phases of the
cycle (growth, regression, resting, shedding, then
growth again), the follicle demonstrates the unusual
ability to completely regenerate itself (11). Normal
hair follicles cycle between a growth stage (anagen),
a degenerative stage (catagen), a resting stage
(telogen) and a shedding stage (exogen). The scalp
hairs have a relatively long life cycle: the anagen stage
ranges from 2 to 5 years, the catagen stage ranges from a
few days to a few weeks, and the telogen stage is
approximately 3 months (12,13). Hair cycle distur-
bances have dramatic effects on visible hair growth. If
anagen gets prematurely terminated and catagen
occurs too early, this must result in effluvium and
alopecia; the affected skin region willsubsequently sport
largely catagen and/or telogen follicles, whose loosely
anchored club hairs are eventually shed (i.e. the normal
anagen/telogen rateon the scalp [roughly 4:1]changes in
favor of telogen). This is exactly what happens, for
example, as a consequence of drug-induced damage
to the proliferating cells of the anagen hair bulb,
such as in drug-induced telogen effluvium or when
inflammatory cells attack the anagen hair bulb in
alopecia areata (12). Therefore, the therapeutic
manipulation of hair follicle cycling is a key challenge
Epithelium/
messenchyme Placode Germ Peg
Folliculogenesis
Bulbose peg
Anagen Catagen
Telogen
S
B
E
H
ORS
P
IRS
CTS
P
HB
B
M
PP
B
B
Figure 1. The formation of hair follicles in the fetus and cycling transformations in the adult. In the fetus, a thickening forms at one focus of the
primitive epithelium to form a placode. Below the placode dermal cells aggregate and thereafter the epithelium grows down as a finger to
produce the multilayer, shaft-producing hair follicle. In the adult, three phases of the growth cycle are recognized: a growth phase (anagen), a
regressing phase (catagen): and a resting phase (telogen). It is the lower follicle that regenerates at the beginning of each cycle by utilizing
intimate and powerful epithelial–mesenchymal interactions of the stem cells in the bulge (B) and the inductive mesenchymal cells of the
papilla (P). CTS, connective tissue sheath; E, epidermis; H, hair shaft; IRS, inner root sheath; M, hair matrix; ORS, outer root sheath;
S, sebaceous gland.
2M. Semalty et al.
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in hair lossmanagement. Effective therapeutic strategies
for hair loss in declining order of importance are:
.inhibition of catagen development in order to
prolong anagen
.induction of anagen in telogen follicles
.inhibition of exogen.
Hair loss and alopecia
Hair loss is a natural daily phenomenon, but this
shedding of hair cannot be the main cause of hair
loss. Every strand of hair on a human head is genet-
ically programmed to a cycle that includes growth,
stabilization, aging and shedding. On average, every
day a human head sheds about 50–125 hairs (depend-
ing on sex), but most of them will come back after the
resting stage as the follicle itself is not destroyed (14).
Trouble begins when the loss exceeds re-growth, or
the re-growth is weak and unhealthy. A loss of 100
hairs per day can be considered ‘normal’not patho-
logic. But a loss of more than 100 hairs per day
constitutes a pathological effluvium. Androgenetic
alopecia (AGA) is one of the dermatological condi-
tions most commonly faced by the dermatologist or
general physician. The condition affects up to 30% of
men under the age of 30 and more than 50% of men
over the age of 50. Despite a widespread belief that
AGA is only experienced by men, it also affects
women, although the clinical signs are usually milder
and the phenotype is different (15). As the condition
progresses, scalp hairs and their follicles become
progressively miniaturized, and the terminal hair
normally found on the adult scalp is replaced by
vellus hairs which are shorter, finer and
non-pigmented. Concomitantly, the average length
of time spent by hairs in anagen (growth phase)
decreases, and the proportion of hairs in telogen
(resting phase) increases (16).
Baldness or alopecia can be classified as follows:
male pattern baldness, female pattern baldness,
alopecia areata (an autoimmune disorder causing
small, patchy circular bald patches in several parts
of the scalp), alopecia totalis (total loss of scalp hair),
and alopecia universalis (total loss of hair from the
entire body) (17). Another way in which hair loss
(alopecia) can be classified is according to factors
leading to it. There are two different types of hair
loss, known medically as:
Anagen effluvium: caused by medications taken
internally, such as chemotherapy representatives,
excessive doses of vitamin A or some hypertension
medications.
Telogen effluvium: caused by an increased number
of hair follicles entering the latent or rather dead stage.
The most common causes of telogen effluvium
leading to alopecia could be physical and emotional
stress, and thyroid or another hormonal irregularity.
The growth of hairs is affected by various factors,
which are listed in Table I (18).
Current strategies for hair growth and
rejuvenation
There are a number of ways in which a drug may
stimulate hair growth: it may increase the linear
Table I. Factors leading to hair loss.
Factors Description
Major physical–emotional stress Surgery, severe illness, diet or nutrition changes and emotional stress can cause hair loss
Chemotherapy Cholesterol-lowering drugs, Parkinson medications, anti-ulcer drugs, anticoagulants, agents for
gout, anti-arthritic drugs derived from vitamin A, anticonvulsants for epilepsy, antidepressants,
beta-blocker drugs, antithyroid agents, antineoplastics, blood thinners, male hormones
(anabolic steroids)
Genetic predisposition Genetic component to androgenetic hair loss exists (polygenic inheritance)
Dihydrotestosterone (DHT) Increased level of DHT (the testosterone metabolite) shortens the hair cycle and progressively
miniaturizes scalp follicles and this may be due to the atherosclerotic process blocking the
microvasculature that nourishes the hair follicles
Excessive sebum Excessive sebum causes a high level of 5-alpha reductase and pore clogging, thus malnutrition of
the hair root
Cardiovascular diseases High levels of LDL in cardiac patients are converted to 5-alpha reductase enzyme, which produces
DHT from testosterone, causing hair loss
Smoking Tobacco smoke damages the lining of blood vessels, leading to less production of nitric oxide and
thus inducing hair loss
Endogenous substances bax, bcl-2 and insulin-like growth factor binding protein-3 (e.g. VEGF) promote hair growth
LDL =low-density lipoprotein; VEGF =vascular endothelial growth factor.
Hair growth and rejuvenation 3
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growth rate of hair; increase the diameter of the hair
fibre; alter the hair cycle, either shortening telogen or
prolonging anagen; or act through a combination of
these effects. Among the surgical treatment methods,
the introduction of micrografts (one to two hair fol-
licular unit grafts) and minigrafts (three to four hair
follicular unit grafts) has made a most significant
advancement in the care of male pattern baldness
and female androgenic alopecia; natural
and aesthetically pleasing results are possible. Addi-
tionally, many other applications in the reconstruction
of facial and scalp hair have been found; some of these
include restoration of hair loss due to (iatrogenic)
post-surgical causes (i.e. after facial rejuvenation pro-
cedures or procedures involving incisions on hair-
bearing facial skin or scalp) and burns or traumatic
injuries (19).
Various non-surgical pharmacotherapeutic alter-
natives available for hair growth and rejuvenation
are discussed in the following sections.
Vitamins, nutrients and minerals
Vitamin deficiencies are also thought to be the cause
of alopecia and for which the treatment would be
dietary vitamin supplementation. The use of biotin as
a treatment for alopecia was suggested by evidence
that biotin (vitamin H) deficiency causes hair loss.
Biotin is a water-soluble vitamin that acts as an
essential cofactor for four different carboxylases,
each of which catalyzes an essential step in interme-
diary metabolism. An analysis of hair shows that it
is composed of iron, oxygen, hydrogen, nitrogen
and sulphur. The blood must be supplied with these
minerals so that nourishment will be carried to
the scalp.
Angiogenesis, the formation of new blood vessels
from the pre-existing vascular network, is a driving
force of hair growth. It is indispensable for embryonic
development as interruption of angiogenic events
blocks the growth of the embryo and results in early
mortality. After birth, angiogenesis plays both adap-
tive role enabling the regeneration of damaged body
parts and is also involved in numerous pathological
changes. Understanding of the basic mechanisms of
blood vessel formation is necessary for the establish-
ment of effective therapeutic strategies for ameliora-
tion of diseases. The major angiogenic regulator is
vascular endothelial growth factor (VEGF), named
also VEGF-A, which is one of several members of the
VEGF family. In adult organisms, physiological
angiogenesis is limited and occurs during regenera-
tion of uterine epithelium in the menstrual cycle,
development of the ovum and formation of corpus
luteum and hair growth (20). VEGF has a central role
in promoting angiogenesis as well as influencing
diverse cell functions, including cell survival, prolif-
eration and the generation of nitric oxide and pros-
tacyclin (21). The perifollicular capillary network is
coupled to the hair cycle, increasing during anagen
and then regressing during catagen and telogen.
It has been investigated that metabolically ‘resting’
telogen follicles have considerably lower perfusion
requirements than larger, rapidly growing, anagen
hair follicles. With the use of standardized quantita-
tive histomorphometry, electron microscopy, and
CD31 (platelet endothelial cell adhesion molecule-1
[PECAM-1]) immunohistochemistry as an endothe-
lial cell marker, it was shown that the cutaneous
microvasculature is substantially rearranged during
anagen development, that there is endothelial cell
proliferation, and that there is an increase in endo-
thelial cell numbers in anagen (22).
Taken together, these studies suggest that anagen
development, at least in species with a synchronized
hair cycle, is associated not only with a rearrangement
of the skin vasculature and a concomitant increase in
skin perfusion, but also with genuine and substantial
angiogenesis. Therefore, modulation of angiogenesis
is considered as therapeutic strategies of great impor-
tance for hair growth (23). The role of various nutri-
ents and minerals in preventing hair loss is
summarized in Table II.
Table II. Role of nutrients and minerals in the prevention of
hair loss.
Nutrients and minerals Mechanism of preventing hair loss
Niacin (vitamin B
3
).Enhances blood flow
to scalp through vasodilatory
effects
.Reduces the level of cholesterol
and hence the level of 5-alpha
reductase on scalp
Vitamin B complex .Improves blood flow
to scalp
.Decreases cholesterol
accumulation to scalp
.Protects hair and scalp from
free radical damage
Ascorbic acid (vitamin C) .Improves blood flow to scalp
and maintains capillaries
carrying blood to follicles
Tocoferol (vitamin E) .Enhances oxygen uptake and
thus improves blood flow to
scalp
Zinc .Enhances immune function
and thus stimulates hair growth
Essential fatty acids
(primrose and salmon oil)
.Improves hair texture
.Prevents loss of dry brittle hairs
Amino acids (L-cysteine
and L-methionine)
.Improves quality of
hair texture
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Anti-androgen therapy
Flutamide and cyproterone acetate in combination
with ethinyl-estradiol have been reported to show
some effectiveness in female pattern baldness. Spir-
onolactone is a steroid used mainly as a diuretic and
antihypertensive agent. Side effects cause androgen-
receptor blockade and direct inhibition of testoster-
one production by the adrenal gland. Therefore, this
aldosterone antagonist (spironolactone) is used in
dosages from 75 mg to 150 mg per day with some
benefit in hair loss.
Heterocyclics
Minoxidil
Minoxidil was first used in tablet form as a medicine
to treat high blood pressure, but it was noticed that
some patients being treated with minoxidil experi-
enced excessive hair growth (hypertrichosis) as a side
effect. Further research showed that by applying
topical minoxidil solution directly to the scalp, it
could prove to be beneficial to those people experi-
encing hair loss. Topical minoxidil (2,4-diamino-
6-piperidino pyrimidine-3-oxide) is the only drug
approved by the Food and Drug Administration to
treat male and female pattern baldness. Orally admin-
istered minoxidil lowers blood pressure by relaxing
vascular smooth muscle through the action of its
sulphated metabolite, minoxidil sulphate, as an
opener of sarcolemmal K
ATP
channels (24). There
is some evidence that the stimulatory effect of minox-
idil on hair growth is also due to the opening of
potassium channels by minoxidil sulphate, but this
idea has been difficult to prove and to date there has
been no clear demonstration that K
ATP
channels are
expressed in the hair follicle (25,26). Minoxidil sti-
mulates mitosis in epithelial cells, inhibits collagen
synthesis, prolongs the survival of epithelial cells in
tissue culture and stimulates vascular endothelial
growth factor and prostaglandin synthesis (27–30).
It has therefore been suggested that the drug slows the
aging of hair matrix cells. It is postulated that it delays
or prevents the entry of some follicles into the next
anagen phase for long periods of time and stimulates
these follicles back into active production. Various
studies have verified the hair growth-promotion
activity of minoxidil (31,32). Also, both 5% and
2% topical minoxidil helped improve psychosocial
perceptions of hair loss in women with female pattern
hair loss (33). Topical minoxidil is effective at a
concentration of 2%. Successful treatment, however,
does require a lifetime commitment. The topical
solution must be applied to the balding area twice a
day, every day. Decreasing the dosage to once a day
results in some hair loss, and discontinuing applica-
tion causes regression to pretreatment baldness within
3–6 weeks.
The disadvantages of minoxidil are: (i) lifetime
commitment; (ii) high cost: it is not covered by health
insurance schemes as it is considered a cosmetic; (iii)
its side effects –including itching and prickling,
headaches, dizzy spells and, in some, heartbeat irreg-
ularities (34). Although apparently safe when rubbed
into the scalp –since little is absorbed into the
bloodstream –it is a vasodilator and not recom-
mended for anyone with heart trouble. Its safety in
pregnant women, men over the age of 49 years and
long-term use is unknown.
Pyridine derivatives
These include pinacidil, nicorandil, RP-49356 and
P-1075. They are K
+
-channel openers. They play a
role in regulation of the hair growth cycle. Potassium
channel biology is a widely diverse field that has an
impact on many aspects of physiology. More than 15
different types of potassium channels have been iden-
tified in various tissues. These channels are classified
into four subtypes: voltage dependent, calcium
dependent, receptor coupled, and miscellaneous.
Specific classes are defined by the magnitude of the
electrical conductance of the channel, the types of
pharmacological agents that block the channel, and
the physiologic properties of the channel. Potassium
channel openers stimulate proliferation of cells in
cultured vibrissae and skin keratinocytes. They elicit
hypertrichosis in humans (35–37). Buhl et al. tested
the effect of topical application of minoxidil and
three other potassium channel openers on scalp
hair growth in balding macaques. Minoxidil, croma-
kalim and P-1075 (a pinacidil analogue) all stimu-
lated hair growth over a 20-week treatment period.
A fourth potassium channel opener, RP-49,356,
was not effective. Systemic pinacidil induces
hypertrichosis in 2–13% of patients (38).
Benzothiazide derivative
Diazoxide is also a K
+
-channel opener. Diazoxide was
reported to increase the uptake of thymidine in a
dose-dependent fashion in 4-day cultures of mouse
vibrissae follicles (31,39). Oral diazoxide causes
hypertrichosis in most hypoglycemic children and
about 1% of adults, and induces some scalp hairs
in 25% of the balding patients (40).
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Steroids
4-Aza steroids
Finasteride is a 4-aza steroidal drug which acts by
inhibiting the 5-alpha reductase (enzyme) that trans-
forms testosterone into the dihydrotestosterone
(DHT) form, responsible for hair loss (41,42). It
was originally used to treat benign prostate hyperpla-
sia or prostate enlargement. Blocking the action of
DHT seems to stimulate growth of stronger, thicker
and more pigmented hair. In a study, finasteride was
administered orally at 0.5 mg/day, alone or in com-
bination with topical 2% minoxidil, for 20 weeks to
determine the effects on scalp hair growth in balding
adult male stump tail macaque monkeys. A l-day
dose-finding study showed that both 0.5- and
2.0-mg doses of the drug produced a similar dimi-
nution in serum DHT in male stumptails (42). In ano-
ther study, finasteride was found to regrow a noticeable
amount of hair in about 40% of balding men (43).
Finasteride may not be very effective in men over
60 years (44). As DHT is required for normal sexual
functions in men, the side effects of finasteride
include sexual performance problems (in about 3%
of the sample), such as impotence, loss of libido,
reduced sperm counts or erectile dysfunction.
Finasteride is also not approved for women (even
in small concentrations it causes a specific birth
defect –hypospadias, which involves abnormalities
of the external genitalia of a male fetus) and has not
been shown to work for a receding hairline at the
temple. These side effects may last for as long as the
medicine is taken. Besides finasteride, other 4-aza
steroidal drugs are dutasteride, episteride and
turosteride.
6-Aza steroids
These are 6-aza androstane derivatives and show
hair growth activity. They are type I 5-alpha reductase
(located in the sebaceous glands) inhibitors but are
not time-dependent like finasteride, which is a
time-dependent inhibitor of type II 5-alpha reductase
(45,46).
Natural products
Many ancient Ayurvedic (ancient Indian system of
medicine) and Chinese herbal drugs have been
reported and documented as potent hair growth pro-
moters. The natural products are reported to be more
effective alternatives for hair growth therapy than the
synthetic drugs. Numerous bioactive plant com-
pounds have been tested for potential clinical applica-
tions. Various natural products associated with hair
growth activity are listed in Table III.
In the search for a safe and effective alternative
therapy for hair loss, many studies on herbal drugs
have been performed in the last few decades.
Recently, it was reported that epigallocatechin-3-gal-
late, a major polyphenolic constituent of green tea,
Table III. Herbal drugs for hair growth promotion.
Herbal drug Mechanism of preventing hair loss
Grape seed .Contains proanthocyanidins, which are potent antioxidants and act as a smooth muscle relaxant in
blood vessels and capillaries, preventing or offsetting damage to the hair follicle blood supply
Rosemary oil .Improves blood flow to scalp
.Cleansing the scalp and stimulating the hair root
Sage (Salvia officinalis).Thickens hair shafts and helps dissolve sebum deposits
.Improves blood flow to scalp
Emu oil .Inhibits 5-alpha reductase and thus lowers the DHT level in the scalp
Aloe vera .Its proteolytic enzymes slough off dead skin cells and open pores
.Increases membrane fluidity and permeability and the outward flow of toxins and inward flow of
nutrients
Ginkgo biloba .Inhibits 5-alpha reductase activity
.Protects small blood vessels and micro-capillaries against loss of tone and fragility
Bee pollen .Being rich in L-cysteine, it stimulates hair growth (since hair is 8% L-Cysteine)
Green tea .A potent inhibitor of 5-alpha reductase and thus lowers the DHT level in the scalp
Saw palmetto (Serenoa repens).Blocks DHT production
Nettles (Urtica dioica).Provides silica for hair growth
.Improves blood flow to scalp
Hibiscus rosasinensis .Improves blood flow to scalp which leads to dense hair growth
DHT =dihydrotestosterone.
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might be useful in the prevention or treatment of
androgenetic alopecia by selectively inhibiting 5-alpha
reductase activity (47–49). Polyphenolic compounds
(such as epigallocatechin-3-gallate) and catechins of
green tea are the major phytoconstituents that are
responsible for its hair growth activity. Adhirajan et al.
(2003) evaluated the petroleum ether extract of the
leaves and flowers of Hibiscus rosasinensis for its poten-
tial on hair growth by in vivo and in vitro methods.
From the study it is concluded that the leaf extract,
when compared to the flower extract, exhibits more
potency on hair growth (50). In another study, Adhir-
ajan et al. (2001) studied a mixture of petroleum ether
extract of Eclipta alba Hassk. (compositiae), Citrullus
colocynthis Schrad. (cucerbitaceae) and Tridax procum-
bens Linn. (compositeae) in various concentrations in
the form of herbal cream and herbal oil (51). The ratio
of E. alba,C. colocynthis and T. procumbens in 3:1:2
showed excellent hair growth activity with 35% more
anagen hair follicles as compared to 20% with a
standard drug (2% ethanolic solution of minoxidil).
Roy et al. studied the effect of successive petroleum
ether and ethanol extracts of C. colocynthis and Cuscuta
reflexa on hair growth in albino rats (52,53). The
extracts were incorporated into an oleaginous oint-
ment base and were applied topically on the shaved
denuded skin of albino rats. The time required for
initiation of hair growth as well as completion of the
hair growth cycle was recorded. The hair growth
initiation time was significantly reduced to half on
treatment with the petroleum ether extracts compared
with untreated control animals. The time required for
complete hair growth was also considerably reduced.
The treatment was successful in bringing a greater
number of hair follicles (>70%) to the anagen phase
than standard minoxidil. In another study, the poly-
herbal formulation of C. reflexa (Roxb.), C. colocynthis
(Schrad.) and E. alba (Hassk.) were developed and
evaluated the same for hair growth-promoting activ-
ity. The hair growth initiation time was markedly
reduced to one-third on treatment with the prepared
formulation compared with control animals (54). The
time required for complete hair growth was also
reduced by 32%. Quantitative analysis (by the method
described by Uno) (55) of the hair growth cycle after
treatment with prepared herbal formulations and
minoxidil (2%) exhibited a greater number of hair
follicles in the anagen phase compared with controls.
Rho et al. examined the effects of 45 plant extracts
that have been traditionally used for treating hair loss
in oriental medicine in order to identify potential
stimulants of hair growth. Asiasari radix extract
showed hair growth-promoting potential (56).
In another study, Rho et al. studied the hair
growth-promoting effect of Sophora flavescens and
showed that it can be used as a potential hair
growth promoter (57).
An independent study was designed to test the
effectiveness of topical crude onion juice (Allium
cepa L.) in the treatment of patchy alopecia areata.
The patients were divided into two groups. The first
group (active: onion juice) consisted of 23 patients
(16 males and seven females). The second group
(control: tap-water) consisted of 15 patients (eight
males and seven females). The two groups were
advised to apply the treatment twice daily for
2 months. Re-growth of terminal coarse hairs started
after 2 weeks of treatment in the active group. At
4 weeks, hair re-growth was seen in 17 patients
(73.9%), and at 6 weeks hair re-growth was observed
in 20 patients (86.9%); it was significantly higher
among males (93.7%) compared with females
(71.4%). In the control group, hair re-growth was
apparent in only two patients (13%) at 8 weeks of
treatment with no sex difference (58).
The extract of Illicium anisatum increases subcuta-
neous blood flow in mice. In a study, an organ culture
system was used to examine the hair follicle elonga-
tion effect of this extract (59). In this study,
B6C3HF1 mouse vibrissae follicles were cultured
in serum-free medium for 7 days at 31C. Follicles
treated with water-soluble extracts of the leaves, fruits
and roots of I. anisatum or shikimic acid grew signif-
icantly longer than controls.
Bisbenzylisoquinoline alkaloids were isolated from
Stephania cepharantha and their proliferative activities
on cultured hair cells from the murine skin were
evaluated (60). Cepharanthine, cepharanoline, isote-
trandrine, and berbamine showed significant acti-
vities in the range of 0.01–0.1 mg/ml, but had no
activity on cultured keratinocytes or fibroblasts
from the murine skin.
Recently, stem cells inducing the anagen phase in
the hair follicle cycle have been discovered in the
bulge region of the outer root sheath (ORS). To
find growth-promoting agents for the ORS cells,
the effect of various botanical extracts on the growth
of cultured human hair follicles was evaluated. It was
found that Laminaria angustata extract increased
ORS cell growth. Further, hair growth in the shaved
skin of C3H mice was also promoted by the topical
application of the extract (61).
The other herbal drugs studied for hair growth
activity include nagarmotha (Cyperus rotundus),
neem (Azadirachta indica), amla (Emblica officinalis),
Brahmi (Bacopa monnieri), bahera (Terminalia
bellirica), methi (Trigonella foenumgraecum), laljari
(Geranium wallichianum), bhallataka (Semecarpus
anacardium) and capsicum. Various patents have
also been granted for hair growth potential of herbal
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drugs such as Ginkgo biloba,Berberis vulgaris,
Zingiberis recens,Pinellia ternata,Flos carthami,
Angelicae sinesis,Paenoiae rubra,Cacumen biotae,
Sesami nigrum,Polygoni multiflori,Fructus mori,
Capsicum annum and Oleum ricin (62–65).
Miscellaneous
Various topical sensitizers such as dinitrochloro-
benzene (DNCB), squaric acid dibutylester
(SADBE), and diphenylcyclopropenone (DPCP)
have determined the re-growth of hair in patients
with alopecia. Anthralin, the only non-specific irritant
widely used for hair growth in alopecia areata, is
applied topically as a 0.5% or 1% cream to affected
areas once per day for 20–45 minutes; overnight
application can also be used in certain patients who
can tolerate the side effects (66).
LY 191704 (a benzoquinoline derivative), All-trans-
retinoic acid [(tretinoin) (3,7-dimethyl-9-(2,6,6-tri-
methyl-1-cyclohexenyl)-non-2,4,6,8 tetraenoic acid)],
6-benzyl-aminopurine (6-BA) and pentadecanoic acid
(PDA), cromakalim, etanercept, infliximab, RU58841
and latanoprost are some newer hair growth-promoting
agents (67,68).
Patient consideration
Alopecia is a disease of enormous psychosocial sig-
nificance. Moreover, drug-induced hair regrowth in
alopecia areata may be very slow; a cosmetic response
may take 1–2 years to achieve. Fiedler reported three
key elements to effectively treat the patient: (i) help
the patient understand the disease; (ii) encourage the
patient to share his or her feelings with the physician,
family, friends, and other sufferers of the disease;
and (iii) help the patient to maintain a sense of
hope for future scientific knowledge and treatment
of the disease (66). With a thorough knowledge of the
potential benefits and risks of each treatment or
combination treatment, the physician, with the
patient’s understanding and cooperation, may then
embark on what may be in severe cases a lengthy
and sometimes unproductive therapeutic process.
Conclusion
Hair growth-promoting agents are lifestyle drugs.
The current status of treatment of alopecia is the
result of recent advances in our understanding of
its aetiology and progression. Angiogenesis (through
endogenous substances), androgen antagonism,
vasodilation through potassium channel opening
and 5-alpha reductase inhibition are the major
non-surgical therapeutic strategies for hair growth
promotion.
Modern synthetic drugs have been found to show
potential in promoting hair growth. Various clinical
trials and studies have validated the use of hair
growth-promoting modern synthetic drugs. But, in
spite of proven hair growth-promotion effects, therapy
with the synthetic drugs has become questionable due
to their occasional lack of efficacy, safety or their side
effects. Herbal drugs may provide a new revolution for
hair growth. A majority of hair growth-promotion
studies performed with herbal drugs are preliminary
and more scientific data are necessary to prove those
activities. This can be attained by careful and accu-
rate characterization of the active chemical com-
pounds, elucidation of the molecular mechanisms
of their actions, development of more reliable hair
follicle organ culture for ex vivo studies, in vivo
studies on proper animal models of hair loss and,
finally, analysis of their safety and effectiveness in
clinical trials.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
References
1. Bertolino AP. Alopecia areata: A clinical overview. Postgrad
Med. 2000;107(7):81–90.
2. Olsen EA. Androgenetic alopecia. In: Olsen EA (ed). Dis-
orders of hair growth: Diagnosis and treatment. New York:
McGraw-Hill, 1993, p. 257–287.
3. Madani S, Shapiro J. Alopecia areata update. J Am Acad
Dermatol. 2000;42:549–566.
4. Bandaranayake I, Mirmirani P. Hair loss remedies –separating
fact from fiction. Cutis. 2004;73:107–114.
5. Uno H, Cappas A, Brigham P. Action of topical minoxidil in
the bald stumptailed macaque. J Am Acad Dermatol.
1987;16:657–668.
6. Goodman LS, Gilman A (eds). The pharmacological basis of
therapeutics. New York: McGraw Hill, 1996, p. 1611.
7. Libecco JF, Bergfeld WF. Finasteride in the treatment of
alopecia. Expert Opin Pharmacother. 2004;5(4):933–940.
8. Takahashi T, Kamiya T, Yokoo Y. Proanthocyanidins from
grape seeds promote proliferation of mouse hair follicle cells in
vitro and convert hair cycle in vivo. Acta Derm Venereol.
1998;78:428–432.
9. Saraf S, Pathak AK, Dixit VK. Hair growth promoting activity
of Tridax procumbens. Fitoterapia. 1991;62:495–498.
10. Hardy MH. The secret life of the hair follicle. Trends Genet.
1992;8:55–61.
11. Stenn KS, Paus R. Control of hair follicle cycling. Physiol Rev.
2001;81:449–494.
12. Paus R, Cotsarelis G. The biology of hair follicles. N Engl
J Med. 1999;341:491–498.
8M. Semalty et al.
J Dermatolog Treat Downloaded from informahealthcare.com by 117.254.208.54 on 06/11/10
For personal use only.
13. Paus R, Rover MS, Veen C, Maurer M, Eichmuller S, Ling G,
et al. A comprehensive guide for the recognition and classi-
fication of distinct stages of hair follicle morphogenesis.
J Invest Dermatol. 1999;113:523–532.
14. Chumlea W, Rhodes T, Girman C, Johnson-Levonas A,
Lilly F, Wu R, et al. Family history and risk of hair loss.
Dermatology. 2004;209(1):33–39.
15. Wolff H, Kunte C. Current management of androgenetic
alopecia in men. Eur J Dermatol. 1999;9(8):606–609.
16. Whiting D. Diagnostic and predictive value of sections of scalp
biopsy specimens in male pattern androgenetic alopecia. J Am
Acad Dermatol. 1993;28:755–763.
17. Rebora A. Pathogenesis of androgenetic alopecia. J Am Acad
Dermatol. 2004;50(5):777–779.
18. Paus R. Therapeutic strategies for treating hair loss. Drug
Discov Today Ther Strateg. 2006;3(1):101–110. DOI:
10.1016/j.ddstr.2006.03.004; www.drugdiscoverytoday.com
19. Barrera A. Hair restoration. Clin Plast Surg. 2005;32(2):
163–170.
20. Carmeliet P. Angiogenesis in health and disease. Nat Med.
2003;9:653–660.
21. Zachary I, Gliki G. Signaling transduction mechanisms medi-
ating biological actions of the vascular endothelial growth
factor family. Cardiovasc Res. 2001;49:568–581.
22. Mecklenburg L, Tobin D, Muller-Rover S, Handjiski B,
Wendt G, Peters EM, et al. Active hair growth (anagen) is
associated with angiogenesis. J Invest Dermatol. 2000;114:
909–916.
23. Dulak J. Nutraceuticals as anti-angiogenic agents: Hopes and
reality. J Physiol Pharmacol. 2005;56:51–67.
24. Meisheri KD, Johnson GA, Puddington L. Enzymatic and
nonenzymatic sulfation mechanisms in the biological actions
of minoxidil. Biochem Pharmacol. 1993;45:271–279.
25. Buhl AE, Waldon DJ, Conrad SJ, Mullholland MJ, Shull KL,
Kubicek MF, et al. Potassium channel conductance: A mech-
anism affecting hair growth both in vitro and in vivo. J Invest
Dermatol. 1992;98:315–319.
26. Harmon CS, Lutz D, Ducote J. Potassium channel openers
stimulate DNA synthesis in mouse epidermal keratinocyte and
whole hair follicle cultures. Skin Pharmacol. 1993;6:170–8.
27. Buhl AE, Waldon DJ, Baker CA, Johnson GA, et al. Minoxidil
sulfate is the active metabolite that stimulates hair follicles.
J Invest Dermatol. 1990;95:553–557.
28. Boyera N, Galey I, Bernard BA. Biphasic effects of minoxidil
on the proliferation and differentiation of normal human
keratinocytes. Skin Pharmacol. 1997;10:206–220.
29. Sakita S, Kagoura M, Toyoda M, Morohashi M, et al.
The induction by topical minoxidil of increased fenestration
in the perifollicular capillary wall. Br J Dermatol. 1999;140:
294–296.
30. Michelet JF, Commo S, Billoni N, Mahe Y, Bernard B, et al.
Activation of cytoprotective prostaglandin synthase-1 by
minoxidil as a possible explanation for its hair growth-
stimulating effect. J Invest Dermatol. 1997;108:205–209.
31. Messenger AG, Rundegren J. Minoxidil: Mechanisms of
action on hair growth. Br J Dermatol. 2004;150:186–194.
32. Chen CH, Sheu MT, Wu AB, Lin KP, Ho HO, et al.
Simultaneous effects of tocopheryl polyethylene glycol succi-
nate (TPGS) on local hair growth promotion and systemic
absorption of topically applied minoxidil in a mouse model.
Int J Pharm. 2005;306(1–2):91–98.
33. Lucky AW, Piacquadio DJ, Ditre CM, Dunlap F, Kantor I,
Pandya AG, et al. A randomized, placebo-controlled trial of 5%
and 2% topical minoxidil solutions in the treatment of female
pattern hair loss. J Am Acad Dermatol. 2004;50(4):541–553.
34. Health News, The latest on baldness cures. Available from:
http://findarticles.com/p/articles/mi_m0857/is_n6_v12/ai_
16395133.
35. Goldberg MR. Clinical pharmacology of pinacidil, a
prototype for drugs that affect potassium channels. J Cardiovas
Pharmacol. 1998;12:S41–S47.
36. Weston AH, Longmore J, Newgreen DT, Edward G,
Bray KM, Duty S, et al. The potassium channel openers: A
new class of vasorelaxants. Blood Vessels. 1990;27:306–313.
37. Roberrtson DW, Steinberg MI. Potassium channel modula-
tors: Scientific applications and therapeutic promise. J Med
Chem. 1990;33:1529–1541.
38. Buhl AE, Conrad SJ, Waldon DJ, Brunden MN. Potassium
channel conductance as a control mechanism in hair follicles.
J Invest Dermatol. 1993;101:148S–152S.
39. Harmon CS, Lutz D, Ducote J. Potassium channel openers
stimulate DNA synthesis in mouse epidermal keratinocyte and
whole hair follicle cultures. Skin Pharmacol. 1993;6:170–178.
40. Roenigk HH. New topical agents for hair growth. Clin
Dermatol. 1988;6:119–221.
41. Zaccheo T, Giudici D, Salle DE. Effect of the dual
5a-reductase inhibitor Pnu 157706 on the growth of dunning
R3327 prostatic carcinoma in the rat. J Steroid Biochem Mol
Biol. 1998;64(3–4):193–198.
42. Diani AR, Mulholland MJ, Shull KL, Kubicek MF,
Johnson GA, Schostarez HJ, et al. Hair growth effects of
oral administration of finasteride, a steroid 5-alpha-
reductase inhibitor, alone and in combination with topical
minoxidil in the balding stumptail macaque. J Clin Endocrinol
Metab. 1992;74:345–350.
43. Rushton DH, Norris MJ, Doverand R, Busuttil N. Causes of
hair loss and the developments in hair rejuvenation. Int J
Cosmet Sci. 2002;24(1):17–23.
44. Price VH. Treatment of hair loss. N Engl J Med. 1999;341
(13):964–973.
45. Frye SV, Haffner CD, Maloney PR. 6-Azasteroids: Potent
dual inhibitors of human type 1 and 2 steroid 5alpha-
reductase. J Med Chem. 1993;36:4313–4315.
46. Jones CD, Audia JE, Hirsch KS, Lawhorn DE, McQuaid LM,
Neubauer BL, et al. Nonsteroidal inhibitors of human type 1
steroid 5alpha-reductase. J Med Chem. 1993;36:421–423.
47. Esfandiari A, Kelley P. The effects of tea polyphenolic
compounds on hair loss among rodents. J Nat Med Assoc.
2005;97(6):816–818.
48. Kwon OS, Han JH, Yoo HG, Chung JH, Cho KH, Eun HC,
et al. Human hair growth enhancement in vitro by green tea
epigallocatechin-3-gallate (EGCG). Phytomedicine. 2007;14
(7–8):551–555.
49. Ganzeveld M. Green tea and hair loss and testimonials for
hair growth. Available from: http://www.greenteaphd.com/
green_tea_hair_loss.html, accessed on August 12, 2009.
50. Adhirajan N, Ravi Kumar T, Shanmugasundaram N,
Babu M. In vivo and in vitro evaluation of hair growth
potential of Hibiscus rosa-sinensis Linn. J Ethnopharmacol.
2003;88(2–3):235–239.
51. Adhirajan N, Dixit VK, Gowri C. Development and evalua-
tion of herbal formulations for hair growth. Indian Drugs.
2001;38(11):559–563.
52. Roy RK, Thakur M, Dixit VK. Effect of Cuscuta reflexa Roxb.
on hair growth in albino rats. Indian Drugs. 2006;43(12):
951–956.
Hair growth and rejuvenation 9
J Dermatolog Treat Downloaded from informahealthcare.com by 117.254.208.54 on 06/11/10
For personal use only.
53. Roy RK, Thakur M, Dixit VK. Effect of Citrullus colocynthis
on hair growth in albino rats. Pharm Biol. 2007;45(10):
739–744.
54. Roy RK, Thakur M, Dixit VK. Development and evaluation
of polyherbal formulation for hair growth-promoting activity.
J Cosmet Dermatol. 2007;6(2):108–112.
55. Uno H. Quantitative models for the study of hair growth in vivo
In: Stenn KS, Messenger AG, Baden HP (eds). Molecular and
structural biology of hairs. Vol. 642. New York: New York
Academy of Science, 1991, p. 107–124.
56. Rho SS, Park SJ, Hwang SL, Lee MH, Kim CD, Lee IH,
et al. The hair growth promoting effect of Asiasari radix
extract and its molecular regulation. J Dermatol Sci.
2005;38(2):89–97.
57. Roh SS, Kim CD, Lee MH, Hwang SL, Rang MJ, Yoon YK,
et al. The hair growth promoting effect of Sophora flavescens
extract and its molecular regulation J Dermatol Sci. 2002;30
(1):43–49.
58. Sharquie KE, Al-Obaidi HK. Onion juice (Allium cepa L.),
a new topical treatment for alopecia areata. J Dermatol.
2002;29(6):343–346.
59. Sakaguchi I, Ishimoto H, Matsuo M, Ikeda N, Minamino M,
Kato Y, et al. The water-soluble extract of Illicium anisatum
stimulates mouse vibrissae follicles in organ culture. Exp
Dermatol. 2004;13(8):499–504.
60. Nakaoji K, Nayeshiro H, Tanahashi T, Su Y, Nagakura N.
Bisbenzylisoquinoline alkaloids from Stephania cepharantha
and their effects on proliferation of cultured cells from the
murine hair apparatus. Planta Med. 1997;63(5):425–428.
61. Osawa Y, Tamaki S, Sawaki S, Tomita Y. Promotion of
hair-growth with Laminaria angustata extracts. Int J
Cosmet Sci. 2004;26(4):215–225. DOI: 10.1111/j.1467-
2494.2004.00224_2.x;
62. Gallwitz E. Stimulation of hair growth by Ginkgo biloba
flavanoids. U.S. Patent No. 20070196316, 2007.
63. Bonte F, Meybeck A. Cosmetic or pharmaceutical composi-
tion, especially dermatological composition, containing oxya-
canthine, intended in particular for stimulating hair growth or
retarding hair loss. U.S. Patent No. 5,607,693, 1997.
64. Chizick E. A natural formulation for treatment of male pattern
hair loss. U.S. Patent No. 5,972,345, 2002.
65. Niazi SK. Herbal composition for the treatment of alopecia.
U.S. Patent No. 6,495,174, 2002.
66. Fiedler VC. Alopecia areata: A review of therapy, efficacy,
safety, and mechanism. Arch Dermatol. 1992;128(11):
1519–1529.
67. Kwon OS, Pyo HK, Oh YJ. Promotive effect of minoxidil
combined with all-trans retinoic acid (tretinoin) on
human hair growth in vitro. J Korean Med Sci. 2007;4:
22–29.
68. Uno H, Zimbric ML, Albert DM, Stjernschantz J. Effect
of latanoprost on hair growth in the bald scalp of the
stump-tailed macacque: A pilot study. Acta Derm Venereol.
2002;82:7–12.
10 M. Semalty et al.
J Dermatolog Treat Downloaded from informahealthcare.com by 117.254.208.54 on 06/11/10
For personal use only.
