Journal of Dermatological Treatment. 2010; Early Online, 1–10

REVIEW ARTICLE

Hair growth and rejuvenation: An overview

MONA SEMALTY1, AJAY SEMALTY1, GEETA PANT JOSHI2 &MOHAN SINGH MANIYARI RAWAT2

1Department of Pharmaceutical Sciences, and 2Department of Chemistry, HNBGarhwal University Srinagar (Garhwal),Uttarakhand, India

AbstractHair has psychological and sociological importance throughout the ages in framing the personality and general appearance ofan individual. Significant progress is beingmade on discovering an effective and safe drug for hair growth. Angiogenesis, androgenantagonism, vasodilation, potassium channel opening and 5-alpha reductase inhibition are the major non-surgical therapeuticstrategies of hair growth promotion. In spite of a flood of drugs claiming to be useful as hair growth promoters, more rationalstrategies, which can target the problem areas or stages of the hair growth cycle effectively, are still awaited. This article highlightsthe 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 anindividual’s personality since time immemorial. Alo-pecia (baldness), a dermatological disorder, is a com-mon problem of cosmetology as well as primaryhealth practice. It is common throughout the worldand has been estimated to affect between 0.2% and2% of the world’s population (1–3). The clinicalseverity of alopecia in a patient may not be a goodindicator of a subsequent downturn in quality of lifeor 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 radicalimprovement in the availability of more precise ther-apies (4). Much of that disappointment appears toresult from unrealistic expectations, ill-targeted (andtherefore inefficient) drug therapy and insufficientindustrial interest in dissecting the basic mechanismsby which hair loss occurs and by which human hairgrowth promoters exert their effects.

Over the past several years about 300 000 productshave claimed to help hair regrowth. With the excep-tion of minoxidil and finasteride, none of them wasfound to be effective in hair growth promotion.Minoxidil, a synthetic (cardiovascular) drug, wasscientifically proved to help the treatment of alopecia.The hair growth activity of minoxidil is actually theside effect of this cardiovascular drug (5). Currently,minoxidil (useful in both male and female patternbaldness) and finasteride (useful in male patternbaldness) are two US FDA-approved synthetic drugsfinding concomitant use for treatment of androgenicalopecia, but their side effects have reduced theirusage (6,7). Moreover, both the drugs are the resultof serendipity, not of rational hair drug design.Therefore, to search for more precise therapies foralopecia, newer synthetic drugs or drugs of plantorigin need to be explored. Herbal drugs havebeen widely used for hair growth promotion sinceancient times in Ayurveda, Chinese and Unani sys-tems of medicine. Natural products are very popularand well accepted in the cosmetic and hair careindustries (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

J D

erm

atol

og T

reat

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

117.

254.

208.

54 o

n 06

/11/

10Fo

r pe

rson

al u

se o

nly.

The goal of the present article is to provide anoverview of available hair loss treatment alternatives.The article provides a brief review of the hair growthcycle and different causes of hair loss, followed byfocuses on the various types of drugs available foralopecia. The article reviews various studies show-ing hair growth-promotion efficacy of modern andherbal 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 areepidermally derived appendages which arise as aresult of inductive events between specialized dermalfibroblasts acting on bipotential epithelial stem cells.The stem cells which commit to a hair follicle fateenter a period of massive proliferation that culminatesin 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 regeneratingsystem (Figure 1). By traversing the phases of thecycle (growth, regression, resting, shedding, thengrowth again), the follicle demonstrates the unusualability to completely regenerate itself (11). Normalhair follicles cycle between a growth stage (anagen),a degenerative stage (catagen), a resting stage(telogen) and a shedding stage (exogen). The scalphairs have a relatively long life cycle: the anagen stageranges from2 to 5 years, the catagen stage ranges from afew days to a few weeks, and the telogen stage isapproximately 3 months (12,13). Hair cycle distur-bances have dramatic effects on visible hair growth. Ifanagen gets prematurely terminated and catagenoccurs too early, this must result in effluvium andalopecia; the affected skin regionwill subsequently sportlargely catagen and/or telogen follicles, whose looselyanchored club hairs are eventually shed (i.e. the normalanagen/telogenrateonthescalp[roughly4:1]changes infavor of telogen). This is exactly what happens, forexample, as a consequence of drug-induced damageto the proliferating cells of the anagen hair bulb,such as in drug-induced telogen effluvium or wheninflammatory cells attack the anagen hair bulb inalopecia areata (12). Therefore, the therapeuticmanipulation of hair follicle cycling is a key challenge

Epithelium/messenchyme Placode Germ Peg

Folliculogenesis

Bulbose peg

Anagen Catagen

Telogen

S

B

E

H

ORS

PIRS

CTS

P

H B

B

MP P

BB

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 theprimitive epithelium to form a placode. Below the placode dermal cells aggregate and thereafter the epithelium grows down as a finger toproduce the multilayer, shaft-producing hair follicle. In the adult, three phases of the growth cycle are recognized: a growth phase (anagen), aregressing phase (catagen): and a resting phase (telogen). It is the lower follicle that regenerates at the beginning of each cycle by utilizingintimate and powerful epithelial–mesenchymal interactions of the stem cells in the bulge (B) and the inductive mesenchymal cells of thepapilla (P). CTS, connective tissue sheath; E, epidermis; H, hair shaft; IRS, inner root sheath; M, hair matrix; ORS, outer root sheath;S, sebaceous gland.

2 M. Semalty et al.

J D

erm

atol

og T

reat

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

117.

254.

208.

54 o

n 06

/11/

10Fo

r pe

rson

al u

se o

nly.

inhair lossmanagement.Effective therapeutic strategiesfor hair loss in declining order of importance are:

. inhibition of catagen development in order toprolong anagen

. induction of anagen in telogen follicles

. inhibition of exogen.

Hair loss and alopecia

Hair loss is a natural daily phenomenon, but thisshedding of hair cannot be the main cause of hairloss. Every strand of hair on a human head is genet-ically programmed to a cycle that includes growth,stabilization, aging and shedding. On average, everyday a human head sheds about 50–125 hairs (depend-ing on sex), but most of them will come back after theresting stage as the follicle itself is not destroyed (14).Trouble begins when the loss exceeds re-growth, orthe re-growth is weak and unhealthy. A loss of 100hairs per day can be considered ‘normal’ not patho-logic. But a loss of more than 100 hairs per dayconstitutes a pathological effluvium. Androgeneticalopecia (AGA) is one of the dermatological condi-tions most commonly faced by the dermatologist orgeneral physician. The condition affects up to 30% ofmen under the age of 30 and more than 50% of menover the age of 50. Despite a widespread belief thatAGA is only experienced by men, it also affectswomen, although the clinical signs are usually milderand the phenotype is different (15). As the conditionprogresses, scalp hairs and their follicles becomeprogressively miniaturized, and the terminal hair

normally found on the adult scalp is replaced byvellus hairs which are shorter, finer andnon-pigmented. Concomitantly, the average lengthof 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 causingsmall, patchy circular bald patches in several partsof the scalp), alopecia totalis (total loss of scalp hair),and alopecia universalis (total loss of hair from theentire body) (17). Another way in which hair loss(alopecia) can be classified is according to factorsleading to it. There are two different types of hairloss, known medically as:Anagen effluvium: caused by medications taken

internally, such as chemotherapy representatives,excessive doses of vitamin A or some hypertensionmedications.Telogen effluvium: caused by an increased number

of hair follicles entering the latent or rather dead stage.The most common causes of telogen effluviumleading to alopecia could be physical and emotionalstress, 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 andrejuvenation

There are a number of ways in which a drug maystimulate 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 forgout, 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 progressivelyminiaturizes scalp follicles and this may be due to the atherosclerotic process blocking themicrovasculature that nourishes the hair follicles

Excessive sebum Excessive sebum causes a high level of 5-alpha reductase and pore clogging, thus malnutrition ofthe hair root

Cardiovascular diseases High levels of LDL in cardiac patients are converted to 5-alpha reductase enzyme, which producesDHT from testosterone, causing hair loss

Smoking Tobacco smoke damages the lining of blood vessels, leading to less production of nitric oxide andthus 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

J D

erm

atol

og T

reat

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

117.

254.

208.

54 o

n 06

/11/

10Fo

r pe

rson

al u

se o

nly.

growth rate of hair; increase the diameter of the hairfibre; alter the hair cycle, either shortening telogen orprolonging anagen; or act through a combination ofthese effects. Among the surgical treatment methods,the introduction of micrografts (one to two hair fol-licular unit grafts) and minigrafts (three to four hairfollicular unit grafts) has made a most significantadvancement in the care of male pattern baldnessand female androgenic alopecia; naturaland aesthetically pleasing results are possible. Addi-tionally, many other applications in the reconstructionof facial and scalp hair have been found; some of theseinclude 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 traumaticinjuries (19).Various non-surgical pharmacotherapeutic alter-

natives available for hair growth and rejuvenationare discussed in the following sections.

Vitamins, nutrients and minerals

Vitamin deficiencies are also thought to be the causeof alopecia and for which the treatment would bedietary vitamin supplementation. The use of biotin asa treatment for alopecia was suggested by evidencethat biotin (vitamin H) deficiency causes hair loss.Biotin is a water-soluble vitamin that acts as anessential cofactor for four different carboxylases,each of which catalyzes an essential step in interme-diary metabolism. An analysis of hair shows that itis composed of iron, oxygen, hydrogen, nitrogenand sulphur. The blood must be supplied with theseminerals so that nourishment will be carried tothe scalp.Angiogenesis, the formation of new blood vessels

from the pre-existing vascular network, is a drivingforce of hair growth. It is indispensable for embryonicdevelopment as interruption of angiogenic eventsblocks the growth of the embryo and results in earlymortality. After birth, angiogenesis plays both adap-tive role enabling the regeneration of damaged bodyparts and is also involved in numerous pathologicalchanges. Understanding of the basic mechanisms ofblood vessel formation is necessary for the establish-ment of effective therapeutic strategies for ameliora-tion of diseases. The major angiogenic regulator isvascular endothelial growth factor (VEGF), namedalso VEGF-A, which is one of several members of theVEGF family. In adult organisms, physiologicalangiogenesis is limited and occurs during regenera-tion of uterine epithelium in the menstrual cycle,development of the ovum and formation of corpusluteum and hair growth (20). VEGF has a central role

in promoting angiogenesis as well as influencingdiverse cell functions, including cell survival, prolif-eration and the generation of nitric oxide and pros-tacyclin (21). The perifollicular capillary network iscoupled to the hair cycle, increasing during anagenand then regressing during catagen and telogen.It has been investigated that metabolically ‘resting’

telogen follicles have considerably lower perfusionrequirements than larger, rapidly growing, anagenhair follicles. With the use of standardized quantita-tive histomorphometry, electron microscopy, andCD31 (platelet endothelial cell adhesion molecule-1[PECAM-1]) immunohistochemistry as an endothe-lial cell marker, it was shown that the cutaneousmicrovasculature is substantially rearranged duringanagen development, that there is endothelial cellproliferation, 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 synchronizedhair cycle, is associated not only with a rearrangementof the skin vasculature and a concomitant increase inskin perfusion, but also with genuine and substantialangiogenesis. Therefore, modulation of angiogenesisis considered as therapeutic strategies of great impor-tance for hair growth (23). The role of various nutri-ents and minerals in preventing hair loss issummarized in Table II.

Table II. Role of nutrients and minerals in the prevention ofhair loss.

Nutrients and minerals Mechanism of preventing hair loss

Niacin (vitamin B3) . Enhances blood flowto scalp through vasodilatoryeffects

. Reduces the level of cholesteroland hence the level of 5-alphareductase on scalp

Vitamin B complex . Improves blood flowto scalp

. Decreases cholesterolaccumulation to scalp

. Protects hair and scalp fromfree radical damage

Ascorbic acid (vitamin C) . Improves blood flow to scalpand maintains capillariescarrying blood to follicles

Tocoferol (vitamin E) . Enhances oxygen uptake andthus improves blood flow toscalp

Zinc . Enhances immune functionand thus stimulates hair growth

Essential fatty acids(primrose and salmon oil)

. Improves hair texture

. Prevents loss of dry brittle hairs

Amino acids (L-cysteineand L-methionine)

. Improves quality ofhair texture

4 M. Semalty et al.

J D

erm

atol

og T

reat

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

117.

254.

208.

54 o

n 06

/11/

10Fo

r pe

rson

al u

se o

nly.

Anti-androgen therapy

Flutamide and cyproterone acetate in combinationwith ethinyl-estradiol have been reported to showsome effectiveness in female pattern baldness. Spir-onolactone is a steroid used mainly as a diuretic andantihypertensive agent. Side effects cause androgen-receptor blockade and direct inhibition of testoster-one production by the adrenal gland. Therefore, thisaldosterone antagonist (spironolactone) is used indosages from 75 mg to 150 mg per day with somebenefit in hair loss.

Heterocyclics

Minoxidil

Minoxidil was first used in tablet form as a medicineto treat high blood pressure, but it was noticed thatsome patients being treated with minoxidil experi-enced excessive hair growth (hypertrichosis) as a sideeffect. Further research showed that by applyingtopical minoxidil solution directly to the scalp, itcould prove to be beneficial to those people experi-encing hair loss. Topical minoxidil (2,4-diamino-6-piperidino pyrimidine-3-oxide) is the only drugapproved by the Food and Drug Administration totreat male and female pattern baldness. Orally admin-istered minoxidil lowers blood pressure by relaxingvascular smooth muscle through the action of itssulphated metabolite, minoxidil sulphate, as anopener of sarcolemmal KATP channels (24). Thereis some evidence that the stimulatory effect of minox-idil on hair growth is also due to the opening ofpotassium channels by minoxidil sulphate, but thisidea has been difficult to prove and to date there hasbeen no clear demonstration that KATP channels areexpressed in the hair follicle (25,26). Minoxidil sti-mulates mitosis in epithelial cells, inhibits collagensynthesis, prolongs the survival of epithelial cells intissue culture and stimulates vascular endothelialgrowth factor and prostaglandin synthesis (27–30).It has therefore been suggested that the drug slows theaging of hair matrix cells. It is postulated that it delaysor prevents the entry of some follicles into the nextanagen phase for long periods of time and stimulatesthese follicles back into active production. Variousstudies have verified the hair growth-promotionactivity of minoxidil (31,32). Also, both 5% and2% topical minoxidil helped improve psychosocialperceptions of hair loss in women with female patternhair loss (33). Topical minoxidil is effective at aconcentration of 2%. Successful treatment, however,does require a lifetime commitment. The topical

solution must be applied to the balding area twice aday, every day. Decreasing the dosage to once a dayresults in some hair loss, and discontinuing applica-tion causes regression to pretreatment baldness within3–6 weeks.The disadvantages of minoxidil are: (i) lifetime

commitment; (ii) high cost: it is not covered by healthinsurance 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 rubbedinto the scalp – since little is absorbed into thebloodstream – it is a vasodilator and not recom-mended for anyone with heart trouble. Its safety inpregnant women, men over the age of 49 years andlong-term use is unknown.

Pyridine derivatives

These include pinacidil, nicorandil, RP-49356 andP-1075. They are K+-channel openers. They play arole in regulation of the hair growth cycle. Potassiumchannel biology is a widely diverse field that has animpact on many aspects of physiology. More than 15different types of potassium channels have been iden-tified in various tissues. These channels are classifiedinto four subtypes: voltage dependent, calciumdependent, receptor coupled, and miscellaneous.Specific classes are defined by the magnitude of theelectrical conductance of the channel, the types ofpharmacological agents that block the channel, andthe physiologic properties of the channel. Potassiumchannel openers stimulate proliferation of cells incultured vibrissae and skin keratinocytes. They elicithypertrichosis in humans (35–37). Buhl et al. testedthe effect of topical application of minoxidil andthree other potassium channel openers on scalphair 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 induceshypertrichosis in 2–13% of patients (38).

Benzothiazide derivative

Diazoxide is also a K+-channel opener. Diazoxide wasreported to increase the uptake of thymidine in adose-dependent fashion in 4-day cultures of mousevibrissae follicles (31,39). Oral diazoxide causeshypertrichosis in most hypoglycemic children andabout 1% of adults, and induces some scalp hairsin 25% of the balding patients (40).

Hair growth and rejuvenation 5

J D

erm

atol

og T

reat

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

117.

254.

208.

54 o

n 06

/11/

10Fo

r pe

rson

al u

se o

nly.

Steroids

4-Aza steroids

Finasteride is a 4-aza steroidal drug which acts byinhibiting the 5-alpha reductase (enzyme) that trans-forms testosterone into the dihydrotestosterone(DHT) form, responsible for hair loss (41,42). Itwas originally used to treat benign prostate hyperpla-sia or prostate enlargement. Blocking the action ofDHT seems to stimulate growth of stronger, thickerand more pigmented hair. In a study, finasteride wasadministered orally at 0.5 mg/day, alone or in com-bination with topical 2% minoxidil, for 20 weeks todetermine the effects on scalp hair growth in baldingadult male stump tail macaque monkeys. A l-daydose-finding study showed that both 0.5- and2.0-mg doses of the drug produced a similar dimi-nution in serumDHT inmale stumptails (42). In ano-ther study, finasteride was found to regrow a noticeableamount 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 sexualfunctions in men, the side effects of finasterideinclude 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 (evenin small concentrations it causes a specific birthdefect – hypospadias, which involves abnormalitiesof the external genitalia of a male fetus) and has notbeen shown to work for a receding hairline at the

temple. These side effects may last for as long as themedicine is taken. Besides finasteride, other 4-azasteroidal drugs are dutasteride, episteride andturosteride.

6-Aza steroids

These are 6-aza androstane derivatives and showhair growth activity. They are type I 5-alpha reductase(located in the sebaceous glands) inhibitors but arenot time-dependent like finasteride, which is atime-dependent inhibitor of type II 5-alpha reductase(45,46).

Natural products

Many ancient Ayurvedic (ancient Indian system ofmedicine) and Chinese herbal drugs have beenreported and documented as potent hair growth pro-moters. The natural products are reported to be moreeffective alternatives for hair growth therapy than thesynthetic drugs. Numerous bioactive plant com-pounds have been tested for potential clinical applica-tions. Various natural products associated with hairgrowth activity are listed in Table III.In the search for a safe and effective alternative

therapy for hair loss, many studies on herbal drugshave 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 inblood 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

nutrientsGinkgo biloba . Inhibits 5-alpha reductase activity

. Protects small blood vessels and micro-capillaries against loss of tone and fragilityBee 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.

6 M. Semalty et al.

J D

erm

atol

og T

reat

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

117.

254.

208.

54 o

n 06

/11/

10Fo

r pe

rson

al u

se o

nly.

might be useful in the prevention or treatment ofandrogenetic alopecia by selectively inhibiting 5-alphareductase activity (47–49). Polyphenolic compounds(such as epigallocatechin-3-gallate) and catechins ofgreen tea are the major phytoconstituents that areresponsible for its hair growth activity. Adhirajan et al.(2003) evaluated the petroleum ether extract of theleaves and flowers ofHibiscus 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 morepotency on hair growth (50). In another study, Adhir-ajan et al. (2001) studied a mixture of petroleum etherextract of Eclipta alba Hassk. (compositiae), Citrulluscolocynthis Schrad. (cucerbitaceae) and Tridax procum-bens Linn. (compositeae) in various concentrations inthe form of herbal cream and herbal oil (51). The ratioof E. alba, C. colocynthis and T. procumbens in 3:1:2showed excellent hair growth activity with 35% moreanagen hair follicles as compared to 20% with astandard drug (2% ethanolic solution of minoxidil).Roy et al. studied the effect of successive petroleum

ether and ethanol extracts ofC. colocynthis andCuscutareflexa on hair growth in albino rats (52,53). Theextracts were incorporated into an oleaginous oint-ment base and were applied topically on the shaveddenuded skin of albino rats. The time required forinitiation of hair growth as well as completion of thehair growth cycle was recorded. The hair growthinitiation time was significantly reduced to half ontreatment with the petroleum ether extracts comparedwith untreated control animals. The time required forcomplete hair growth was also considerably reduced.The treatment was successful in bringing a greaternumber of hair follicles (> 70%) to the anagen phasethan standard minoxidil. In another study, the poly-herbal formulation of C. reflexa (Roxb.), C. colocynthis(Schrad.) and E. alba (Hassk.) were developed andevaluated the same for hair growth-promoting activ-ity. The hair growth initiation time was markedlyreduced to one-third on treatment with the preparedformulation compared with control animals (54). Thetime required for complete hair growth was alsoreduced by 32%. Quantitative analysis (by the methoddescribed by Uno) (55) of the hair growth cycle aftertreatment with prepared herbal formulations andminoxidil (2%) exhibited a greater number of hairfollicles 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 lossin oriental medicine in order to identify potentialstimulants of hair growth. Asiasari radix extractshowed hair growth-promoting potential (56).In another study, Rho et al. studied the hairgrowth-promoting effect of Sophora flavescens and

showed that it can be used as a potential hairgrowth promoter (57).An independent study was designed to test the

effectiveness of topical crude onion juice (Alliumcepa L.) in the treatment of patchy alopecia areata.The patients were divided into two groups. The firstgroup (active: onion juice) consisted of 23 patients(16 males and seven females). The second group(control: tap-water) consisted of 15 patients (eightmales and seven females). The two groups wereadvised to apply the treatment twice daily for2 months. Re-growth of terminal coarse hairs startedafter 2 weeks of treatment in the active group. At4 weeks, hair re-growth was seen in 17 patients(73.9%), and at 6 weeks hair re-growth was observedin 20 patients (86.9%); it was significantly higheramong males (93.7%) compared with females(71.4%). In the control group, hair re-growth wasapparent in only two patients (13%) at 8 weeks oftreatment with no sex difference (58).The extract of Illicium anisatum increases subcuta-

neous blood flow in mice. In a study, an organ culturesystem was used to examine the hair follicle elonga-tion effect of this extract (59). In this study,B6C3HF1 mouse vibrissae follicles were culturedin serum-free medium for 7 days at 31�C. Folliclestreated with water-soluble extracts of the leaves, fruitsand roots of I. anisatum or shikimic acid grew signif-icantly longer than controls.Bisbenzylisoquinoline alkaloids were isolated from

Stephania cepharantha and their proliferative activitieson cultured hair cells from the murine skin wereevaluated (60). Cepharanthine, cepharanoline, isote-trandrine, and berbamine showed significant acti-vities in the range of 0.01–0.1 mg/ml, but had noactivity on cultured keratinocytes or fibroblastsfrom the murine skin.Recently, stem cells inducing the anagen phase in

the hair follicle cycle have been discovered in thebulge region of the outer root sheath (ORS). Tofind growth-promoting agents for the ORS cells,the effect of various botanical extracts on the growthof cultured human hair follicles was evaluated. It wasfound that Laminaria angustata extract increasedORS cell growth. Further, hair growth in the shavedskin of C3H mice was also promoted by the topicalapplication 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 (Terminaliabellirica), methi (Trigonella foenumgraecum), laljari(Geranium wallichianum), bhallataka (Semecarpusanacardium) and capsicum. Various patents havealso been granted for hair growth potential of herbal

Hair growth and rejuvenation 7

J D

erm

atol

og T

reat

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

117.

254.

208.

54 o

n 06

/11/

10Fo

r pe

rson

al u

se o

nly.

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 patientswith alopecia. Anthralin, the only non-specific irritantwidely used for hair growth in alopecia areata, isapplied topically as a 0.5% or 1% cream to affectedareas once per day for 20–45 minutes; overnightapplication can also be used in certain patients whocan 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, RU58841and latanoprost are some newer hair growth-promotingagents (67,68).

Patient consideration

Alopecia is a disease of enormous psychosocial sig-nificance. Moreover, drug-induced hair regrowth inalopecia areata may be very slow; a cosmetic responsemay take 1–2 years to achieve. Fiedler reported threekey elements to effectively treat the patient: (i) helpthe patient understand the disease; (ii) encourage thepatient 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 ofhope for future scientific knowledge and treatmentof the disease (66). With a thorough knowledge of thepotential benefits and risks of each treatment orcombination treatment, the physician, with thepatient’s understanding and cooperation, may thenembark on what may be in severe cases a lengthyand sometimes unproductive therapeutic process.

Conclusion

Hair growth-promoting agents are lifestyle drugs.The current status of treatment of alopecia is theresult of recent advances in our understanding ofits aetiology and progression. Angiogenesis (throughendogenous substances), androgen antagonism,

vasodilation through potassium channel openingand 5-alpha reductase inhibition are the majornon-surgical therapeutic strategies for hair growthpromotion.Modern synthetic drugs have been found to show

potential in promoting hair growth. Various clinicaltrials and studies have validated the use of hairgrowth-promoting modern synthetic drugs. But, inspite of proven hair growth-promotion effects, therapywith the synthetic drugs has become questionable dueto their occasional lack of efficacy, safety or their sideeffects. Herbal drugs may provide a new revolution forhair growth. A majority of hair growth-promotionstudies performed with herbal drugs are preliminaryand more scientific data are necessary to prove thoseactivities. This can be attained by careful and accu-rate characterization of the active chemical com-pounds, elucidation of the molecular mechanismsof their actions, development of more reliable hairfollicle organ culture for ex vivo studies, in vivostudies on proper animal models of hair loss and,finally, analysis of their safety and effectiveness inclinical trials.

Declaration of interest: The authors report noconflicts of interest. The authors alone are responsiblefor the content and writing of the paper.

References

1. Bertolino AP. Alopecia areata: A clinical overview. PostgradMed. 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 AcadDermatol. 2000;42:549–566.

4. Bandaranayake I, Mirmirani P. Hair loss remedies – separatingfact from fiction. Cutis. 2004;73:107–114.

5. Uno H, Cappas A, Brigham P. Action of topical minoxidil inthe bald stumptailed macaque. J Am Acad Dermatol.1987;16:657–668.

6. Goodman LS, Gilman A (eds). The pharmacological basis oftherapeutics. New York: McGraw Hill, 1996, p. 1611.

7. Libecco JF, Bergfeld WF. Finasteride in the treatment ofalopecia. Expert Opin Pharmacother. 2004;5(4):933–940.

8. Takahashi T, Kamiya T, Yokoo Y. Proanthocyanidins fromgrape seeds promote proliferation of mouse hair follicle cells invitro and convert hair cycle in vivo. Acta Derm Venereol.1998;78:428–432.

9. Saraf S, Pathak AK, Dixit VK. Hair growth promoting activityof 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 EnglJ Med. 1999;341:491–498.

8 M. Semalty et al.

J D

erm

atol

og T

reat

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

117.

254.

208.

54 o

n 06

/11/

10Fo

r pe

rson

al u

se o

nly.

13. Paus R, RoverMS, Veen C,MaurerM, 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 androgeneticalopecia in men. Eur J Dermatol. 1999;9(8):606–609.

16. Whiting D. Diagnostic and predictive value of sections of scalpbiopsy specimens in male pattern androgenetic alopecia. J AmAcad Dermatol. 1993;28:755–763.

17. Rebora A. Pathogenesis of androgenetic alopecia. J Am AcadDermatol. 2004;50(5):777–779.

18. Paus R. Therapeutic strategies for treating hair loss. DrugDiscov 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 growthfactor 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) isassociated with angiogenesis. J Invest Dermatol. 2000;114:909–916.

23. Dulak J. Nutraceuticals as anti-angiogenic agents: Hopes andreality. J Physiol Pharmacol. 2005;56:51–67.

24. Meisheri KD, Johnson GA, Puddington L. Enzymatic andnonenzymatic sulfation mechanisms in the biological actionsof 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 InvestDermatol. 1992;98:315–319.

26. Harmon CS, Lutz D, Ducote J. Potassium channel openersstimulate DNA synthesis in mouse epidermal keratinocyte andwhole hair follicle cultures. Skin Pharmacol. 1993;6:170–8.

27. Buhl AE,WaldonDJ, Baker CA, JohnsonGA, et al. Minoxidilsulfate 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 minoxidilon the proliferation and differentiation of normal humankeratinocytes. Skin Pharmacol. 1997;10:206–220.

29. Sakita S, Kagoura M, Toyoda M, Morohashi M, et al.The induction by topical minoxidil of increased fenestrationin 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 byminoxidil as a possible explanation for its hair growth-stimulating effect. J Invest Dermatol. 1997;108:205–209.

31. Messenger AG, Rundegren J. Minoxidil: Mechanisms ofaction 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 systemicabsorption 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 femalepattern 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, aprototype for drugs that affect potassium channels. J CardiovasPharmacol. 1998;12:S41–S47.

36. Weston AH, Longmore J, Newgreen DT, Edward G,Bray KM, Duty S, et al. The potassium channel openers: Anew class of vasorelaxants. Blood Vessels. 1990;27:306–313.

37. Roberrtson DW, Steinberg MI. Potassium channel modula-tors: Scientific applications and therapeutic promise. J MedChem. 1990;33:1529–1541.

38. Buhl AE, Conrad SJ, Waldon DJ, Brunden MN. Potassiumchannel conductance as a control mechanism in hair follicles.J Invest Dermatol. 1993;101:148S–152S.

39. Harmon CS, Lutz D, Ducote J. Potassium channel openersstimulate DNA synthesis in mouse epidermal keratinocyte andwhole hair follicle cultures. Skin Pharmacol. 1993;6:170–178.

40. Roenigk HH. New topical agents for hair growth. ClinDermatol. 1988;6:119–221.

41. Zaccheo T, Giudici D, Salle DE. Effect of the dual5a-reductase inhibitor Pnu 157706 on the growth of dunningR3327 prostatic carcinoma in the rat. J Steroid Biochem MolBiol. 1998;64(3–4):193–198.

42. Diani AR, Mulholland MJ, Shull KL, Kubicek MF,Johnson GA, Schostarez HJ, et al. Hair growth effects oforal administration of finasteride, a steroid 5-alpha-reductase inhibitor, alone and in combination with topicalminoxidil in the balding stumptail macaque. J Clin EndocrinolMetab. 1992;74:345–350.

43. Rushton DH, Norris MJ, Doverand R, Busuttil N. Causes ofhair loss and the developments in hair rejuvenation. Int JCosmet 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: Potentdual 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 1steroid 5alpha-reductase. J Med Chem. 1993;36:421–423.

47. Esfandiari A, Kelley P. The effects of tea polyphenoliccompounds 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 teaepigallocatechin-3-gallate (EGCG). Phytomedicine. 2007;14(7–8):551–555.

49. Ganzeveld M. Green tea and hair loss and testimonials forhair 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 growthpotential 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 D

erm

atol

og T

reat

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

117.

254.

208.

54 o

n 06

/11/

10Fo

r pe

rson

al u

se o

nly.

53. Roy RK, Thakur M, Dixit VK. Effect of Citrullus colocynthison hair growth in albino rats. Pharm Biol. 2007;45(10):739–744.

54. Roy RK, Thakur M, Dixit VK. Development and evaluationof 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 vivoIn: Stenn KS, Messenger AG, Baden HP (eds). Molecular andstructural biology of hairs. Vol. 642. New York: New YorkAcademy 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 radixextract 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 flavescensextract 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 anisatumstimulates mouse vibrissae follicles in organ culture. ExpDermatol. 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 themurine hair apparatus. Planta Med. 1997;63(5):425–428.

61. Osawa Y, Tamaki S, Sawaki S, Tomita Y. Promotion ofhair-growth with Laminaria angustata extracts. Int JCosmet 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 bilobaflavanoids. 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 orretarding hair loss. U.S. Patent No. 5,607,693, 1997.

64. Chizick E. A natural formulation for treatment of male patternhair 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 minoxidilcombined with all-trans retinoic acid (tretinoin) onhuman hair growth in vitro. J Korean Med Sci. 2007;4:22–29.

68. Uno H, Zimbric ML, Albert DM, Stjernschantz J. Effectof latanoprost on hair growth in the bald scalp of thestump-tailed macacque: A pilot study. Acta Derm Venereol.2002;82:7–12.

10 M. Semalty et al.

J D

erm

atol

og T

reat

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

117.

254.

208.

54 o

n 06

/11/

10Fo

r pe

rson

al u

se o

nly.