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Drug Discovery Today Volume 13, Numbers 17/18 September 2008 REVIEWS
Male pattern baldness: current
treatments, future prospects
Justine A. Ellis
1,2
and Rodney D. Sinclair
3
1
Department of Physiology, University of Melbourne, Victoria 3010, Australia
2
Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria 3052, Australia
3
University of Melbourne, Department of Dermatology, St Vincent’s Hospital, Fitzroy, Victoria 3065, Australia
Male pattern baldness affects up to half of the male Caucasian population by middle age, and almost all
Caucasian men by old age. Especially in younger men, this heritable form of hair loss can have
significant psycho-social consequences. Although approved pharmacological agents exist to manage the
condition, none of the currently available options are highly efficacious. New treatments under
development, and acceleration in our understanding of the underlying molecular genetic aetiology of
this condition provide increased hope for future targeted treatment strategies.
Male pattern baldness (MPB), also known as androgenetic alope-
cia, affects up to half of the Caucasian male population by middle
age. By age 80, over 95% of Caucasian males are affected to some
degree [1]. This high prevalence in older men suggests that this
form of hair loss may be considered a normal consequence of
ageing. However, particularly in younger men, hair loss can have
significant psycho-social manifestations [2,3]. Consequently the
baldness treatment industry is worth billions of dollars worldwide
annually [4]. A large proportion of this expenditure funds a section
of the industry that preys on the eagerness of sufferers to halt their
hair loss by pushing untested and usually worthless treatments [5].
However, there are now several approved pharmacological options
shown by proper rigorous scientific processes to assist with the
halting of hair loss and, in some men, may encourage renewed hair
growth. Several more are currently being trialled for efficacy. These
advancements are coupled with a growing understanding of the
hair loss process and, in particular, the molecular mechanisms
through which the process acts, furthering future potential for
targeted therapeutic options based on disease aetiology.
Pathophysiology
Common patterned hair loss occurs in men and in women. In
men, the pattern of loss follows the scale developed by Hamilton
[6], and later extended by Norwood [7] (Fig. 1). The Hamilton–
Norwood baldness scale defines seven distinct categories, begin-
ning with type I representing no hair loss and a normal (pre-
pubertal) frontal hairline. Type II demonstrates some mild frontal
recession, but this category is not considered cosmetically signifi-
cant. Types III–VII represent noticeable balding, incorporating
frontal, and as the loss progresses, vertex hair loss. Even in the
most severe categories, hair is retained on the occipital region of
the scalp. Although this review focuses on MPB, it is worth
pointing out to readers that the pattern of loss experienced by
women is diffuse, manifesting itself as a widening of the central
part, and is defined by the Ludwig scale [8]. The commonality of
aetiology of these two conditions is a current topic of debate, thus
the commonly used term for females is female pattern hair loss
(FPHL) [9,10] (Table 1).
The process of hair loss is a progressive one, and is dependent on
changes to the normal cycling of the hair follicle (Fig. 2). Follicles
undergo a period of growth, known as anagen. In the normal state,
this phase can last several years and result in scalp hair of some
length. The anagen phase is followed by a brief transition phase,
called catagen, where involution of the hair follicle occurs. Follow-
ing this structural transition, the follicle enters telogen. This phase
is hallmarked by a resting state, where the follicle appears dor-
mant, followed by shedding of the hair from the follicle. Following
telogen, the follicle returns to the anagen phase, and a new hair is
grown [11,12]. In MPB, a perturbation of this cycle causes a
progressive shortening of the anagen phase, coupled with a
lengthening of the telogen phase. Over time, as the follicle moves
through several cycles, the length of the hair that can be grown
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Corresponding author: Ellis, J.A. (justine.ellis@mcri.edu.au)
1359-6446/06/$ - see front matter ß2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2008.05.010 www.drugdiscoverytoday.com 791
shortens. This process is married with a miniaturisation of the
follicle itself, the result of which is that with each hair cycle, the
hair is shorter, finer and less pigmented. Eventually, the follicle
becomes incapable of producing a hair that reaches the skin sur-
face, and the region is recognised as bald [13].
The pattern on hair loss indicates that hair follicles undergo this
balding process in a pre-programmed fashion. Loss initially occurs
bitemporally, usually followed by vertex loss, with the eventual
joining of the two balding regions. It is worth noting that the
speed with which frontal and vertex loss occurs can vary, produ-
cing some variation in the usually recognised pattern types [14].
The lack of such programming of follicles in the occipital region of
the scalp, and the fact that, if transplanted to balding regions,
occipital follicles retain their non-balding characteristics, is a
fascinating aspect of the biology of the balding process that has
been exploited in follicle transplant techniques [15]. Defining the
differences in the follicle biology between balding and occipital
regions is also likely to unlock clues to MPB aetiology.
Aetiology
The use of the medical term androgenetic alopecia to describe MPB
reflects current knowledge regarding the important role of both
androgens and genes in MPB aetiology. It has long been known
that the presence of testosterone in hair follicles is a pre-requisite
for MPB. Common balding is not observed in eunuchs [16]. The
more specific role of androgen is also demonstrated by a lack of
MPB in pseudohermaphrodites who lack a functional 5a-reductase
type II enzyme [17]. This enzyme, along with its isozyme, 5a-
reductase type I, is responsible for the conversion of testosterone
(T) to dihydrotestosterone (DHT) [18]. Both T and DHT bind to the
androgen receptor (AR) and effect transcription of androgen-
dependent genes [19]. The importance of AR in the balding process
is further demonstrated by reduced prevalence of MPB in indivi-
duals with Kennedy’s Disease in whom partial androgen insensi-
tivity is caused by the loss of receptor function [20].
The crucial role of genes in MPB is also well-recognised. The
observation that baldness runs in families was made in the early
1900s by Osborn [21]. Initially an autosomal dominant mode of
inheritance was postulated. However, MPB is now recognised as a
genetically multifactorial trait, with a complex underlying genetic
architecture [22,23]. Interestingly, many such multifactorial
human diseases and traits are usually hallmarked by a complex
interplay of genetic and environmental risk factors. By compar-
ison, twin studies of MPB have demonstrated that risk of devel-
oping MPB is determined almost exclusively by genetic
predisposition [24].
Little was known as to the genetic architecture of MPB until the
late 1990s. Candidate gene association studies focused on genes
related to the sex-steroid pathways, and were guided by reports of
REVIEWS Drug Discovery Today Volume 13, Numbers 17/18 September 2008
FIGURE 1
Hamilton–Norwood male pattern baldness scale. Reproduced from Norwood,
O.T. (1973) Hair Transplant Surgery (1st edn), courtesy of Charles C. Thomas
Publisher Ltd., Springfield, IL, USA.
TABLE 1
Summary of currently approved, and developing pharmacological agents for the treatment of male pattern baldness
Drug Action Status Refs
Minoxidil Unknown A [4,36–40]
Vasodilation?
Cell proliferation?
Prostaglandin synthesis?
Finasteride 5a-reductase type II inhibition A [41–48]
Dutasteride Dual 5a-reductase inhibition D [49–51]
Latanoprost Prostaglandin analogue possible hair cycle regulator? D [52–55]
Ketoconazole Anti-fungal AO [56–58]
Inhibition of inflammation?
Anti-androgenic?
A, approved for use in treating MPB; D, under development, not approved; AO, approved for the treatment of other conditions.
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differing levels of expression of sex-steroid receptors and metabo-
lising enzymes between balding and occipital regions of scalp. In
relation to androgens, evidence emerged that both the 5a-reduc-
tase enzymes and the androgen receptor were more highly
expressed in balding follicles compared to non-balding follicles
on the same scalp [25,26]. Thus, the genes encoding 5a-reductase
type I (SRD5A1) and type II (SRD5A2)[23] and AR [27] were
examined. It was demonstrated that sequence variation in AR
differed significantly between young balding men (high genetic
predisposition) and older men with full heads of hair (low genetic
predisposition). This finding earmarked AR as a gene responsible
for increased risk of MPB [27], and has subsequently been con-
firmed in multiple independent studies [28–30]. Neither SRD5A1
or SRD5A2 were found to be associated with MPB [23]. However,
advances in methodology used to more accurately identify genetic
associations that include comprehensive consideration of
sequence variants throughout the gene coding and non-coding
regions in large sample sizes [31] provide impetus to return to these
genes to further assess their involvement.
It has been estimated that AR may confer up to 40% of total
genetic risk for MPB [29]. This is a high level of risk for a single gene
involved in a multifactorial trait [32]. Even so, this estimation
indicates that there are likely to be several as-yet unidentified
genes that contribute to the remaining 60% of genetic predisposi-
tion. These genes may be involved, for example, in the sex-steroid
pathways; they may be genes controlling hair follicle cycling, or
they may include genes not yet known to be involved in hair
growth and loss. Genome-wide association analyses, a hypothesis-
free approach to gene discovery that has recently harvested several
new genes for multifactorial diseases and traits such as diabetes
and obesity [33,34], may be the best approach to identifying the
remaining genes. It will not be until such genes are identified, and
the function of important variation within them is understood,
that we will achieve a proper understanding of the molecular
mechanisms underlying MPB [35]. Such an understanding is cru-
cial for targeted, effective development of pharmacological treat-
ment regimes.
Currently approved treatments
The progressive, pre-programmed nature of MPB means that
unless a therapeutic intervention occurs to halt the process, hair
loss will become continually more severe. Particularly in younger
menwherehairlossisprematureincomparisontothegeneral
population, the psycho-social consequences of this progressive
baldness can be significant. Research-based and anecdotal evi-
dence suggests significant decreases in self-esteem, and a higher
incidence of anxiety, depression, aggressiveness and hostility in
men with hair loss, often manifesting as social, personal and
work-related difficulties [2,3]. Thus there is high motivation by
sufferers to seek a cure for their hair condition that has led to an
entire industry devoted to the sale of treatment products where
the only proof of efficacy lies in manufacturer’s claims. These
include various herbal remedies [5]. However, there are govern-
ment-approved treatments that have been shown in scientifically
rigorous double-blind placebo-controlled trials to halt, and some-
times reverse the hair loss progress in a significant number of
sufferers. Interestingly, these treatments are not based on knowl-
edge of the underlying molecular aetiology of the hair loss pro-
cess, but rather hair regrowth was identified as a beneficial side
effect when these pharmaceutical agents were used to treat other
conditions.
Minoxidil
The vasodilator minoxidil was initially approved as a drug to
control hypertension [4]. Following observations that hyperten-
sive patients taking minoxidil showed increases in hair growth, a
2% topical solution, and later a 5% topical solution of minoxidil
was approved by the US Food and Drug Administration (FDA) for
use as a treatment for MPB. In approximately half of men using
minoxidil solution, the hair loss process is arrested by minoxidil.
Drug Discovery Today Volume 13, Numbers 17/18 September 2008 REVIEWS
FIGURE 2
Phases of the hair follicle cycle. Growth of the hair occurs during anagen. The hair is shed at the end of telogen, and the follicle returns to anagen. In follicles
undergoing the baldness process, anagen shortens and the follicle miniaturises. Reproduced from [14] with permission.
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In addition, a small percentage of men experience mild to mod-
erate degrees of hair regrowth [36].
Minoxidil appears to halt hair shedding; however, the biological
basis for this effect remains unknown. It was originally thought
that the vasodilatory properties of this compound that served to
increase blood supply to the scalp provided the mechanism
through which minoxidil may exert its effects [4], perhaps by
removing locally produced androgens from the follicles, but this
has since been shown to be improbable [37]. Other proposed
actions of minoxidil include stimulation of cell proliferation,
and of prostaglandin (PG) synthesis [38]. It is not immediately
clear how these properties might promote hair growth. It is
known, however, that minoxidil does not permanently inhibit
hair loss processes; cessation of minoxidil treatment is quickly
followed by rapid shedding of hairs returning the scalp to an
untreated state [39]. Despite these factors, minoxidil has become
a mainstay in clinical management of MPB.
A recent advancement in the use of minoxidil as a hair loss
treatment is the development of a 5% topical foam [40]. Efficient
delivery of topical pharmaceuticals to relevant structures in the
hair follicle in a cosmetically acceptable fashion is challenging.
The traditional topical solution consists of a liquid vehicle with a
tendency to spread beyond the intended site of treatment, and
that takes time to dry. It also contains a high concentration of
propylene glycol, a potential irritant. The newly developed topical
hydroalcoholic foam is propylene glycol-free, and has been shown
to be more easily applied specifically to target areas. Placebo-
controlled double-blind trials have demonstrated that the hydro-
alcoholic foam is efficacious, safe and well accepted cosmetically
by patients [40].
Finasteride
Finasteride is a synthetic azo-steroid that selectively inhibits
theactionsofthetypeII5a-reductase enzyme [41].TypeII
5a-reductase is the predominant isozyme in prostate, and a
5 mg daily oral dose is approved for the treatment of benign
prostatic hyperplasia (BPH) [42].Onthebasisoftheobserved
lack of balding in pseudohermaphrodites, who are naturally
deficient in type II 5a-reductase, it was predicted that finasteride
would also affect male pattern balding [43].Doserangingstu-
dies favoured a 1 mg daily dose [44]. The FDA-approved daily
oral dose of 1 mg for the treatment of MPB has been demon-
strated to reduce concentrations of DHT in scalp significantly,
where type II 5a-reductase is also the predominantly (but not
exclusively) expressed isozyme [45]. In many, but not all, men,
hair loss is halted by finasteride treatment and in some men,
thereisnoticeablehairregrowth within two years of treatment
uptake [46]. The 1 mg daily oral treatment is well tolerated by
patients, with rare side effects that may include some loss of
libido and erectile function [47]. As for minoxidil, cessation of
treatment recommences the balding process, indicating that the
effects of finasteride are not curative [48].
Thus, neither of the approved MPB treatments is based firmly
on an understanding of the molecular aetiology of the condition,
or the pharmacological mechanism of action. The individual
variability in efficacy, and the rapid return to the balding state
when treatments are ceased, are therefore not surprising. How-
ever, there are treatments under development that are more
firmly based on aetiological understanding that provide hope
for more well targeted and more highly efficacious pharmacolo-
gical options.
Treatments in development
Dutasteride
Dutasteride is a dual type I and type II 5a-reductase inhibitor that
is approximately 3 times as potent as finasteride at inhibiting type
II enzyme action, and 100 times as potent at inhibiting type I
enzyme action [49]. It is capable of decreasing serum DHT by up to
90%, about a 20% greater reduction compared to finasteride.
Dutasteride is approved at the 0.5 mg level as a treatment for
BPH. This dual inhibitor has recently been tested for improved
efficacy over finasteride in promoting hair growth [49]. Although
type II 5a-reductase is the predominant 5a-reductase enzyme
expressed in scalp, expression of the type I enzyme occurs in scalp
also. Type I 5a-reductase is the principally expressed isozyme in
scalp sebaceous glands [50], and many studies have also demon-
strated expression of this isozyme within the hair follicle itself [51].
Both enzymes metabolise T to DHT, and therefore it is probable
that type I 5a-reductase acts as a source of DHT in hair follicles. In a
treatment regime that aims to block DHT production, therefore, a
dual 5a-reductase inhibitor should be preferable to a selective
inhibitor. In a randomised placebo-controlled study, Olsen et al.
assessed target area hair counts in patients receiving placebo,
finasteride 5 mg and dutasteride 2.5 mg over 24 weeks of treat-
ment. Both 5a-reductase inhibitors increased hair counts over
placebo, and dutasteride 2.5 mg was shown to be more rapid
and superior to finasteride 5 mg in promoting hair growth [49].
Thus, the further development of a dual 5a-reductase inhibitor for
the treatment of MPB appears warranted.
Latanoprost
Latanoprost is a prostaglandin analogue that was originally intro-
duced as a treatment for glaucoma and ocular hypertension to
reduce intraocular pressure. Soon after, the stimulatory effects of
this compound on eyebrow and eyelash hair growth and pigmen-
tation in high numbers of patients were reported. Thus the poten-
tial for the use of latanoprost as a hair growth stimulant was swiftly
touted [52,53]. The expression of PG receptors was examined in
mouse skin hair follicles, and mRNA was identified in dermal
papilla and outer root sheath follicular structures during anagen.
However, this expression was found to be absent on follicles in the
telogen phase. Depilation, which forced the follicles back into
anagen, resulted in re-expression of the PG receptors. Other studies
have demonstrated the ability of PG to stimulate movement from
telogen to anagen in mice [54]. These results suggest that, in least
in rodents, PG may be important in regulating the hair follicle
cycle. Studies of the application of high doses of latanoprost to the
scalp of the stump-tailed macaque, an animal model of human
common baldness, demonstrated the ability of this PG analogue to
stimulate marked hair regrowth [55].
Taken together, the above studies provide strong evidence to
suggest that further investigation of the efficacy of PG as a hair
growth agent may have significant merit. As previously men-
tioned, one proposed action of minoxidil that may be relevant
to hair regrowth is stimulation of PG synthesis [38]. If this is
correct, it would seem sensible to consider the direct application
REVIEWS Drug Discovery Today Volume 13, Numbers 17/18 September 2008
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of a PG analogue such as latanoprost to the hair follicle, rather
than to indirectly stimulate PG synthesis via minoxidil [52].
Ketoconazole
The anti-fungal agent ketoconazole is used topically for the treat-
ment of seborrheic dermatitis and dandruff [56]. There is some
evidence, both in humans [57] and in rodents [56], that this agent
may stimulate hair growth. The mechanism is unknown, but may
involve inhibition of inflammation, or anti-androgenic properties
of the agent [58]. To date the evidence is based on small sample
sizes and does not include clinical trials. Thus, further research is
required to determine its efficacy.
Future treatment potential
The approved and developing treatments for MPB are largely based
upon accidental observations of hair regrowth side-effects of drugs
developed for other purposes. As our understanding of the mole-
cular genetic aetiology of MPB gains pace, it is reasonable to expect
that development of more targeted pharmaceuticals based on new
knowledge will similarly accelerate. In this section we examine
probable new directions for hair loss treatment based on current
and developing molecular genetic understanding.
Androgen receptor blockers
Knowledge of the important role of androgen, particularly
increased ARs, in genetically predisposed individuals leads to
the idea that blockage of response to androgen by hair follicles
through the use of AR blockers may halt or reverse hair loss. The
use of AR blockers has been investigated as a treatment of MPB for
some time. However, systemic anti-androgen treatments cannot
be used in men, owing to the potential risks of development of
gynaecomastia, feminisation and impotence [59]. The key to
exploiting this approach will lie in the development of AR blockers
that block AR selectively in scalp hair follicles and not elsewhere in
the body. Interestingly, there is no evidence of perturbation of sex-
steroid action in other tissues outside the scalp in carriers of the
MPB-relevant AR variant. This suggests that the effect of the
variant AR may be site-specific, possibly through alteration of a
scalp-specific AR transcription factor-binding site. It should be
noted that whilst the existence of a variant AR that predisposes
to MPB is well established, the exact functionally relevant varia-
tion(s) within this gene has not yet been identified [60]. Indeed,
there is little known regarding the regulation of expression of AR;
however, it is known that the gene is flanked by large non-coding
regions harbouring stretches of sequence that are highly conserved
across species [61]. These characteristics are hallmarks of the
presence of functionally important and often tissue-specific reg-
ulatory elements, sequence variation within which may hold the
key to altered scalp AR expression levels in variant AR carriers.
Identification of such elements may hold the key to MPB disease
pathogenesis, and provide opportunities for pharmacological
treatment development that is targeted to the molecular mechan-
isms underlying the hair loss process.
Identification of other predisposing genes, and use of such
findings for treatment development
As previously mentioned, other candidate genes have been inves-
tigated in relation to MPB risk, and have mostly focused upon
genes relevant to sex-steroid pathways. These include SRD5A1,
SRD5A2 [23] and the gene encoding aromatase (CYP19A1)[62].
Aromatase metabolises T to estrogens, and has been shown to be
expressed in reduced quantities in balding scalp [25]. Presumably
aromatase may serve to reduce the amount of T available for
conversion to DHT in the hair follicle. None of these genes were
shown to be associated with MPB. However, the more successful
contemporary gene-hunting strategies of today demonstrate that
these previous studies lacked both statistical power through small
sample sizes, and comprehensive evaluation of sequence variation
in each of these gene regions [31]. It is now clear that to identify
genes contributing moderate to low increases in risk of complex
multifactorial traits like MPB, genetic association studies must be
performed in hundreds, to thousands, of cases and controls to
achieve adequate statistical power. Additionally, sequence varia-
tion such as single nucleotide polymorphisms (SNPs) relevant to
multifactorial disease risk may be located in both protein coding
and non-coding regions of the genome. Such variation within a
gene locus must be considered comprehensively using panels of
tens to hundreds of SNPs [31]. This process is augmented by a more
thorough understanding of human genetic architecture that
demonstrates common co-inheritance of closely lying groups of
SNPs, termed haplotypes, across the genome at a population level.
The advantage of this is that only a single representative of such
co-inherited SNPs needs to be examined to identify genetic asso-
ciation of that haplotype with disease [63]. On the basis of these
new approaches, SNP panels to comprehensively evaluate the
involvement of sequence variation in and around SRD5A1,
SRD5A2 and CYP19A1 are currently being designed and validated
(Ellis, unpublished), with the future intention of thorough inves-
tigation of the role of these genes in MPB.
There are a myriad of other genes that could justifiably be
considered candidate genes for MPB both within and outside
the sex-steroid pathway, and therefore the identification of
MPB-relevant genes might best be achieved by a genome-wide
analysis of SNP sequence variation. Technological advances now
allow genotyping of up to one million SNPs throughout the
genome in a single experiment for less than $1000 per DNA
sample. Highly significant differences in SNP allele frequency
between case and control groups points to possible involvement
in disease. Interestingly, genome-wide association analyses of
other multifactorial conditions have both confirmed the involve-
ment of genes previously identified via candidate gene approaches,
and identified new and replicable association with sequence var-
iants both within and outside known gene loci [33]. Application of
this approach to large MPB case–control populations will probably
provide similar new knowledge of the underlying genetic archi-
tecture of common hair loss and open up considerable new
avenues for targeted pharmacological intervention in the hair loss
process. Such interventions might include application of follicle-
specific synthetic analogues of molecules suffering genetically
moderated reduced expression, or blockers of molecules whose
expression is upregulated. The key to efficacious treatment based
on molecular mechanisms will probably be the development of
vehicles that specifically and efficiently deliver drugs to follicles.
Another important future aspect to targeted drug therapy for any
multifactorial condition will be the consideration of the underlying
unique geneticmakeup of each patient. The complexity of common
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diseases suggests that in conditions that are determined by many
genes that confer a range of risk levels, the expression of the
condition will be dependent upon the individual mix of genes
inherited. Prior studies have suggested that AR may be necessary,
but not sufficient, to cause baldness, at least in prematurely balding
young men [27]. A combination of other risk genes will therefore
work with AR to determine overall risk of hair loss, and the number
of predisposing genes inherited might determine age of onset and
baldness severity [23]. The genetic combination is therefore likelyto
be different across different individuals. Therefore, truly targeted
pharmaceutical therapies will need to be matched to the underlying
genetic combination. This growing field of research has beentermed
pharmacogenomics [64], and provides great promise for future
personalised treatment strategies in multifactorial disease.
Conclusions
Despite the potential market for effective targeted treatments for
MPB, pharmacological approaches to the prevention of hair loss
and to hair regrowth are in their infancy. This is underpinned by a
paucity in understanding the underlying molecular mechanisms
that contribute to the pathogenesis of baldness. It is known that,
in the presence of sufficient androgen, hair loss is determined
almost entirely by genetic predisposition. However, gene-hunting
research, to date, has uncovered only one replicable genetic asso-
ciation, with AR. The utilisation of this finding in treatment
development is hampered by a lack of understanding of the
relevant sequence variation in this gene that leads to upregulation
of AR in balding follicles, and the fact that methods to very
specifically direct androgen-blockers to follicular target tissues
to avoid systemic effects are not yet available. The currently
approved MPB treatments, minoxidil and finasteride are variably
effective, and hair regrowth is achieved in only a small subset of
patients. Some developing treatment options including dutaste-
ride and latanoprost, hold increased promise, but are still not
based on a full understanding of disease aetiology. Increased
understanding of the underlying MPB genetic architecture, which
may be gleaned from comprehensive candidate gene and/or gen-
ome-wide association studies, will provide a pathway to the devel-
opment of more efficacious, personalised future pharmacological
treatment options.
References
1 Gan, D.C. and Sinclair, R.D. (2005) Prevalence of male and female pattern hair loss
in Maryborough. J. Investig. Dermatol. Symp. Proc. 10, 184–189
2 Hunt, N. and McHale, S. (2005) The psychological impact of alopecia. BMJ 331, 951–
953
3 Stough, D. et al. (2005) Psychological effect, pathophysiology, and management of
androgenetic alopecia in men. Mayo Clin. Proc. 80, 1316–1322
4 Haber, R.S. (2004) Pharmacologic management of pattern hair loss. Facial Plast. Surg.
Clin. North Am. 12, 181–189
5 Bandaranayake, I. and Mirmirani, P. (2004) Hair loss remedies – separating fact from
fiction. Cutis 73, 107–114
6 Hamilton, J.B. (1951) Patterned loss of hair in man; types and incidence. Ann N Y
Acad. Sci. 53, 708–728
7 Norwood, O.T. (1975) Male pattern baldness: classification and incidence. South
Med. J. 68, 1359–1365
8 Ludwig, E. (1977) Classification of the types of androgenetic alopecia (common
baldness) occurring in the female sex. Br. J. Dermatol. 97, 247–254
9 Dinh, Q.Q. and Sinclair, R. (2007) Female pattern hair loss: current treatment
concepts. Clin. Interv. Aging 2, 189–199
10 Shapiro, J. (2007) Clinical practice. Hair loss in women. N. Engl. J. Med. 357, 1620–
1630
11 Kligman, A.M. (1959) The human hair cycle. J. Invest. Dermatol. 33, 307–316
12 Krause, K. and Foitzik, K. (2006) Biology of the hair follicle: the basics. Semin. Cutan.
Med. Surg. 25, 2–10
13 Courtois, M. et al. (1994) Hair cycle and alopecia. Skin Pharmacol. 7, 84–89
14 Sinclair, R. (1998) Male pattern androgenetic alopecia. BMJ 317, 865–869
15 Sadick, N.S. and White, M.P. (2007) Basic hair transplantation: 2007. Dermatol. Ther.
20, 436–447
16 Hamilton, J. (1942) Male hormone stimulation is a prerequisite and an incitant in
common baldness. Am. J. Anat. 71, 451–480
17 Imperato-McGinley, J. et al. (1975) Steroid 5alpha-reductase deficiency in man. An
inherited form of male pseudohermaphroditism. Birth Defects Orig. Artic. Ser. 11, 91–
103
18 Jenkins, E.P. et al. (1992) Genetic and pharmacological evidence for more than one
human steroid 5 alpha-reductase. J. Clin. Invest. 89, 293–300
19 Janne, O.A. et al. (1993) Androgen receptor and mechanism of androgen action.
Ann. Med. 25, 83–89
20 Sinclair, R. et al. (2007) Men with Kennedy disease have a reduced risk of
androgenetic alopecia. Br. J. Dermatol. 157, 290–294
21 Osborn, D. (1916) Inheritance of baldness. J. Hered. 7, 347–355
22 Kuster, W. and Happle, R. (1984) The inheritance of common baldness: two B or not
two B? J. Am. Acad. Dermatol. 11, 921–926
23 Ellis, J.A. et al. (1998) Genetic analysis of male pattern baldness and the 5alpha-
reductase genes. J. Invest. Dermatol. 110, 849–853
24 Severi, G. et al. (2003) Androgenetic alopecia in men aged 40-69 years: prevalence
and risk factors. Br. J. Dermatol. 149, 1207–1213
25 Sawaya, M.E. and Price, V.H. (1997) Different levels of 5alpha-reductase type I and
II, aromatase, and androgen receptor in hair follicles of women and men with
androgenetic alopecia. J. Invest. Dermatol. 109, 296–300
26 Hibberts, N.A. et al. (1998) Balding hair follicle dermal papilla cells contain higher
levels of androgen receptors than those from non-balding scalp. J. Endocrinol. 156,
59–65
27 Ellis, J.A. et al. (2001) Polymorphism of the androgen receptor gene is associated
with male pattern baldness. J. Invest. Dermatol. 116, 452–455
28 Hayes, V.M. et al. (2005) The E211 G>A androgen receptor polymorphism is
associated with a decreased risk of metastatic prostate cancer and androgenetic
alopecia. Cancer Epidemiol. Biomark. Prev. 14, 993–996
29 Hillmer, A.M. et al. (2005) Genetic variation in the human androgen receptor gene is
the major determinant of common early-onset androgenetic alopecia. Am. J. Hum.
Genet. 77, 140–148
30 Levy-Nissenbaum, E. et al. (2005) Confirmation of the association between male
pattern baldness and the androgen receptor gene. Eur. J. Dermatol. 15, 339–340
31 Hattersley, A.T. and McCarthy, M.I. (2005) What makes a good genetic association
study? Lancet 366, 1315–1323
32 Hirschhorn, J.N. and Daly, M.J. (2005) Genome-wide association studies for
common diseases and complex traits. Nat. Rev. Genet. 6, 95–108
33 (2007) Wellcome Trust Case Control Consortium. Genome-wide association study
of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447,
661–678
34 Frayling, T.M. et al. (2007) A common variant in the FTO gene is associated with
body mass index and predisposes to childhood and adult obesity. Science 316, 889–
894
35 Altshuler, D. and Daly, M. (2007) Guilt beyond a reasonable doubt. Nat. Genet. 39,
813–815
36 Savin, R.C. (1987) Use of topical minoxidil in the treatment of male pattern
baldness. J. Am. Acad. Dermatol. 16, 696–704
37 Price, V.H. (1999) Treatment of hair loss. N. Engl. J. Med. 341, 964–973
38 Messenger, A.G. and Rundegren, J. (2004) Minoxidil: mechanisms of action on hair
growth. Br. J. Dermatol. 150, 186–194
39 Olsen, E.A. and Weiner, M.S. (1987) Topical minoxidil in male pattern baldness:
effects of discontinuation of treatment. J. Am. Acad. Dermatol. 17, 97–101
40 Olsen, E.A. et al. (2007) A multicenter, randomized, placebo-controlled, double-
blind clinical trial of a novel formulation of 5% minoxidil topical foam versus
placebo in the treatment of androgenetic alopecia in men. J. Am. Acad. Dermatol. 57,
767–774
41 Finn, D.A. et al. (2006) A new look at the 5alpha-reductase inhibitor finasteride. CNS
Drug Rev. 12, 53–76
REVIEWS Drug Discovery Today Volume 13, Numbers 17/18 September 2008
796 www.drugdiscoverytoday.com
Reviews POST SCREEN
42 Gormley, G.J. et al. (1992) The effect of finasteride in men with benign prostatic
hyperplasia. The Finasteride Study Group. N. Engl. J. Med. 327, 1185–1191
43 Imperato-McGinley, J. et al. (1974) Steroid 5alpha-reductase deficiency in man: an
inherited form of male pseudohermaphroditism. Science 186, 1213–1215
44 Roberts, J.L. et al. (1999) Clinical dose ranging studies with finasteride, a type 2
5alpha-reductase inhibitor, in men with male pattern hair loss. J. Am. Acad.
Dermatol. 41, 555–563
45 Drake, L. et al. (1999) The effects of finasteride on scalp skin and serum androgen
levels in men with androgenetic alopecia. J. Am. Acad. Dermatol. 41, 550–554
46 Kaufman, K.D. et al. (1998) Finasteride in the treatment of men with androgenetic
alopecia. Finasteride Male Pattern Hair Loss Study Group. J. Am. Acad. Dermatol. 39,
578–589
47 Whiting, D.A. et al. (2003) Efficacy and tolerability of finasteride 1 mg in men aged
41 to 60 years with male pattern hair loss. Eur. J. Dermatol. 13, 150–160
48 Sinclair, R.D. (2001) Management of male pattern hair loss. Cutis 68, 35–40
49 Olsen, E.A. et al. (2006) The importance of dual 5alpha-reductase inhibition in the
treatment of male pattern hair loss: results of a randomized placebo-controlled
study of dutasteride versus finasteride. J. Am. Acad. Dermatol. 55, 1014–1023
50 Thiboutot, D. et al. (1995) Activity of the type 1 5 alpha-reductase exhibits regional
differences in isolated sebaceous glands and whole skin. J. Invest. Dermatol. 105,
209–214
51 Bayne, E.K. et al. (1999) Immunohistochemical localization of types 1 and 2 5alpha-
reductase in human scalp. Br. J. Dermatol. 141, 481–491
52 Wolf, R. et al. (2003) Prostaglandin analogs for hair growth: great expectations.
Dermatol. Online J. 9, 7
53 Colombe, L. et al. (2007) Prostaglandin metabolism in human hair follicle. Exp.
Dermatol. 16, 762–769
54 Torii, E. et al. (2002) Expression of prostaglandin E(2) receptor subtypes in mouse
hair follicles. Biochem. Biophys. Res. Commun. 290, 696–700
55 Uno, H. et al. (2002) Effect of latanoprost on hair growth in the bald scalp of the
stump-tailed macacque: a pilot study. Acta Derm. Venereol. 82, 7–12
56 Jiang, J. et al. (2005) Topical application of ketoconazole stimulates hair growth in
C3H/HeN mice. J. Dermatol. 32, 243–247
57 Pierard-Franchimont, C. et al. (1998) Ketoconazole shampoo: effect of long-term use
in androgenic alopecia. Dermatology 196, 474–477
58 Hugo Perez, B.S. (2004) Ketocazole as an adjunct to finasteride in the treatment of
androgenetic alopecia in men. Med. Hypotheses 62, 112–115
59 Ellis, J.A. et al. (2002) Androgenetic alopecia: pathogenesis and potential for
therapy. Expert Rev. Mol. Med. 4, 1–11
60 Ellis, J.A. et al. (2007) Baldness and the androgen receptor: the AR polyglycine repeat
polymorphism does not confer susceptibility to androgenetic alopecia. Hum. Genet.
121, 451–457
61 Cobb, J. et al. (2008) Searching for functional genetic variants in non-coding DNA.
Clin. Exp. Pharmacol. Physiol. 35, 372–375
62 Ellis, J.A. and Harrap, S.B. (2001) The genetics of androgenetic alopecia. Clin.
Dermatol. 19, 149–154
63 Kruglyak, L. (2008) The road to genome-wide association studies. Nat. Rev. Genet. 9,
314–318
64 Evans, W.E. and Relling, M.V. (2004) Moving towards individualized medicine with
pharmacogenomics. Nature 429, 464–468
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