Hair: W hat i s N ew in D iagn o s is

and M anagement ?
Female Pattern Hair Loss Update: Diagnosis
and Treatment
Natasha Atanaskova Mesinkovska, MD, PhD,
Wilma F. Bergfeld, MD*

KEYWORDS
 Alopecia  Pattern hair loss  New  Update  Treatment  Androgenetic

KEY POINTS
 Female pattern hair loss (FPHL) is the most common cause of alopecia in women, and it is charac-
terized by follicular miniaturization.
 Androgens and estrogens are the main hormonal regulators implicated in FPHL.
 Realistic expectations need to be set when treating patients with FPHL.
 All treatments seem to work best when initiated early and when used in combinations.

DEFINITION A 4-mm cylindrical punch from the central area of

Female pattern hair loss (FPHL) is the most
common cause of alopecia in women. It affects
6% to 12% of women between the ages of 20 and
30 years, and more than 55% of women older
than 70 years.1 FPHL clinically presents with diffuse
nonscarring loss of hair, with prominent thinning
over the frontal, central, and parietal scalp. The
frontal hairline is characteristically retained. A
similar pattern of hair loss with follicular miniaturiza-
tion is seen in male androgenetic alopecia (AGA).
Because the role of androgens on alopecia in
women remains uncertain, FPHL has emerged as
the preferred term rather than AGA in women.2
DIAGNOSIS
The diagnosis of FPHL is made clinically based on
the appearance of the scalp. Biopsies are reserved
only for situations when the diagnosis is uncertain.
hair loss is preferred. It is recommended to avoid
biopsies from the temporal area, because minia-
turized hair follicles can be found there even in
the absence of FPHL.3 Preferably vertical and hori-
zontal tissue sections should be processed, and
reviewed by a dermatopathologist experienced in
interpreting alopecia biopsies.
FPHL is characterized histologically with increased
numbers of miniaturized, velluslike hair follicles. In
FPHL, the ratio of terminal to velluslike hairs is usually
less than 3:1.4 There is a reduction in follicle size,
depth, and hair shaft diameter, with an increased tel-
ogen/anagen ratio.5 Low levels of inflammation can
be found as lymphocytic microfolliculitis targeting
the hair bulge, with IgM and complement deposits
on the basement membrane.6
Although most patients with FPHL have normal
levels of testosterone, this type of alopecia can
be a marker of hyperandrogenism in women.7
Evaluation of patients with FPHL should include
derm.theclinics.com

Department of Dermatology, Dermatology and Plastic Surgery Institute, Cleveland Clinic, A61, 9500 Euclid
Avenue, Cleveland, OH 44195, USA
* Corresponding author.
E-mail address: bergfew@ccf.org

Dermatol Clin 31 (2013) 119127

http://dx.doi.org/10.1016/j.det.2012.08.005
0733-8635/13/$ see front matter 2013 Elsevier Inc. All rights reserved.
120 Atanaskova Mesinkovska & Bergfeld
clinical assessment for hirsutism, menstrual ab-
normalities, and acne. Hormonal studies should
include serum levels of androgens, to evaluate
for presence of polycystic ovary syndrome
(PCOS), androgen-producing tumors, or congen-
ital adrenal hyperplasia. A referral to an endocri-
nologist may be helpful in complicated cases.
Additional useful laboratory tests include thyroid,
iron studies with ferritin, prolactin, and zinc levels.
PATHOGENESIS
Androgens and estrogens are the main hormonal
regulators implicated in FPHL. The hair follicle is
sensitive to alterations in circulating estrogen and
androgen levels; these hormones are also syn-
thesized and metabolized locally.8 Most of the
evidence about the role of androgens comes from
studies of male AGA. Androgens have a clearly
established role via binding of dihydrotestosterone
(DHT) to hair follicle androgen receptors (AR) in
male pattern hair loss. In scalp hair follicles, testos-
terone is converted to DHT by the enzyme 5-a
reductase type II. DHT has a 5-fold higher affinity
for the AR and is believed to be the more important
player in AGA.9 The 5a reductase inhibitors, fi-
nasteride and dutasteride, can be used to block
DHT synthesis and arrest hair loss in men. Func-
tional polymorphisms of AR can be a marker for
premature AGA in men and can predict treatment
response to 5a reductase inhibitors.10
In contrast, the role of androgens in FPHL has not
been clearly established and it does not seem to be
as essential as in AGA. Pattern hair loss has been
described in cases with complete androgen insen-
sitivity syndromes, suggesting that mechanisms
other than androgens may be involved.11 Although
FPHL can be associated with hyperandrogenic
states, the circulating testosterone levels do not
differ between patients with FPHL and normal
controls.7 Many women with FPHL have low levels
of circulating sex hormone binding globulin (SHBG),
which may increase the available free testosterone
at the level of the hair follicle.11 Although it has
been postulated that there is an increased periph-
eral sensitivity to androgens in FPHL, the response
to treatment with 5a reductase inhibitors is unpre-
dictable. Also, AR polymorphisms have not been
uniformly confirmed and cannot completely explain
the mechanism of FPHL.12
The observed differences between androgen
regulation in FPHL and male AGA may lie in the
presence of estrogens. Estrogen signaling can
modify androgen metabolism at the hair follicle,
by unclear mechanisms. Estrogens may positively
affect hair loss through inhibition of 5a reduc-
tase.13 High systemic estrogen levels in pregnancy
are implicated in the prolongation of anagen. The
sudden loss of estrogen postpartum is believed
to lead to shedding, known as telogen gravida-
rum.14 Conversely, lower systemic estrogen levels
have been implicated in the increase of FPHL after
menopause.15 FPHL has been correlated with low
systemic estrogen levels when aromatase inhibi-
tors are used in cancer therapy. Topical estrogen
preparations are used to treat FPHL in some coun-
tries, but their efficacy is questionable.16
Outside the sex hormonal milieu, FPHL may be
influenced by insulin resistance, microvascular in-
sufficiency, and inflammatory abnormalities. In-
sulin resistance has been associated with low
circulating levels of SHBG and early onset of AGA
in male patients.17 Patients with FPHL show higher
prevalence of carotid atheromatosis, with higher
levels of inflammatory markers, such as C-reactive
protein, fibrinogen, and D-dimer.18 Increased sy-
stolic blood pressures are found in patients with
FPHL in comparison to control individuals.
Genetic Studies
Studies on the genetic base of FPHL show increased
frequency of alopecia in both male (54%) and female
(21%) first-degree relatives.19 Based on the experi-
ence from AGA, the speculated FPHL genetic link
may lie in variations of the AR gene.20 The AR gene
is a nuclear transcription factor located on the
X-chromosome. The amino-terminal domain of the
AR gene contains a region of CAG repeats, which
affects its transcriptional activity.20 The number of
CAG repeats inversely correlates with androgen
function. Particular CAG variants in the AR gene are
implicated with a risk of developing AGA in men.10
Variations in the CAG length have been associated
with PCOS, hirsutism, and acne in women.21 These
findings led to the development of a screening test
for FPHL and AGA, the Hair Genetic Test (http://
hairdx.com), which differs for men and women. In
women, the Hair Genetic Test measures the length
of CAG and GGC repeats within the AR gene. Shorter
CAG and GGC repeats are associated with a signifi-
cant risk of developing FPHL. Short repeat lengths
(15 or less) correlate with types of FPHL in 97.3%
of patients.22
TREATMENT
The goal of treatment of FPHL is to arrest hair loss
progression and stimulate hair regrowth. Realistic
expectations need to be set, because the efforts
to treat FPHL have mixed success and do not
accomplish complete regrowth. All treatments
seem to work best when initiated early. Combina-
tions of treatments tend to be more efficacious
than single products (Fig. 1). The treatments for

Fig. 1. (A) A 41-year-old patient with FPHL at initial visit. (B) Improvement with a combination therapy for minox-
idil, spironolactone, ketoconazole shampoo, and biotin/zinc supplement after 14 months.
FPHL can be divided into androgen-dependent
and androgen-independent (Table 1). There is an
important adjuvant role for nutritional supple-
ments, light therapy, and hair transplants.
Antiandrogen Therapies
The antiandrogenic agents used in FPHL can be di-
vided into 2 classes: the classic androgen receptor
Table 1
Treatments for FPHL
Product Mechanism of Action
Spironolactone Antiandrogen, reduces
testosterone levels, and
competitive AR blocker
Cyproterone acetate Antiandrogen,
competitive AR blocker,
decreases testosterone
levels by suppressing
luteinizing hormone
and follicle-stimulating
hormone
Flutamide Antiandrogen,
competitive AR blocker
Finasteride 5-a reductase inhibitor
Dutasteride 5-a reductase inhibitors
Minoxidil Unknown, possible
antiandrogenic,
vasodilatory, and
antiinflammatory
effects
Ketoconazole Decreases DHT levels at
the hair follicle
Female Pattern Hair Loss Update 121
antagonists, which prevent testosterone and DHT
from binding to their receptors, and the peripheral
antiandrogens, which alter androgen levels at the
hair follicle.
Androgen receptor antagonists
Spironolactone
Spironolactone and cyproterone acetate are the
most commonly used oral antiandrogens in the
Pregnancy
Treatment Recommendations Category
100200 mg by mouth D
daily in divided doses
2 mg cyproterone acetate X
by mouth daily generally prescribed
together with an oral contraceptive,
or cyproterone acetate 2550 mg/d
on days 110 of menstrual cycle
62.5 mg250 mg by mouth once daily D
0.25 mg by mouth once daily X
0.250.5 mg by mouth daily X
2%5% topical application once or C
twice daily to scalp
Shampoo scalp every other day as C
tolerated. Leave on for 5 min and
then rinse
122 Atanaskova Mesinkovska & Bergfeld
treatment of FPHL. The effects of these agents are
comparable, with 44% of patients with FPHL expe-
riencing regrowth.23 Spironolactone is a potas-
sium-sparing diuretic, a structural antagonist of
aldosterone. It acts as an antiandrogenic by
reducing the levels of total testosterone and com-
petitively blocking the androgen receptor in target
tissues. It is commonly used to treat hirsutism asso-
ciated with PCOS.24 It has been used to treat FPHL
off-label in doses of 50 to 200 mg daily, ideally for at
least 6 months.25 Commonly described transient
side effects are lethargy, nausea, and menorrhagia,
which tend to improve after 3 months of therapy.
Low-dose oral contraceptive pills (OCP) can be
added to help reduce the menorrhagia.24 Spirono-
lactone can be associated with hyperkalemia, which
warrants monitoring of potassium levels. Topical
spironolactone 2% solution exists and has been
used in combination with minoxidil with variable
success. Spironolactone is pregnancy category D.
Cyproterone acetate
Cyproterone acetate is an oral antiandrogen that can
directly block AR and decrease testosterone levels
by suppressing luteinizing hormone and follicle-
stimulating hormone release.25 Treatment with
cyproterone can improve hair growth in patients
with FPHL, alone or in combination with ethinyl
estradiol or spironolactone.26 Cyproterone has
shown efficacy in treating patients with FPHL with
both increased and normal androgen levels.27 It is
approved for use in Europe and Canada to treat
hirsutism, acne, and female alopecia. It can cause
feminization of the male fetus, and it is best used in
combination with an OCP. It is absolutely contraindi-
cated in patients with liver disease.25 This medica-
tion is not available in the United States.
Flutamide
Flutamide is a potent orally administered antian-
drogen that competitively blocks the binding of
androgen to its receptor.28 It is an effective treat-
ment of hirsutism and FPHL in hyperandrogenic
women.29 Flutamide can improve hair growth after
only 6 months of treatment, and offers long-term
stability in FPHL.28 Its use is limited because of
the risk of severe liver toxicity, which seems to be
dose-dependent. The doses that have been shown
efficacious in FPHL (62.5 mg/d) are low and well
tolerated.29
Fluridil
Fluridil is a novel topical antiandrogen. This
compound is highly hydrophobic, with high local effi-
cacy and tolerance, but systemically nonresorbable.
In men with AGA, application of fluridil for 3 months
resulted in increased anagen to telogen rates.30 In
FPHL, fluridil 2% solution prevented progression of
hair loss and increased hair diameter in an open clin-
ical study.31 Fluridil is being used throughout Eu-
rope, but is still awaiting approval from the Food
and Drug Administration (FDA) in the United States.
5-a reductase inhibitors
The treatment of male AGA has been revolutionized
by the advent of the 5-a reductase inhibitors. These
agents work by inhibiting the conversion of testos-
terone to DHT, and result in increased hair growth
and halt progression of hair loss. Their use in
women is limited because they are contraindicated
in women of childbearing age. Finasteride has not
shown the same efficacy in FPHL as seen in male
AGA. In postmenopausal women, a 1-year course
of finasteride 1 mg daily failed to improve hair loss
over placebo.32 In premenopausal women, finaster-
ide has shown benefit in treating FPHL associated
with hyperandrogenism.33 In normoandrogenic
women, it seems to be efficacious when used in
higher doses (5 mg) or in combination with drospir-
enone and ethinyl estradiol OCP.34,35 The specific
subset of women who respond well to finasteride
may have excessive activity of the 5-a reductase
enzyme. In men with AGA, greater efficacy of finas-
teride is correlated with shorter CAG repeats of the
AR gene, whereas the efficacy in patients with
FPHL cannot be predicted with certainty.36
Topical preparations of finasteride 0.05% have
a potential role in the treatment of male AGA and
FPHL.37 Finasteride is metabolized in the liver,
and it should be used with caution in patients
with liver abnormalities.32 It is a pregnancy cate-
gory X medication, associated with feminization
of a male fetus. Women of childbearing age should
use strict birth control, and should not handle
crushed or broken pills.
Dutasteride
Dutasteride is a 5-a reductase inhibitor with supe-
rior antiandrogenic effects to finasteride. It can
decrease serum DHT levels by more than 90%.38
In male patients with AGA, dutasteride can stop
the progression of hair loss and increase scalp
hair growth in a dose-dependent fashion. Dutas-
teride is not currently approved by the FDA for
the treatment of hair loss. The off- label use of du-
tasteride (0.250.5 mg/d) has led to resolution of
FPHL in postmenopausal women.39 This medica-
tion should not be administered to women of
reproductive age. Liver function needs to be moni-
tored in all patients.
Fulvestrant
The pure estrogen receptor antagonist, fulvestrant
(ICI 182,780), was developed as a treatment of
estrogen-sensitive breast cancer. In vitro studies
have shown that fulvestrant can increase hair

growth in mice, by stimulating telogen hair follicles
to re-enter anagen.40 Topical formulation of fulves-
trant was subsequently developed to be used as
a potential treatment of AGA. In human studies,
topical fulvestrant preparations have not been
shown to be superior over control vehicle in the
treatment of FPHL.41
Androgen-Independent
Minoxidil
Minoxidil is a hair growth stimulator that is the
current standard of treatment of hair loss in women.
It was originally produced as an oral hypertensive
agent, with a peculiar side effect of increased scalp
hair growth. This serendipitous discovery led to the
production of topical formulations, now available as
solution or foam, in 2% or 5% strength. Its mecha-
nisms of action remain unknown, and include
proposed enhanced vasodilatory, proliferative,
antiandrogenic, and antiinflammatory effects.26
The efficacy of minoxidil in pattern hair loss has
been proved in double-blind, placebo-controlled
trials.42,43 There is also evidence that minoxidil
prolongs the anagen stage of the hair cycle and
increases hair follicle size. Minoxidil has a significant
ability to maintain and thicken preexisting hair. In
addition, patients with FPHL treated with minoxidil
2% have 10% to 16% more regrowth compared
with controls, with higher concentrations (5%)
potentially more effective.44 Minoxidil has a well-
established safety profile. The most frequently
associated side effects are facial hypertrychosis,
contact dermatitis, pruritus, scale, and dryness.
Ketoconazole
Ketoconazole is an antifungal used in the treat-
ment of seborrheic dermatitis. The use of ketoco-
nazole shampoo, especially in combination with
finasteride, results in increased hair growth in
FPHL.45 The mechanism by which it can improve
hair growth is unclear. It has antiinflammatory
properties, and it reduces colonization of the skin
by Malassezia. Ketoconazole also affects steroido-
genesis locally and it decreases DHT levels at the
hair follicle.46 It should be part of the treatment
regimen in women with FPHL who have accompa-
nying inflammatory seborrheic dermatitis or se-
bopsoriasis. Hyperandrogenic women with FPHL
can benefit from the antiandrogenic mechanism
of ketoconazole.47
Adjunctive Therapies
Hair transplantation
Hair transplant surgery is emerging as an important
option for patients with FPHL who do not have
success with medical therapies. The hair transplant
Female Pattern Hair Loss Update 123
procedure is an outpatient procedure performed
under local anesthesia, in which classically har-
vested strips from the occipital area are divided
into individual hair follicles. The transplanted hair
follicles are then placed in recipient sites, where
hair grows over the next 3 to 6 months.48
A new trend in hair transplants is the adjuvant
use of platelet-rich plasma (PRP). The efficacy
of adjuvant plasma and platelet growth factors
has been well described in wound healing pro-
cesses.49 The growth factors and plasma compo-
nents such as fibrin, fibronectin, and vitronectin
can increase hair follicle growth. When used in
hair transplant procedures, the hair grafts may
be stored in PRP until placed on the scalp, or
PRP can be injected directly into the scalp before
placement of grafts.50
Hair transplantation requires preservation of
hair growth over the occipital donor area, which
is typically found in men with AGA. In FPHL, there
is more diffuse thinning of the scalp, including
thinning of the occipital area, which limits the
usefulness of hair.48 The newer techniques of har-
vesting follicular extraction units, especially the
robotic-assisted ones (Restoration Robotics, San
Jose, CA), may help increase the usefulness of
hair transplants in women.
Camouflage
In recent years, hair extensions and wigs have
become widely accepted among women as tools
for improving hair appearance. This trend has alle-
viated some of the stigma associated with their
use in FPHL. The medical side effects of hair-
pieces are limited to irritant dermatitis and traction
alopecia. Special attention should be used when
choosing attachment methods (eg, glue, pins) to
minimize damage to the scalp. The weight of the
attached hair needs to be minimized to prevent
traction damage.
Camouflage of frontal hair loss in FPHL with hair-
pieces may create a challenge. In this scenario, the
use of camouflaging topical sprays, powders, or
keratin fibers may be a better alternative to achieve
sufficient density.
Light therapy
A variety of laser and light sources have been
tried for treatment of hair loss, with varied
success. The idea to use laser light therapy stems
from experimental observations that low-powered
ruby laser can increase hair growth in mice.51 Par-
adoxic increase in hair growth has been observed
with the use of 810-nm pulsed laser and intense
pulsed light intended for hair removal.52 The
mechanism of low-level lasers on hair growth is
not yet known; it is hypothesized that the light
124 Atanaskova Mesinkovska & Bergfeld

enhances mitochondrial respiratory activity and
production of adenosine triphosphate.53
Several products using low-energy laser light
beams are available without a prescription for the
treatment of alopecia. They are designed as a hair-
brush or comb, which shines red light directly on
the scalp. The HairMax LaserComb (Lexington
International, LLC, Boca Raton, FL) is a handheld,
noninvasive device that was approved by the FDA
for treatment of male AGA.54 It is designed to be
used 3 times per week for 15-minute sessions,
with noted results in 8 to 16 weeks. In a double-
blind study, men treated with the laser comb had
a significantly greater increase in hair density and
better subjective assessments of hair growth,
compared with the control group at 26 weeks.
No individual experienced any serious adverse
events.54 The HairMax LaserComb received clear-
ance for use in women with FPHL in 2011.55
In addition to low-level lasers, high-energy lasers
are being explored for treatment of hair loss. The
fractional erbium-glass 1550-nm laser was used
successfully to treat FPHL.56 After 10 treatments
with this laser, hair density and fiber thickness
markedly increased (P<.001). Associated side
effects were immediate postprocedural erythema
and pruritus in some patients. Although the mech-
anism of laser treatment in improving hair growth
is not clear, the current evidence supports the
potential use of lasers for the treatment of alopecia.
Adjuvant therapies
Common topical and nutritional supplements are
listed in Table 2.
FUTURE DIRECTIONS
Innovative treatments for FPHL are in high
demand. The prostaglandin analogues, which are
successfully used to treat eyelash hypotrichosis,
may present a new option. There are high expec-
tations for the use of topical prostaglandin in
patients with alopecia. However, topical applica-
tions of prostaglandins have not proved effica-
cious. A trial of injected bimatoprost solution was
ineffective in a patient with FPHL.68 The efficacy
of different prostaglandin analogues and higher
concentrations need to be studied in FPHL.
Botulinum toxins have been introduced for
treatment of hair loss with some success. In an
open-label study, male patients with AGA received
150 units of botulinum toxin into the muscles
surrounding the scalp.69 The botulinum injections
reduced hair loss significantly, and in some men,
increased hair growth. Botulinum toxin may stop
hair loss by improving blood flow to the hair follicle.

Table 2
Adjuvant treatments of FPHL

Product Mechanism of Action Treatment Recommendations

Biotin Regulates mitochondrial
carboxylase enzymes in hair
roots57
Caffeine Inhibits phosphodiasterase,
stimulates cyclic adenosine
monophosphate, counteracts
testosterone effects on hair
follicles59
Cimetidine H2 blocker, a peripheral antiandrogen,
blocks binding of DHT to AR61
Ferritin Unclear, lack of ferritin causes hair
follicles to enter telogen62,63
Melatonin Antiandrogenic effects at the hair
follicle64
Zinc Unclear, deficiency nutritional or
iatrogenic causes alopecia66
Zinc pyrithium shampoo Zinc ions have antiinflammatory and
antioxidant effects,15 and inhibit
5-a reductase in vitro67
No clinical trials showing efficacy
treating hair loss58
Caffeine lotion and shampoo,
potential increase in hair tensile
strength and numbers60
300 g by mouth 5 times per day
(1500 mg/d)
Not FDA approved for hair loss
Maintain serum ferritin level
>40 ng/mL. Supplement women
with anemia and vegetarians
1 mg topical compounded in alcohol
and glycerin, no evidence that oral
supplementation helps65
Supplement 815 mg by mouth daily
(>18 years old)
1% pyrithione zinc shampoo daily
use results in significant (P<.05)
net increase in total visible hair
counts67

A more oxygenated environment at the hair follicle
is believed to favor conversion of testosterone to
estrogen, rather than to DHT. The mechanisms
are not understood, but botulinum toxin offers
a new treatment option for women with FPHL.
SUMMARY
FPHL is the most common cause of hair loss in
women, which carries a significant psychosocial
burden in affected patients. The currently available
treatments offer suboptimal results. Most of the
treatments have been developed based on the
understanding of AGA mechanisms in men. Clearly,
the pathogenesis of FPHL is more complicated, and
additional hormonal and growth factors regulators
need to be considered. Further studies of FPHL
may explain the currently observed variable res-
ponse to antiandrogen treatments. In the future,
FPHL will likely encompass different subtypes
based on underlying cause, which can be treated
with a better-targeted approach.
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