Female Pattern Hair Loss: a clinical and pathophysiological review.

INTRODUCTION
Etymologically, the word "alopecia" comes from the Greek άλώπηξ
(alōpēx) , which means "fox". It is an allusion to the constant hair
loss suffered by these animals during life. According to the Brazilian-Portuguese
Spelling Vocabulary (VOLP), alopecia should not be marked with an accent (paroxytone
stress) due to the influence of Latin (alopecia). The term is also
registered this way among the health science descriptors (DECS) for scientific indexing
in Brazil.1-3
The description of the classical clinical pattern of baldness in men is known since
antiquity. As an example, we may cite Hippocrates' (400 BC) observation that eunuchs did
not develop baldness. Later, Joseph Plenck, in his book "Doctrina de Morbis
Cutaneis" (Vienna, 1776) (Vienna, 1776) identified, in these cases, the
miniaturization of hair follicles, which he called "calvities". He also
distinguished the disease in two ways, according to its extension:
universalem e partialem; and in ten ways according
to its cause: febrisequa, puerperarum, morborum exantematicorum, acrimoniosa,
phtisicorum, a debilitate nervosa, fenum, hereditaria, a vapore mercurii and
a caufa externa.4
However, the diffuse balding process (affecting mainly women) still causes confusion in
its nomenclature nowadays.5
Initially, the term "diffuse alopecia in women" was widely used to characterize the
disease.6,7 After 1942, when Hamilton demonstrated of the involvement
of male hormones in the development of classic pattern baldness in men, the term
androgenetic alopecia was established to emphasize the hormonal and genetic factors
associated with the development of the disease.8,9 Because diffuse pattern
alopecia (which often affects women) was thought to be a variant of the same entity, the
term female androgenic alopecia or female pattern baldness, started to be
used.7
Although the follicular changes that lead to alopecia are similar between men and women,
clinical presentation and response to antiandrogen therapy are different. In addition,
the participation of androgens in the development of female pattern baldness has not yet
been fully elucidated. Given these differences in relation to male pattern baldness, the
term Female Pattern Hair Loss (FPHL) has been preferred over female androgenic
alopecia.5 In this paper, we
adopt the term FPHL to name baldness in women and male pattern alopecia (MPA) to name
baldness in men. Despite this division, women may eventually present baldness similar to
the male pattern and vice versa.
FPHL is characterized as a non-scarring diffuse alopecia, evolving from the progressive
miniaturization of hair follicles and subsequent reduction of the number of hairs,
especially in the central, frontal and parietal scalp regions (Figure 1).10
FPHL is the condition that most commonly leads to hair loss in adult females. Its
prevalence increases with age and the disease shows an inconsistent response to
treatment.11 These elements
compromise body image and strongly affect self-esteem, negatively impacting the
patients' quality of life.

EPIDEMIOLOGY
Hair loss and hair thinning complaints are common in dermatological practice. According
to a census conducted by the Brazilian Society of Dermatology in 2006 with 36,253 female
patients, non-scarring alopecia (unspecified) was one of the ten most common
diagnoses.14
The frequency of FPHL varies among population groups and increases with age. However, a
comparison between prevalence studies is hampered by the lack of universally accepted
criteria for the diagnostic definition of the disease.10
In general, FPHL has its onset during the reproductive years. More severe cases of the
disease are already noticeable at puberty. However, there is a greater demand for
treatment among patients aged 25-40 years. There is a second peak incidence at
menopause, between 50 and 60 years of age.10,15,16
Since the disease has a slow and progressive course, studies considering only clinical
criteria usually identify cases with marked reduction of hair volume and show modest
prevalence among young people. Nevertheless, if more sensitive diagnostic procedures,
such as dermoscopic identification of hair miniaturization, start to be used, the
prevalence of FPHL might become higher in all age groups.17
In 2001, a US study conducted with 1,008 Caucasoid women revealed a 3% prevalence in the
third decade of life. Prevalence showed a gradual increase with age, reaching 32% in the
ninth decade of life. Overall prevalence was 19%.18
In 2001, a study conducted in England with 377 patients showed a 6% prevalence among
women under 50 years of age. The highest prevalence was found among women over 70 years
of age: 38%.19
In 2005, an Australian study conducted with 717 women found a 13% prevalence in the
third decade of life, and a 54% prevalence in the eighth decade of life. Overall
prevalence was 32%.20
A study conducted with 4601 Korean women in 2001 found an overall prevalence of 5.6% and
progressively higher frequencies with increasing age.21
In 2010, a population study involving 8446 Chinese women found similar prevalence rates
to the ones found in the Korean study.22
A recent study conducted in Taiwan with 26,226 women showed lower overall prevalence of
FPHL in Caucasoids. However, FPHL prevalence in Caucasoid women was still higher than in
Korean or Chinese women.23 In addition
to prevalence, the study also sought to identify possible risk factors associated with
FPHL. The authors found a positive association between FPHL and body mass index >26
kg/m (OR = 1.1), fasting glucose> 110 mg% (OR = 1.1), puberty before 16 years of age
(OR = 1.2), lower (≤3 ) number of births (OR = 1.2), use of oral contraceptives for more
than one year (OR = 1.2) and sun exposure for more than 16 hours per week (OR: 1.2).
However, women who had breastfed (OR = 0.9), avoided sun exposure (OR = 0.8) or had
menstrual cycle shorter than 35 days (OR = 0.9) were less likely to develop the disease.
These data suggest that higher exposure to estrogen may positively correlate with FPHL,
which suggests a potential epigenetic control of FPHL.23
To date, there are no population studies on the prevalence of FPHL in African and
Brazilian women.
Table 1 summarizes the weighted results of
different studies on the prevalence of FPHL in Caucasoid and Asian women, according to
age. These studies show a higher frequency in Caucasoid women at all ages.18-23
Although most patients with FPHL do not display other signs of hyperandrogenism, FPHL is
associated with hyperandrogenic conditions, the most common being the polycystic ovary
syndrome (PCOS).24 In a study
conducted in England in 2003, 89 women with FPHL were evaluated and compared to a
control group. Among those patients with FPHL, 67% were diagnosed with PCOS, compared to
27% in the control group
Although FPHL more frequently manifests in adulthood, it may also occur in childhood and
adolescence. In 2004, Tosti and colleagues reported 20 cases of children aged between
6-10 years (12 of whom were girls) with diffuse-pattern androgenetic alopecia. None of
them had laboratory abnormalities, however, they all had strong family
history.26 A case series
involving 43 children (8 of whom were girls) aged between 12 and 18 years also described
a high level of family involvement. Only one subject experienced hormonal
changes.27
There is evidence that FPHL has a phenotype independently associated with insulin
resistance and atherosclerosis. The causal model for this finding has not yet been
established, but it may be related to a hyperandrogenic state induced by insulin
resistance, which also favors atherosclerosis.28-30
A case-control study conducted in Spain in 2011 evaluated 240 subjects (60 men and 60
women with hair loss and 120 controls without alopecia). The authors found an
association between early onset of baldness (<35 years of age), hyperglycemia,
diabetes and low levels of SHBG. SHBG also showed to be an independent predictor of
hyperglycemia in patients with alopecia, even after adjustment for waist circumference,
gender and testosterone level (OR = 3.35). There was no association between low levels
of SHBG and hyperglycemia in the controls.31
In order to investigate the relationship between baldness and metabolic syndrome, an
epidemiological study was conducted in Korea in 2012. 1701 women and 1707 men were
evaluated. Women with metabolic syndrome had higher prevalence of FPHL when compared
with women without FPHL (OR = 1.7). This relationship, however, was not observed in the
male population, which suggests that follicle miniaturization in FPHL and MPA arises
from different stimuli.32 On the other
hand, in patients without metabolic syndrome, no relationship was found between FPHL and
insulin resistance.33
An epidemiological study conducted in 2013 in Taiwan with 7,252 subjects of both sexes
showed that FPHL and MPA are independent risk factors for cardiovascular disease
mortality (HR = 2.3) and diabetes mellitus (HR = 3.0 ).34
Similarly, a study conducted in 2005 in Iran with 51 women with coronary artery disease
(CAD) and 55 controls who underwent coronary angiography found an association between
FPHL and CAD (RR = 1.26).35
Another case-control study conducted in Spain with 37 patients with FPHL and 37 controls
showed a higher prevalence of carotid atheromatous disease (OR = 4.2) and metabolic
syndrome (OR = 10.7) in cases than in controls.36

PATHOPHYSIOLOGY
The pathophysiology of FPHL is not yet completely understood. There is evidence that
genetic, hormonal and possibly environmental factors are involved.37
The biological cycle of the hair follicles is not synchronized among the adjacent units,
assuming a mosaic pattern in the scalp. It is didactically divided into three phases:
anagen (growth phase), catagen (regression) and telogen (resting phase). At the end of
the telogen phase, the original hair falls out (exogenous phase) and is replaced by a
new hair at early growth stage. Normally, the anagen phase lasts between 2 and 8 years;
the catagen phase last between 2 and 3 weeks, and the telogen phases lasts about 3
months.38
Thus, in a normal adult scalp, there are around 80-90% of hair in the anagen phase,
10-20% in the telogen phase and 1-2% in the catagen phase. This can be evidenced by
trichogram or anatomopathological examination.17
In FPHL there is a reduction in the duration of the anagen phase and a miniaturization
of the dermal papilla (thinning of the hair). Thick pigmented hairs are gradually
replaced by miniaturized hairs (Figure 2).
Moreover, there is a delay between the end of the telogen phase and the beginning of the
new anagen phase.39 This resting
phase, during which the hair follicle remains empty, is known as the kenogen
phase.40There is a gradual
decrease in capillary density in the affected areas. Although FPHL and MPA have clinical
presentations with different patterns, these changes also occur in MPA.
The hair follicle is a complex structure in constant activity. An imbalance between
various growth factors and cytokines which mantain the anagen phase and promote
apoptosis can determine the beginning of the catagen phase (Chart 1).41-48
The diffuse apoptosis of the follicular keratinocytes leads to the follicular regression
observed in the catagen phase. The premature termination of the anagen phase is a
landmark event in the development of FPHL.39
Apoptosis can be triggered in two ways: by the extrinsic pathway, through specific
binders to a membrane receptors group from the superfamily of necrosis factor receptors;
or by the intrinsic pathway, which may result from a loss in adhesion between
keratinocytes, a decrease in growth factors, among other flags.49
In the hair follicle, the apoptosis starts in the melanogenic area (late anagen),
propagates to the array (premature catagen) and then to the internal and external root
sheath.50,51
Apoptosis in the various sites of the hair follicle present different forms of
regulation. The direct role of cytokines and growth factors in the control of the
apoptosis of follicular keratinocytes in this process has not yet been fully
established.50,51
The diameter of the follicles is directly determined by the size of the dermal
papilla.52 Therefore, the
miniaturization process is due to the decrease in the volume of the papillae. As the
hair keeps the same thickness from the tip to the proximal portion, it is concluded that
no thinning occurs during the anagen phase. Thus, it is understood that miniaturization
occurs sometime between the catagen phase and the formation of the new hair.53,54 The factors that directly lead to a decrease in volume of the
papillae are not known and should become primary targets in the developing of FPHL
treatments and prevention strategies.
The miniaturized hair is very similar to vellus hair, but is not a true vellus hair.
Although the hair is thin, it has a developed piloerector muscle, unlike the vellus
hair, which has no or absent muscle.
A possible mechanism of follicle miniaturization is the decrease in the number of
papilla cells due to apoptosis.55
Although apoptosis can be induced in the papilla fibroblasts in experimental situations,
the papilla is the only component of the follicle which permanently expresses high
levels of the antiapoptotic protein bcl-2, which in theory confers resistance against
proapoptotic stimuli.50,51,55,56 The failure of
antiapoptotic mechanisms should be investigated as a key element in the pathophysiology
of FPHL.
Despite the importance of hormonal factors in the development of baldness, the action
mechanisms through which they lead to shortening of the anagen phase and the
miniaturization of the follicles have not yet been elucidated.

HORMONAL FACTORS
The dependence on androgens for the development of baldness in men was observed by
Hippocrates (400 BC) and established by Hamilton in 1942. It was observed that eunuchs
and men castrated before puberty did not develop baldness. However, the administration
of testosterone (T) induced alopecia in individuals with a family history of
baldness.8 These observations
together indicate that T, or one of its metabolites, were involved in the development of
MPA in individuals with genetic predisposition.
Androgens spread through the cytoplasmic membrane and connect themselves to specific
intracellular receptors. This complex hormone-receptor promotes the transcription of
genes that are primarily responsible for its tissue actions.57
The observation that men with a genetic deficiency of type-2 5α-reductase (5αR) did not
develop baldness suggested that dihydrotestosterone (DHT) was the main androgen involved
in the development of MPA.58
5αR is an enzyme that converts T in DHT metabolite. There are two types of 5αR: type 1
and type 2. Type-1 5αR is present in sebaceous glands, and type-2 5αR is present in the
genitourinary tract and in the hair follicles.59
The miniaturization of the hair follicle caused by androgens occurs primarily due to the
action of DHT, which has five times greater affinity for the androgen receptor (AR) than
testosterone.59 The androgen
linked to the AR leads to the transcription of the genes responsible for its biological
action on the target cells (Figure 3).
In addition, DHT may interfere with the follicular cycle by interacting with the Wnt
signaling pathway. The Wnt pathway induces dermal papilla cells to maintain the anagen
phase.45 The addition of DHT
mediated by Wnt3a suppressed the growth of keratinocytes in culture with cells derived
from the dermal papilla of the patient with baldness.60 The interplay of these pathways might be an important
target for the treatment of baldness. A recent phase I clinical trial showed
improvements in hair density and thickness in men with MPA through the infiltration of a
complex containing Wnt activity.61
Despite the fact that the evidence indicating that androgens participate in baldness has
emerged from studies in men, androgens were also assumed to play such role in female
baldness, due to the idea that, in spite of the clinical differences, male and female
baldness are the same entity.
Blocking of type-2 5αR proved effective in the treatment of MPA, confirming the
importance of DHT in the pathophysiology of the disease. However, finasteride and
dutasteride (even at higher doses) showed less consistent results in the treatment of
FPHL.62-68
Aromatase is an enzyme that converts androstenedione to estrone and testosterone to
estradiol, exerting an antiandrogenic action. In 1997, in a study by Sawaya involving 12
men and 12 women with baldness, the aromatase levels of the follicles of the frontal
region of women with FPHL were half as high as those of the occipital region. When
compared with the follicles of the frontal region of men showed, these levels were six
times greater.69 These data suggest
that aromatase may exert a protective action against baldness by converting androgens to
estrogens.

MICROINFLAMATION
In baldness, the miniaturization process may be accompanied by a mild to moderate
lymphohistiocytic inflammatory infiltrate in the peri-infundibular region. To term
microinflamation has been used in order to differentiate it from the inflammation that
occurs in scarring alopecia.70,71
The frequency of this process is variable. In 1993, Whiting evaluated the presence of
inflammatory infiltrate in 106 men with MPA and 22 controls (13 men and 9 women). Mild
inflammatory infiltrate was found in 30% of cases and controls. However, moderate
inflammatory infiltrate was found in 36% of cases compared to only 9.1% of
controls.72
The fact that the inflammatory process occurs in the upper part of the follicle suggests
that the causal factor may affect this region. External factors such as ultraviolet
radiation, environmental pollutants, inhabitants of the skin microbiota and follicle
(such as Propionibacterium sp.; Staphylococcus sp.;
Malassezia sp.), among others, could be involved in the induction of
the microinflamation process.70
The real meaning of this inflammatory process for development of FPHL, as well as its
possible relation to the miniaturization process and the hormonal elements involved in
FPHL have not yet been established.

GENETICS
Patients with FPHL often report family members affected by the disease (40-54%),
especially in cases with early clinical presentation (<40 years).21 A comparative study which assessed
baldness in male twins found a twice higher agreement level in monozygotic twins than in
dizygotic twins.73
Family segregation is not yet fully understood, however, the high prevalence of FPHL and
the fact that FPHL manifests with varying degrees of intensity and has its onset at
different ages, suggest a polygenic pattern with incomplete penetrance.74,75 In addition, family influence in the development of baldness may
vary between men and women and according to the form of presentation (classical or
diffuse).76
Despite the importance of DHT in the development of MPA, no correlation was found
between the SRD5A1 and SRD5A2 genes (responsible for the production of type 1 and type 2
5α-reductase enzymes) and the development of baldness.77
The strongest evidence of genetic involvement in the development of baldness comes from
studies involving the AR gene in men. A single nucleotide polymorphism in the first
exon, known as STUL was associated with baldness. Although this change is found in 98%
of men with premature baldness and in 92% of men with late baldness, it was also found
in 77% of men without baldness.78-80
These elements suggest that other changes are necessary for development of MPA, which
supports the hypothesis of a polygenic origin and epigenetic control of this entity,
such as hormonal changes, medications, and environmental stimuli.
The number of CAG repeats in the first exon of the AR gene varies among individuals. An
inverse relationship between the number of CAG repeats in its amino-terminal portion and
the activation of AR was observed. This implies that individuals with shorter
repetitions are at increased risk of baldness.75
However, as the AR gene is located on chromosome X, this does not justify the agreement
of phenotypes of fathers and sons. Thus, there is either a direct maternal transmission
or a polygenic inheritance (autosomal). Another hypothesis is that, in addition to this
gene, other environmental elements are involved in the development of baldness.
There is less evidence of the participation of the AR gene in the pathophysiology of
FPHL than in that of MPA. No relationship has been found between the presence of the
StuI restriction fragment and FPHL.81
However, just as in men, the number of CAG repeats in the first exon of the AR gene was
inversely correlated with FPHL.82,83 This observation allowed the development
of genetic testing, in which the detection of a small number of CAG repeats is
associated with an increased risk of development of FPHL, whereas a larger number of
repeats is associated with a lower risk (http://www.hairdx.com).
In women with FPHL (especially in younger women), nonfunctioning single nucleotide
polymorphism (rs4646) was identified in the gene that encodes aromatase
(CYP19A1).84
A meta-analysis of seven genome-wide association studies identified six susceptibility
loci associated with MPA: 1p36.22, 2q37.3, 7p21.1, 7q11.22, 17q21.31 and
18q21.1.85 However, a study
conducted by Redler in 2013, involving 405 women with baldness and 469 controls found no
association between these loci and FPHL.86
In a subsequent study, four new loci associated with MPA (2q35, 3q25.1, 5q33.3 and
12p12.1) were not associated with FPHL.87,88 These data together
suggest that MPA and FPHL have different etiopathogenic factors.
Besides genetics, external factors may also be important for the development of FPHL. A
US study conducted in 2012 with 98 female identical twins, raised several environmental
factors possibly related to FPHL. These included: testosterone levels, psychological
stress, hypertension, diabetes mellitus, smoking, multiple marriages, lack of
photoprotection, higher income and little physical activity.89 However, the actual role of these factors in the causal
model of FPHL still need be determined.

CLINICAL PRESENTATION AND CLASSIFICATION
Reduction in hair thickness and density leads to a reduction in the overall hair volume
(average hair thickness x number of hairs).19,78
This phenomenon can be noticed by the patient in various ways. By dividing the hair in
the middle, the dividing line becomes more evident (line sign); and when the hair is
tied together (ponytail), the ponytail holder becomes loose or it is necessary to pull
the hair more often through the used rubber band.17As the clinical picture evolves, the scalp becomes more visible
and may be fully visible in more advanced cases.
Clinically, FPHL can manifest in three ways:90
1.Diffuse thinning of the upper biparietal and vertex region preserving the anterior
hair implantation line. This pattern can be classified using two scales. That of
Ludwig,7 which divides it into
three degrees, from a mild light thinning in the first degree to the complete absence of
hairs in the affected area in the third degree (Figure
4). Although widely used, this scale has limitations because does not make it
possible to classify intermediate stages more precisely. Moreover, it is not a good tool
for therapeutic evaluation, as treatment - even follicular transplant - can hardly go
back a full stage in the classification. Sinclair's classification is similar, but the
disease is subdivided into four levels of intensity based on the normal scalp, which
makes it more adjustable to the reality of each patient (Figure 5).91
1. Thinning of the upper bitemporal region and vertex with frontal accentuation
(Christmas tree pattern). In this pattern which was described by Olsen in
1999,92,93 in addition to the diffuse thinning process, there is an
accentuation in the central line, opening up into a triangle with its base at the
anterior hair implantation line (Figure 6).
1. Thinning with bitemporal recess (Figure 7).
This is said to be the classical clinical presentation. It was proposed by Hamilton in
1951 and modified by Norwood in 1975.9,94 This system is mainly used for the
classification of male baldness, however, this pattern can also rarely occur in
women.
In 2011, a new classification known as BASP (basic and speficic) was developed by Lee.
Lee's aim was to develop a unified scale, which was easy to remember and apply and could
be used in various types of baldness presentation in both men and women.95-97
The basic forms are represented by the shape of the anterior hair implantation line (L,
M, C and U). Specific features relate to the hair density in different areas (frontal
and vertex). The final classification depends on the combination of basic and specific
forms (Figure 8).97
On physical examination, the pull test (Sabouraud's sign) may reveal an increase in the
release of telogen hairs. The amount of hairs that come off depends on the amount of
hairs pulled. Considering that 10 to 20% of hairs are in the telogen phase and many of
them are still firmly adhered to the epithelial bag, it is expected that up to 10% of
the hairs pulled may come off.17
When the test is positive in FPHL, it is restricted to the areas affected by the
disease. A diffusely positive test indicates telogen effluvium or diffuse alopecia
areata.96 The presence of
telogen hairs smaller than three centimeters represents the telogen phase of the
miniaturized follicles and are strongly suggestive of the diagnosis of FPHL.15 The test shows great inter-examiner
variability and lack of standardization. A recent hair wash with detachment of telogen
hairs can influence the test results.
Usually, FPHL is not accompanied by systemic symptoms or clinical findings extending
beyond the scalp.
Clinically, the initial forms of FPHL or diffuse thinning can make diagnosis difficult
due to other forms of non-scarring diffuse alopecia such as chronic telogen effluvium,
senile alopecia, diffuse alopecia areata, alopecia areata incognita, loose anagen hair
syndrome and syphilitic alopecia.98-109
The overlap between diagnoses occurs with some frequency, eventually revealing clinical
pictures of initial FPHL. The use of additional semiotic techniques such as trichogram,
dermoscopy, TrichoScan® and histopathological examination helps the diagnosis
of FPHL in such cases.

TRICHOGRAM
Trichogram is a technique in which a sample of hairs - generally containing between 50
and 100 hairs - removed from the scalp is analyzed with a light microscope.
This test allows to assess the number of hairs in each phase of the cycle (anagen,
catagen or telogen) and is especially indicated in case of suspicion of anagen effluvium
or loose anagen syndrome. It should only be performed by trained dermatologists who
frequently perform this test.16,90

DERMOSCOPY
Dermoscopy is noninvasive test. It is easy to perform and can contribute to the
diagnosis of FPHL, especially in the early stages of the disease.110-112
The main dermoscopic finding is the diversity of the thickness of the hairs with an
increased number of miniaturized hairs, especially in the frontoparietal region (Figure 9).110 In 2012, in a study involving 34 patients with FPHL, these
changes were found in all subjects.113 The single observation of more than 10% of fine hairs is strongly
suggestive of the diagnosis.114
A decrease in the number of hairs per follicular unit is another important element.
Typically, most hairs emerge from the follicular ostium in groups of 2 to 4. In PFA, the
hairs emerge alone or in groups of 2 (Figure
9).
The peripilar sign, a light brown area, slightly atrophic around the follicle, usually
occurs in the early stages of FPHL. This sign shows correlation with the inflammatory
infiltrate seen in the anatomopathological examination.115
Yellow dots may be seen in more advanced cases, probably as a result of sebum and
keratin buildup in dilated follicles.114 With increasing thinning of the hairs, there is greater penetration
of ultraviolet radiation into the scalp and alterations typical of photoaging, such as
the honeycomb pigmented network, may occur.
These signs, when evaluated together, allow the early diagnosis of FPHL, before the
occurrence of significant reduction in hair volume. In 2009, Rakowska standardized some
criteria for the diagnosis of FPHL based on dermoscopic findings (Chart 2).114

TRICHOSCAN®
TrichosScan® is a system that combines epiluminescence microscopy and
automated digital image analysis. It allows the estimation of the number and density of
hairs, of the percentage of terminal and vellus hairs, and by mathematical
approximation, of the percentage of hairs in the anagen and telogen phases.116,117
To perform the test, a small area of the scalp (aproximately 1 cm2) is shaved and evaluated after 48 to 72
hours The software performs an automatic analysis of the image captured by the camera.
The total number of hairs in the area, the hair density per cm2, and the percentage of terminal hairs (thickness greater
than 40 µm) and vellus hairs (thickness smaller than 40 µm) is determined.
Anagen hairs, unlike telogen hairs, undergo a continuous growth process. As the images
are analyzed 72 hours after shaving, the length of the hair allows to differentiate
between those hairs that grew and those that did not. Those hairs that grew are
classified as anagen and those who did not are classified as telogen.
TrichosScan® can be used as a diagnostic aid tool and for monitoring patients
in treatment. To ensure reproducibility in subsequent assessments, it is advisable to
tattoo the area to be assessed.

LABORATORY ALTERATIONS
FPHL is not associated with characteristic laboratory alterations. The investigation of
the causes of telogen effluvium can benefit the therapeutic response in patients with
concomitant conditions.
An association between possible changes in ferritin levels and FPHL is controversial.
Some studies have demonstrated lower ferritin levels in patients with FPHL when compared
to controls, and improved response to antiandrogen therapy in patients with ferritin
levels greater than 40 µg/l.118,119
However, a review conducted by Trost and colleagues in 2006 concluded that there is no
evidence for routine determination of ferritin levels in hair loss research, as well as
there is no evidence for iron supplementation in patients without anemia. The decision
to perform or not perform a laboratory research and supplementation should be taken
individually.120
Trost also states that, despite the lack of evidence, he does perform routine laboratory
tests and treats iron deficient patients irrespective of whether or not they have
anemia. He justifies his conduct by saying that he believes that patients show a better
therapeutic response when their serum ferritin levels are above 20 µg/ml.120
Most women with PFA do not have hyperandrogenism. The presence of other signs and
symptoms that are indicative of hyperandrogenism, such as changes in the menstrual
cycle, infertility, clitoral hypertrophy, changes in libido, hirsutism, acne, oily skin
and changes in voice timbre should be clinically evaluated and constitute a warning
sign.121
The European Consensus held in 2011 recommends free androgen index (FAI) and prolactin
dosage as screening tests. The FAI is the relationship between total testosterone and
sex hormone-binding glubulin (SHBG) [Total Testosterone (nmol/L)/SHBG (nmol/L) x 100].
Depending on the results and on the clinical context, a complementary endocrinologic
evaluation can be performed. FAI of 5 or greater is indicative of polycystic ovary
syndrome. The use of hormonal contraceptives causes alterations in SHBG levels.
Therefore, laboratory tests should only be carried out after a hormonal contraceptive
pause of at least 2 months.90
Likewise, TSH levels should be controlled, as thyroid dysfunctions may contribute to the
effluvium associated with FPHL.122
The importance of vitamin D, in addition to calcium metabolism, has been widely
discussed in recent years. A recent study involving 80 female patients with telogen
effluvium or FPHL and 40 controls showed lower levels of vitamin D in cases than in
controls.123 However, its role
in the hair cycle and in the development of alopecia has yet to be
established.124,125

ANATOMOPATHOLOGIC CHANGES
Most of the times, the diagnosis of FPHL can only be established based on clinical
elements. Very early cases, atypical presentations and possible coexistence with other
types of alopecia may require the performance of a histopathological examination for its
definition.
The traditional analysis of longitudinal sections allows visualization of the entire
follicle, which is essential for the assessment of alopecias associated with lichenoid
infiltrate, interface and subcutaneous alterations.71 However, longitudinal sections allow the assessment of only a
small number of sample follicles, making it impossible to perform a quantitative
analysis of the follicles, which is necessary for the diagnosis of FPHL.
The analysis of the follicles using transverse sections standardized by Whiting in 1993,
allows the benchmarking among all the follicles of the sample and is a standard method
for the histological evaluation of patients with suspicion of FPHL.72
Therefore, ideally a two-point biopsy (4mm punch) should be performed to allow both the
transverse and the horizontal sections.71
The main alteration found in the horizontal section is the increase in the proportion of
miniaturized hairs when compared to terminal hairs (Figure 10).
Conceptually, terminal hairs have a diameter greater than 0.03 mm and are thicker than
their inner root sheath. Vellus hairs and miniaturized hairs have a diameter smaller
than 0.03 mm and are thinner than the inner root sheath. The differentiation between
primary vellus hair and miniaturized hairs can be made by observing the outer root
sheath (which is more structured) and the piloerector muscle (which is more developed)
of miniaturized hairs.
There is a reduction in the anagen/telogen ratio and, in advanced cases, a reduction in
the follicular density. In addition, a discreet perifollicular lymphohistiocytic
inflammatory infiltrate and fibrosis, associated with a worse prognosis, may
occur.72,126
In vertical sections, a band which is characteristic of the residual connective tissue
can be seen in the depth of the dermis, under the miniaturized follicles.106

QUALITY OF LIFE
Although the hairs do not exhibit a vital biological function, they are of marked
importance for appearance, self-esteem and social identity function.13
The severity of alopecia, established by the dermatologist through classification
systems, does not predict the perception of the patient about the severity of his/her
case or its impact on his/her quality of life.12 Therefore, dermatologists should be aware of the emotional
components and use specific tools to assess the impact of FPHL patients' quality of
life.
For women, having healthy hair involves feelings of self-esteem, mutability and social
interaction. A study conducted in Brazil in 2012, the fear of losing all the hairs was
as great as the fear of developing a myocardial infarction.127
Despite the existence of several generic questionnaires to assess quality of life, they
do not always properly cover all areas of specific diseases. In 2000, Dolte and
colleagues developed and validated a specific questionnaire to assess quality of life in
patients with FPHL: the "Women's Androgenetic Alopecia Quality of Life Questionnaire"
(WAAQOL).128
Although the questionnaire has demonstrated excellent psychometric properties, the
WAA-QOL is still little used in clinical research, and has not yet been translated and
culturally adapted into Brazilian Portuguese. However, it is an important tool for
assessing both the individual impact of FPHL in patients' quality of life and treatment
response in clinical trials.

FINAL CONSIDERATIONS
Despite the high prevalence of FPHL, its management still imposes several difficulties
to dermatologists' clinical practice.
Its nomenclature and diagnostic definition still generate conflicts between authors of
different publications. Genetic elements are not completely known. The actual
participation of hormones is still unclear.5
Although the microscopic alterations between FPHL and MPA are identical, when
considering the diversity of clinical presentations and responses to treatment, we
cannot be sure that they are the same entity with different presentations between the
sexes.5
Although treatment is not considered part of the scope of this text, it should be noted
that the therapeutic response of FPHL is variable and less expressive than that of MPA.
Even with use of antiandrogens, combined oral contraceptives, topical minoxidil and low
power laser, there is no full recovery, and sometimes recovery is not even clinically
noticeable in patients.129,130 Follicular transplantation has certain
limitations with regard to the availability of donor areas in diffuse cases and the
augmentation of capillary volume in the transplanted area. Moreover, prolonged medical
treatment is still necessary.131-133
The identification of vulnerable patients associated with the diagnosis of early forms
of FPHL, as well as the early introduction of therapy may promote better clinical
results than those achieved in more advanced cases or even stop the progression of the
disease.
It should be noted that there is still low accuracy in FPHL detection though clinical
photographs. Patients' reports, dermoscopy and TrichoScan® should be used for
the objective and longitudinal evaluation of alopecia in therapeutic clinical trials
associated with FPHL. Improvement in semiotic techniques will allow a more accurate
diagnosis and better detection of outcomes in clinical trials.134
It is essential to advance in the knowledge of the pathophysiology of FPHL in order to
develop new and more effective therapies for the prevention and reversing of the disease
process. This includes detailed investigation of other potential elements (other than
genetic and hormonal elements) involved in its pathogenesis.37
More than describing in detail the minutiae of the hair cycle, the elucidation of the
epidemiology, genetics and pathophysiology of FPHL are a hope for improving the quality
of life of patients affected by this disease.