Diagnosis and Treatment - Female Alopecia: Guide to Successful Management 2013th Edition

Female Alopecia: Guide to Successful Management 2013th Edition

3. Diagnosis and Treatment

Ralph M. Trüeb¹

(1)

Center for Dermatology and Hair Diseases, Wallisellen, Switzerland

Abstract

Clinical trichology should represent an integral part of medical training, and the dermatologist participates with the other medical disciplines in the diagnosis and treatment of all types of hair problems relating to systemic disease. On the other hand, hair loss is an important cause of discomfort and disability. The general physician is not always aware of the significance of hair loss and therefore may fail to refer patients with hair disorders to the dermatologist for appropriate management. Too often, the delay of correct diagnosis, and as a result the delay of appropriate therapy, leads to potentially irreversible loss of hair, prolongs the discomfort, and promotes the disfigurement. Knowledge of the main types of hair loss is prerequisite to providing appropriate patient care.

Diagnosis is one of the commonest diseases

Karl Kraus (1874–1936)

3.1 Telogen Effluvium

Diffuse shedding of hair has originally been called defluvium capillorum. In 1932 Sabouraud restricted the term to sudden diffuse loss of hair following shortly after a severe emotional shock, while others applied it to all forms of alopecia. During the 1950s chronic diffuse alopecia in women was differentiated from acute and reversible diffuse alopecia, attributable to a readily identifiable cause. However, a majority of these patients were women with female androgenetic alopecia who did not display any endocrinologic abnormalities. The term was also used to describe women with diffuse hair loss of as yet unexplored etiology, such as thyroid dysfunction, or malnutrition.

3.1.1 Pathologic Dynamics of Hair Loss

In general, disease states that cause hair loss are categorized according to whether the hair loss is diffuse or localized and to whether the follicle remains intact or is destroyed and replaced by scar.

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Except for the scarring alopecias, hair loss represents a disorder of hair follicle cycling. Whatever the cause, the follicle tends to behave in a similar way. To grasp the meaning of this generalization requires understanding of the hair cycle and its derangements.

The hair follicle is subject to constant turnover in the course of perpetual cycles through phases of proliferation in anagen, involution in catagen, and resting in telogen, with regeneration in the successive hair cycle (Fig. 3.1).

Fig. 3.1

Hair cycle

It is a major characteristic of anagen that not only the hair shaft is growing but most epithelial hair follicle compartments undergo proliferation, with the hair matrix keratinocytes showing the highest proliferative activity. During catagen, hair follicles enter a process of involution that is characterized by a burst of programmed cell death (apoptosis) in the majority of follicular keratinocytes. The resulting shortening of the regressing epithelial strand is associated with an upward movement of the follicle. In telogen, the hair shaft matures into a club hair, which is held tightly in the bulbous base of the follicular epithelium, before it is eventually shed. It is still unresolved whether shedding of the telogen hair (teloptosis) is an active, regulated process or represents a passive event that occurs at the onset of subsequent anagen, as the new hair grows in.

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Cyclic hair growth activity occurs in a random mosaic pattern with each follicle possessing its own individual control mechanism over the evolution and triggering of the successive phases, though systemic factors as well as external factors linked to the environment have influence, such as:

· Hormones

· Cytokines and growth factors

· Toxins

· Deficiencies of nutrients, vitamins, and energy (calories)

Finally, there are considerable variations in length of these phases depending on the body site location, with the duration of anagen determining the type of hair produced, particularly its length. On the scalp, hairs remain in anagen for a 2- to 6-year period of time, whereas that of telogen is approximately 100 days, resulting in a ratio of anagen to telogen hairs of 9:1. On average, the amount of new scalp hair formation matches the amount that is shed, thereby maintaining a consistent covering. With a range of 75,000–150,000 hairs on the head, the reported average daily telogen hair shedding varies from 35 to 180 hairs. In general, the anagen phase is longer in women than in men.

Many factors can lead to pathologically increased hair loss. The pathologic dynamics of hair loss can be related to disorders of hair cycling.

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Telogen effluvium is by far the commonest cause of hair loss and results from increased shedding of hairs from the telogen phase of the hair cycle.

An increase in the percentage of follicles in telogen >20 % leads to increased shedding of normal club hairs. In Kligman’s original description, telogen effluvium is an acute and diffuse hair loss brought about by a variety of triggers. Clinical experience, however, suggests that chronic telogen effluvium also exists. It is defined as diffuse telogen hair loss that persists longer than 6 months.

On the basis of changes in different phases of the follicular cycle, Headington proposed further classification of telogen effluvium into five functional types depending on changes in different phases of the hair cycle (Table 3.1).

Table 3.1

Functional types of telogen effluvium

In immediate anagen release, follicles that would normally complete a longer cycle by remaining in anagen prematurely enter telogen. It is a very common form of telogen effluvium, typically occurring after periods of physiologic stress including episodes of high fever. In fever, the pyrogens, basically circulating cytokines, drive the hair follicle keratinocytes into apoptosis, initiating catagen with following telogen. Because the shedding is dependent on transition from anagen through catagen and telogen with subsequent release of telogen hairs, hair loss occurs 3–4 months after the inciting event.

In delayed anagen release, hair follicles remain in prolonged anagen rather than cycling into telogen. When finally released from anagen, the clinical sign of increased shedding of telogen hair will be found. This type of telogen effluvium underlies postpartum hair loss.

In immediate telogen release, hair follicles normally programmed for release of the club hair after an interval of usually 100 days after the end of anagen are prematurely stimulated to cycle into anagen. There is premature teloptosis. This type of telogen effluvium underlies the shedding of hair upon initiation of therapy with topical minoxidil (shedding phase).

In delayed telogen release, hair follicles remain in prolonged telogen rather than being shed and recycling into anagen. When finally teloptosis sets in, again the clinical sign of increased shedding of club hairs is observed. This process underlies molting in mammals and probably also seasonal shedding of hairs in humans or mild telogen effluvia following travel from low-daylight to high-daylight conditions.

Finally, a short anagen phase (without synchronization) results in a slight but persistent telogen effluvium in association with decreased hair length: This may occur in hereditary hypotrichosis, ectodermal dysplasia (trichodental syndrome), and as an isolated disorder in otherwise healthy children, as originally described by Barraud-Klenovsek and Trüeb. Far more frequent is acquired progressive shortening of anagen due to androgenetic alopecia.

From Headington (1993)

3.1.2 Acute Telogen Effluvium

Acute telogen effluvium presents as a diffuse, non-patterned hair loss from the scalp that occurs around 3 months after a triggering event and is usually self-limiting within 6 months by definition.

A host of different triggers has been implicated and identifies the clinical species of the genus, for example, postfebrile, postpartum, and psychogenic effluvium. Severe febrile illness, childbirth, accidental trauma, or surgical operations with a large hemorrhage, a crash diet, or severe emotional distress (psychogenic effluvium) are among the most common causes.

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Hair loss is usually less than 50 % of scalp hair. The diffuse hair loss from the scalp may produce thinning of hair all over the scalp but frequently manifests with symmetrical bitemporal thinning.

Reassuring patients that they are not going bald and that the telogen effluvium is temporary is usually sufficient. If the cause is not obvious from the patient’s history, iron studies, thyroid function tests, syphilis serology, and an antinuclear antibody titer should be performed. A drug history and, in women in particular, a change in the contraceptive pill or hormone replacement therapy should be inquired about, as these are common causes of telogen effluvium related to female androgenetic alopecia.

3.1.3 Psychogenic Effluvium

The literature on the subject of the cause relationship of emotional distress and hair loss has been more confounding than helpful. The presence of emotional stress is not indisputable proof of its having incited the patient’s hair loss. The relationship may also be the inverse.

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Nevertheless, case–control studies suggest that women who experience high stress are more likely to experience hair loss; moreover, the distress caused by the alopecia itself may eventually contribute to its perpetuation.

3.1.4 Chronic Telogen Effluvium

Diffuse shedding of telogen hairs that persists longer than 6 months either represents a primary disorder and is then a diagnosis of exclusion or is secondary to a variety of identifiable systemic disorders summarized in Table 3.2.

Table 3.2

Identifiable causes of chronic telogen effluvium

Iron deficiency, other dietary deficiencies (protein–calorie malnutrition, zinc deficiency) rare

Thyroid disease, other metabolic diseases (chronic renal or liver failure, advanced malignancy, pancreatic disease, and upper gastrointestinal disorder with malabsorption) rare

Systemic lupus erythematosus, other connective tissue disorders rare

Syphilis, HIV infection

Drug-induced telogen hair loss

Table 3.3

Primary cicatricial alopecias: proposed working classification of NAHRS (modified)

Lymphocytic group

(Classic) lichen planopilaris and variants:

Disseminated (Lassueur–Graham Little–Piccardi syndrome)

Patterned:

Frontal fibrosing alopecia (Kossard)

Fibrosing alopecia in a pattern distribution (Zinkernagel and Trüeb)

Chronic cutaneous lupus erythematosus

(Classic) pseudopelade of Brocq

Central centrifugal cicatricial alopecia?

Neutrophilic group

Folliculitis decalvans (Quinquaud) and variants:

Tufted hair folliculitis (Sanderson and Smith)

Cicatrizing seborrheic eczema (Laymon)

Dissecting cellulitis (Hoffmann)

Mixed group

Keratosis follicularis spinulosa decalvans (Siemens)/folliculitis spinulosa decalvans

Folliculitis (acne) keloidalis (nuchae)

Folliculitis (acne) necrotica (varioliformis/miliaris)

Erosive pustular dermatosis (of the scalp)

End-stage nonspecific group

Pseudopeladic state (Degos)

While chronic telogen effluvium may be triggered by an acute telogen effluvium, in primary chronic telogen effluvium, no specific trigger is evident. It predominantly affects women, while men with short hair tend not to notice increased hair shedding. The presentation of this type of diffuse hair loss tends to be distinctive and was first described in detail by Guy and Edmundson as diffuse cyclic hair loss in women and revived by Whiting in 1996, who additionally characterized the histopathologic features. The typical patient is a vigorous otherwise healthy woman between 30 and 60 with a full, thick head of hair. On examination there is some bitemporal thinning (see Fig. 2.11a) and a positive hair pull test equally over the vertex and occiput. There is no widening of the central part, as is common in androgenetic alopecia. Nevertheless, patients are adamant that they previously had more hair and are distressed by the prospect of going bald. Many frequently bring large balls of hair for inspection (see Fig. 2.11b) but despite this do not show any obvious balding. The condition tends to run a fluctuating course, possibly reflecting seasonal periodicity in the growth and shedding of hair with a maximal proportion of telogen hairs at the end of summer and the beginning of autumn.

It has been proposed that this disorder may be due to synchronization phenomena of the hair cycle, shortening of the anagen phase, or premature teloptosis. As often happens in skin diseases in women, guilt feelings about cosmetics come out. Shampoos and hair colorants are blamed. While absence of effects of shampoos on hair loss rates has been demonstrated, telogen effluvium after allergic contact dermatitis of the scalp has been reported. In the long run, the disorder appears to be self-limiting, and it is important to reassure patients that this condition represents exaggerated shedding rather than actual hair loss.

3.1.5 Treatment

Management and prognosis of diffuse hair loss depend on the cause and underlying pathomechanism in its relation to the hair growth cycle.

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Most acute telogen effluvia, particularly those due to acute-onset physiologic events, for example, postfebrile, postpartum, as well as the mild seasonal telogen effluvium, and shedding phase upon initiation of topical minoxidil treatment are self-limiting and will undergo normal reversal.

If not, another diagnosis or combination with female androgenetic alopecia is to be considered. Ikeda and Yamada originally pointed out that the risk of developing telogen effluvia increases in the presence of androgenetic alopecia.

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The cause of chronic telogen effluvium may be multifactorial and difficult to establish.

Systemic diseases known to cause telogen effluvium, such as iron deficiency, thyroid dysfunction, systemic lupus erythematosus, and syphilis, need to be systematically excluded or treated.

Drugs known to cause hair loss, such as anticoagulants (heparin, warfarin), oral retinoids (acitretin, isotretinoin), interferon, agents with antithyroid action (carbimazole, propylthiouracil, amiodarone), hypolipidemic agents (fibrates), colchicine, antimetabolites (methotrexate, azathioprine, cyclophosphamide), and hormones with pro-androgen action (norethisterone, levonorgestrel, tibolone) should be discontinued unless they are essential for the patient.

Finally, in young women dietary habits should be addressed. If anorexia nervosa/bulimia is suspected, the aid of a psychiatrist should be sought; in other cases the informed patient will be happy to abandon any dietary culprit.

Differential diagnosis may be complicated through considerable overlap, especially with female androgenetic alopecia, for instance, in postpartum effluvium that does not necessarily return to the same antepartum texture and length of hair. In these cases the addition of topical minoxidil to the treatment regimen is usually helpful. Ultimately, synchronization phenomena of hair cycling, also on a seasonal basis, seem to be more pronounced in patients with androgenetic alopecia, since with a shorter anagen phase, a greater proportion of hair follicles will synchronize.

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Recommendations for treatment of primary chronic telogen effluvium are scanty and include topical or systemic corticosteroids, topical minoxidil, and dietary supplements on the basis of millet extract, pantothenic acid, biotin, their combination, or combinations of L-cystine, medicinal yeast, and pantothenic acid (CYP complex).

The rationale for the use of L-cystine is based on the biochemistry of cystine metabolism, clinical observations in disorders of cystine metabolism, and cystine deficiency and results of animal and human studies.

In the 1960s, the role of L-cystine in the production of wool was investigated, and it was found that enrichment of even what appeared to be a normal diet with sulfur-containing amino acids increased wool production in sheep. When considering which dietary supplements could be used for improving hair growth in humans, L-cystine was therefore a candidate.

In the early 1990s studies on the effect of dietary supplements containing L-cystine, in combination with B-complex vitamins and medicinal yeast, a rich natural source of B-complex vitamins, have been published, showing improvements in the trichogram, in hair swelling as a criterion for hair quality, and in the tensile strength of the hair fiber.

We performed a double-blind, placebo-controlled study in 30 otherwise healthy women suffering from telogen effluvium who demonstrated that a dietary supplement with CYP complex increased the anagen hair rate within 6 months of treatment, while placebo did not (Fig. 3.2).

Fig 3.2

Double-blinded, placebo-controlled study in healthy women with hair loss using oral combination of cystine, yeast, and pantothenic acid (CYP complex): Active compound led to statistically significant improvement and normalization of mean anagen hair rates within 6 months of treatment (From Lengg et al. 2007)

The supplement did not have any effect on terminal hair counts, hair density, and cumulative hair shaft diameter and thus would not seem suitable for treatment of alopecia due to cycle shortening, such as androgenetic alopecia. Since synchronization phenomena tend to complicate the course of alopecias due to anagen shortening, adding a CYP-complex-based dietary supplement to the treatment with minoxidil may nevertheless be beneficial. It has been shown in whole hair follicle cultures that minoxidil not only increases the incorporation of thymidine as marker of cell division but also leads to an increased uptake of cysteine by the hair follicle.

Finally, the issue of psychogenic effluvium and of overvalued ideas in relation to the condition of the hair is not always easy to resolve; however, it is important to control stress as a complication of hair loss or fear of hair loss. For this purpose, strong psychological support is essential to help limit patient anxiety, and patients need to be educated about the basics of the hair cycle. Information about the hair cycle can be useful to explain how hair loss not related to cycle shortening (as in androgenetic alopecia) generally precedes new regrowth and why considerable patience is required for effective cosmetic recovery.

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Most importantly, women with chronic telogen effluvium need to be reassured that it represents exaggerated shedding rather than actual hair loss and that the shed hair is mostly being replaced; therefore, the risk of total baldness is remote.

3.2 Iron Deficiency

Iron deficiency represents the most common nutritional deficiency with the highest prevalence in adolescent girls and women of childbearing age. Nevertheless, the prevalence of iron deficiency is 6–9 % in women 50 years of age and older in the USA. While the most common causes of iron deficiency are menstrual blood loss, pregnancy, and lactation in premenopausal women, in postmenopausal women they are decreased absorption and gastrointestinal bleeding.

Total body iron is distributed among storage iron, transport iron, and functional iron. Storage iron is the body’s iron reserves that are tissue bound and measured by serum ferritin concentration, transport iron is transported to the tissues and measured by transferrin concentration and saturation, and functional iron consists of iron that is bound to hemoglobin, myoglobin, and diverse enzymes. It is measured by hemoglobin concentration.

Iron deficiency is viewed as a continuum ranging from iron depletion to iron deficiency anemia. In the former, body iron stores are reduced, but functional and transport iron remain normal, leaving little reserves if the body requires more iron; in the latter, storage, transport, and functional iron are severely decreased and can lead to impaired function of multiple organ sites.

Several studies have evaluated the relationship between iron deficiency and hair loss. Almost all of these studies have focused exclusively on women. Although non-anemic iron deficiency as an etiologic factor for diffuse hair loss in women was first postulated by Hard in 1961, it is not until recently that the significance of iron stores as assessed by serum ferritin levels in women with hair loss has been systematically studied.

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The various observational studies that evaluated the association between decreased ferritin levels and hair loss have resulted in opposing conclusions.

The controversy starts with a debate over what is the normal serum ferritin level for women and is further complicated by the use of different reference ranges by different laboratories, based on individual interpretations of the literature on this subject. A cutoff point of 10–15 μL⁻¹ is considered to yield a sensitivity of 59 % and a specificity of 99 % for diagnosing iron deficiency and is used by many laboratories as the lower limits of normal based on reference sample groups. In women of childbearing age, using a cutoff of 10–15 μL⁻¹ yields a sensitivity of 75 % and specificity of 98 %. A cutoff of 30 μL⁻¹ yields a sensitivity of 92 % and a specificity of 98 %.

To evaluate the relationship between serum ferritin levels and hair loss activity determined by trichograms, we performed a retrospective case study of 181 women with hair loss who underwent biochemical investigations and trichograms. 61.9 % had a ferritin level > 30 μL⁻¹, 30.4 % between 10 and 30 μL⁻¹, and 7.7 % ≤ 10 μL⁻¹, and no correlation was found between ferritin levels > 10 μL⁻¹and telogen rates. We only found a correlation between serum ferritin levels and patient age (Fig. 3.3a). We concluded that in women with hair loss, the role of tissue iron status within limits regarded as normal has probably been overestimated, since a majority of otherwise healthy women with hair loss had ferritin levels > 30 μL⁻¹ (cutoff with 92 % sensitivity and 98 % specificity for iron deficiency), and no correlation was found between hair loss activity and ferritin levels > 10 μL⁻¹ (Fig. 3.3b–d).

Fig. 3.3

(a) Shows correlation between patient age (years) and serum ferritin values (μg L⁻¹). (b–d) Correlation between telogen rates and ferritin levels in (b) all subjects (n = 181), (c) subjects with female androgenetic alopecia (n = 159), and (d) in total subjects with telogen effluvium, irrespective of combination with female androgenetic alopecia or not (n = 135). Diagram shows the ferritin values (μg L⁻¹) and corresponding telogen rates (%) of the frontal and occipital scalp of all patients in a linear scale. Vertical line A represents the lower reference limit of normal with 75 % sensitivity and 98 % specificity for diagnosing iron deficiency in women of childbearing age; vertical line B represents the cutoff point with sensitivity of 92 % and specificity of 98 % for diagnosing iron deficiency. Horizontal line X represents cutoff point for pathologic telogen rate (>15 %) (From Bregy and Trueb 2008)

Finally, a caveat should be spoken against uncritical iron supplementation, since there is a possibility that increased iron storage could enhance DNA oxidative injury by inducing the Fenton reaction.

3.3 Postpartum Hair Loss

On the basis of changes in different phases of the follicular cycle, Headington proposed classification of telogen effluvium into five functional types depending on changes in different phases of the hair cycle. Among these, he proposed a delayed anagen release type of telogen effluvium, in which hair follicles remain in prolonged anagen rather than cycling into telogen. When finally released from anagen, the clinical sign of increased shedding of telogen hair will be found. This type of telogen effluvium underlies postpartum hair loss.

During the second half of pregnancy, the percentage of anagen hairs increases from the normal 85 % to 95 %; at this time also the percentage of hairs of large shaft diameter is higher than in nonpregnant women of the same age. After partuition, the follicles, in which anagen has been prolonged, rapidly enter catagen and then telogen, with an increased shedding of hair evident after 3–4 months (postpartum effluvium). Most women will return to their usual hair growth cycle between 6 and 12 months after birth. Postpartum hair loss usually returns the hair to pre-pregnancy thickness, unless it leads over to female androgenetic alopecia.

3.3.1 Persistent Postpartum Effluvium

In case of persistent postpartum effluvium (> 12 months), excessive hair loss may be caused by common conditions, such as female androgenetic alopecia, iron deficiency, or hypothyroidism. Lesser common conditions include persistent hyperprolactinemia (Chiari–Frommel syndrome) and postpartum hypopituitarism (Sheehan syndrome) caused by pituitary necrosis due to blood loss and hypovolemic shock during childbirth.

3.3.2 Treatment

Prenatal vitamin supplement, with a special care to adequate supplementation of iron and folic acid.

3.4 Seasonal Hair Shedding

On the basis of changes in different phases of the follicular cycle, Headington proposed classification of telogen effluvium into five functional types depending on changes in different phases of the hair cycle. Among these, he proposed a delayed telogen-release type of telogen effluvium, in which hair follicles remain in prolonged telogen rather than being shed and recycling into anagen. When finally teloptosis sets in, again the clinical sign of increased shedding of club hairs is observed. This process underlies molting in mammals and probably also seasonal shedding of hairs in humans or mild telogen effluvia following travel from low-daylight to high-daylight conditions.

A number of women complain of recurrent hair loss. The condition tends to run a fluctuating course, presumably reflecting seasonal periodicity in the growth and shedding of hair. To test the hypothesis that periodicity in shedding of hairs in otherwise healthy women complaining of hair loss reflects seasonal changes in human hair growth, we performed a study of telogen rates as assessed by the trichogram technique in otherwise healthy women with or without clinically apparent alopecia complaining of hair loss in relation to the season.

Our study of 823 otherwise healthy women with telogen effluvium over a period of 6 years demonstrated the existence of overall annual periodicity in the growth and shedding of hair, manifested by a maximal proportion of telogen hairs in July. Taking a telogen phase duration of approximately 100 days into account, one would expect shedding of these hairs by autumn. A second peak seems to exist, although less pronounced, in April (Fig. 3.4a). The telogen rate was lowest towards the beginning of February. These fluctuations also reflected in subsequent clinical images taken of patients (Fig. 3.4b–d).

Fig. 3.4

(a) Fluctuations in frontal telogen rates (n = 823) in relation to the day of the year. (b–d) Seasonal hair shedding. Subsequent images taken in (b) January 2007, (c) August 2007, and (d) February 2008 (From Kunz et al. 2009)

These results confirm the findings of authors who have formerly demonstrated seasonal changes in human hair growth, though this is the first study performed systematically in women:

· Orentreich originally reported three women in New York who experienced maximum hair loss in November.

· By studying a group of 14 men during 18 months, Randall and Ebling showed that the proportions of telogen hair and of hair shedding were maximal in September. Courtois et al. observed ten men, with or without alopecia, for a period of between 8 and 14 years, and also demonstrated a maximal proportion of telogen hairs at the end of summer. Some subjects also exhibited a periodicity approximately corresponding to two annual peaks.

· Finally, our observation of a far larger number of patients led to statistically more significant calculations of these variations.

· The cyclical activities of the hair follicle are the mechanism by which mammals change their coat of hair to meet the exigencies of growth, seasonal changes in the ambient environment, and, perhaps, normal wear and tear. It seems likely that environmental factors, such as the photoperiod, mediate through the optic pathway and the neuroendocrine system coat phenotype and function to photoperiod-dependent environmental changes. The fact that human hair follicles, just as those of other mammals, undergo cyclical activity and are influenced by hormones implies that human hair is not unaffected by these phenomena. From an evolutionary point of view, the maintenance of the low winter level of hair shedding and the postponement of hair fall until the end of summer might, perhaps, be postulated as having a selective advantage with respect to isolation of the head against the cold in winter and protection of the scalp against the midday sun in summer, resp.

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Most importantly, the existence of seasonal fluctuations in hair growth and shedding complicates the assessment of pharmacological effects.

Awareness of these fluctuations is prerequisite to providing the correct cause and prognosis to the patient, ensuring patient compliance with therapy, but also has potentially serious implications for investigations with new hair growth-promoting agents: Depending on the stage of periodicity in growth and shedding of hair for a particular subject, the heterogenicity of included subjects may be enough to distort the clinical efficacy results and the perceived benefit of an investigational agent. In the active stage of seasonal telogen effluvium, the involved hair follicles would probably fail to respond to the therapeutic agent, which may cause a false-negative result. In the recovery stage, the increased amounts of spontaneously regrowing hair might be interpreted falsely as a positive result.

3.5 Female Androgenetic Alopecia

Androgenetic alopecia, also referred to as male-pattern hair loss or common baldness in men, and as female-pattern hair loss in women, affects at least 50 % of men by the age of 50 years and up to 70 % of all males in later life. Estimates of its prevalence in women have varied widely, though recent studies claim that 6 % of women aged under 50 years are affected, increasing to a proportion of 30–40 % of women aged 70 years and over.

The hair loss is heritable, androgen dependent, and occurs in a defined pattern. It is assumed that the genetically predisposed hair follicles are the target for androgen-stimulated hair follicle miniaturization, leading to gradual replacement of large, pigmented hairs (terminal hairs) by barely visible, depigmented hairs (vellus hairs) in affected areas. The result is a progressive decline in visible scalp hair density.

While male-pattern hair loss is characterized by its typical bitemporal recession of hair and balding vertex, female-pattern hair loss is set apart by its rather diffuse thinning of the crown and a usually intact frontal hairline.

3.5.1 Pathobiology of Androgenetic Alopecia

Androgenetic alopecia is characterized by progressive shortening of the duration of anagen with successive hair cycles, leading to decreased numbers of hair in anagen at any given time and progressive follicular miniaturization with conversion of terminal to vellus-like follicles. The result is increased shedding of short-lived telogen hairs (telogen effluvium), while the affected hair follicles produce shorter, finer hairs that cover the scalp poorly.

Since androgenetic alopecia involves a process of premature termination of anagen associated with premature entry into catagen, it is critically important to dissect the molecular controls of the anagen–catagen transformation of the hair cycle: Catagen has been suggested to occur as a consequence of decreased expression of anagen-maintaining factors, such as insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF), and increased expression of cytokines promoting apoptosis, such as transforming growth factor beta 1 (TGFβ 1), interleukin-1alpha (IL-1α), and tumor necrosis factor alpha (TNFα).

The controls that underlie the constant turnover of the hair follicle in the course of perpetual cycles through anagen, catagen, and telogen reside within the hair follicle itself and are believed to result from changes in the intra- and perifollicular expression of specific regulatory molecules and their receptors. Much circumstantial evidence suggests that the dermal papilla, which is composed of specialized fibroblasts located at the base of the follicle, determines hair follicle growth characteristics, especially the regulation of cell proliferation and differentiation of hair follicle matrix. There is substantial evidence from bioassays that cultured dermal papilla cells can secrete a number of cytokines, growth factors, and other, yet unidentified, bioactive molecules that influence growth in other dermal papilla cells, outer root sheath cells, keratinocytes, and endothelial cells. Ultimately, the hair cycle is subject to cycle modulation by numerous extrinsic influences, such as androgens.

Responses to androgens are obviously also intrinsic to the individual hair follicle: Not only does the response vary from stimulation to inhibition of hair growth depending on the body site but androgen sensitivity also varies within individual areas, that is, regression in androgenetic alopecia occurs in a patterned, progressive manner. Since many extrinsic hair growth-modulatory factors, such as androgens, apparently operate at least in part via the dermal papilla, research is currently also focused on identifying androgen-regulated factors deriving from dermal papilla cells.

Of the several factors that have been suggested to play a role in hair growth, insulin-like growth factor (IGF-1) has been reported as altered in vitro by androgens, and stem cell factor (SCF) has been found to be produced in higher amounts by androgen-dependent beard cells than in control non-balding scalp cells, presumably also in response to androgens. Since SCF is the ligand for the cell surface receptor c-kit on melanocytes, this may also play a role for hair pigmentation.

3.5.2 Androgens, Androgen Metabolism, and the Androgen Receptor

Of various hormones that affect hair growth, the most studied are the androgens, particularly as they pertain to androgenetic alopecia. Since Aristotle first noted that maleness and sexual maturity were required for balding, it was not until 1942 that Hamilton’s observations on men deprived of testicular androgens by castration established beyond doubt that androgens, in the form of testosterone or its metabolites, were prerequisites for development of common baldness: Hamilton observed that men who were castrated before puberty did not develop androgenetic alopecia and that androgenetic alopecia can be triggered in castrated men by injecting testosterone.

Androgen metabolism comprises glandular and extraglandular production, transport, target cell metabolism, and cellular response. While androgen biology in the adrenals and gonads and the influence of the pituitary axis go beyond the scope of this chapter, androgen metabolism within the skin, as it pertains to hair growth and its disorders, is the focus.

The androgen metabolism pathway begins with pregnenolone, a 21-carbon steroid substrate, converted from cholesterol. Following α-hydroxylation at the C-17 position, the action of the enzyme C17-20 lyase cleaves distal carbon moieties, leaving a C19 carbon steroid with a C-17 ketone in the distal ring. These 17-ketosteroids make up a group of weak androgens, such as dehydroepiandrosterone (DHEA), defined by a low affinity for the androgen receptor. These weak androgens, however, can be enzymatically converted to more potent androgens with greater affinity for the androgen receptor, such as testosterone. Testosterone is the major circulating androgen. In women, systemic levels of testosterone are low compared with men, but the more abundant weak androgens serve as a source of precursors for potent androgens, which provide the physiologic or pathophysiologic androgen activity. Only a small fraction of androgens exists as free steroids in the circulation, with an equilibrium between free hormones and protein-bound androgens. The most important protein for androgen binding is sex-hormone binding globulin (SHBG). Normally 70 % of testosterone is bound to SHBG and 19 % to albumin. The remainder is circulating unbound. In most target organs testosterone can be metabolized to DHT by the enzyme steroid 5α-reductase. Based on its affinity for the androgen receptor, DHT is fivefold more potent than testosterone. DHT is implicated in the pathogenesis of several disorders, including benign prostatic hyperplasia, prostate cancer, hirsutism, acne vulgaris, and androgenetic alopecia.

The skin and pilosebaceous unit are enzymatically equipped for local metabolism and conversion of sex steroids: The skin is capable of synthesizing active androgens from the systemic precursor DHEA-sulfate (DHEA-S). The first step is the desulfatation of DHEA-S by the enzyme steroid sulfate (STS). The principal pathways involved in conversion of weak androgens like DHEA to more potent androgens are through activity of the enzymes 3β-hydroxysteroid dehydrogenase-Δ5->4-isomerase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD), and 5α-reductase. Once formed, potent androgens, such as testosterone and DHT, can be removed by conversion back to the weaker 17 ketosteroids, or are metabolized via other enzymatic pathways, including aromatase, which convert androgens to estrogens, and 3α-hydroxysteroid dehydrogenase to form androsterone and androstanediol. The latter can be glucuronidated to form androgen conjugates that are more rapidly cleared from the circulation. Remarkably, some target tissues, such as the hair follicle, show enhanced androgen metabolism and androgen sensitivity. The activity of enzymes involved in androgen metabolism within the skin has been studied in a variety of tissue preparations: The sebaceous glands in balding skin have been shown to express increased 3β-HSD activity when compared to non-balding scalp areas. Very early it was shown that plucked human hair follicles or hair follicles from balding stump-tailed macaques express considerable 17β-HSD activity. In a study of plucked hair follicles from young adults not yet expressing androgenetic alopecia but with a strong family history of baldness, two populations were found, one with high 17β-HSD activity and one with low enzyme activity. The study suggested that low enzyme activity may be related to lesser degrees of balding. Eventually, both men and women with androgenetic alopecia were shown to have higher levels of 5α-reductase enzyme activity in frontal follicles than in their own occipital follicles, whereas higher levels of aromatase were found in their occipital follicles.

Since STS converts DHEA-S to DHEA that is eventually metabolized to more potent androgens in the periphery and elevated plasma levels of DHEA-S and DHEA have been reported to correlate with balding in young men, the hypothesis was advanced that men with genetic STS deficiency (X-linked recessive ichthyosis, XRI) do not or only develop minor forms of androgenetic alopecia. In a survey of patients with XRI, we showed that this was not the case, since these men also showed advanced androgenetic alopecia. In genetically determined deficiencies of the enzymes 3β-HSD, or 17β-HSD, respectively, the presence or absence of androgenetic alopecia has not been investigated so far.

The description of an unusual form of incomplete male pseudohermaphroditism, due to a genetic deficiency of the type 2 steroid 5α-reductase by Imperato-McGinley et al. in 1974, implicated DHT as principal mediator of androgen-dependent hair loss: Affected men, who are homozygous for mutation of the gene, do not develop androgenetic alopecia.

Mutations of the human gene encoding aromatase (CYP19) are rare and result in aromatase deficiency. Affected girls show pseudohermaphroditism at birth and at puberty develop virilization and hirsutism due to an androgen excess, pubertal failure with no signs of estrogen action, hypergonadotropic hypogonadism, polycystic ovaries, and a tall stature. Males are rather tall with eunuchoid skeletal proportions. In theory, females and males might develop early onset of androgenetic alopecia. Consistent with the role of aromatase in avoiding androgen-mediated effects on androgen-dependent hair follicles is the observation that women taking aromatase inhibitors for the treatment of breast cancer often experience an androgenetic alopecia-like hair loss.

Finally, the absence of balding in individuals with the androgen-insensitivity syndrome who lack functional AR clearly demonstrates the need for AR for androgenetic alopecia to occur. All steroid hormones act by diffusing through the plasma membrane into the target cell and binding to specific intracellular receptors. The hormone-receptor complex undergoes conformational changes, exposing DNA-binding sites, and then binds to specific hormone response elements in the DNA, promoting the expression of specific hormone-regulated genes. The AR is believed to be responsible for determining the sensitivity of cells to androgens. Besides androgen insensitivity, various mutations have been described in the gene encoding the AR in a variety of diseases, including spinal and bulbar muscular atrophy (Kennedy’s disease) and prostate cancer. Some of these are associated with functional changes in AR expression. Expression of the AR has also been found to be increased in balding scalp. More recently, polymorphism of the AR gene has been found to be associated with male-pattern baldness.

3.5.3 Estrogens, Estrogen Metabolism, and the Estrogen Receptor

Although androgens have dominated endocrinologic research in hair growth control, and androgen metabolism and the androgen receptor have been the key targets for systemic, pharmacological treatment of androgenetic alopecia in dermatological practice, it has long been known that estrogens influence hair follicle growth and cycling by binding to locally expressed high-affinity estrogen receptors (ERs). The discovery of a second intracellular estrogen receptor (ERbeta) with different cell-specific roles to the classic estrogen receptor (ERalpha), and the identification of cell surface estrogen receptors in the hair follicle, has provided further challenges to understanding the mechanism of estrogen action on hair growth. Besides altering the transcription of genes with estrogen-responsive elements, 17beta-estradiol (E2) also modifies androgen metabolism within the pilosebaceous unit, which itself displays prominent aromatase activity, the key enzyme for androgen conversion to E2. Therefore, the hair follicle is both a target and source for estrogen.

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Clinical evidence for the role of estrogens for hair growth is observations of the effects of pregnancy, hormonal treatments that affect estrogen metabolism, and menopause on the condition of the hair.

The observation that many women show increased shedding of hair from 2 weeks to 3–4 months after they stop taking an oral contraceptive probably simulates that which is commonly seen after parturition. More frequently, contraceptive pills or hormone replacement therapies with progestogens that possess net androgenic activity (norethisterone, levonorgestrel, tibolone) induce hair loss in genetically predisposed women. It has been proposed that in the presence of a genetic susceptibility, it is the estrogen-to-androgen ratio that might be responsible for triggering hair loss in women. In the same line is the observation of hair loss induced in the susceptible women by treatment with aromatase inhibitors for breast cancer.

3.5.4 Genetic Involvement

The genetic involvement is pronounced, and the importance of genes concurs with marked racial differences in prevalence of androgenetic alopecia; non-Caucasians often exhibit significantly less balding. While major progress has been done in the understanding of androgen metabolism, the genetic predisposition to androgenetic alopecia remains poorly understood. A very high frequency of androgenetic alopecia has complicated attempts to establish a mode of inheritance. Moreover, it is not clear whether androgenetic alopecia is genetically homogeneous.

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Some authorities suggest that female-pattern hair loss is not the female counterpart of male androgenetic alopecia and not androgen dependent.

The genes for type 1 and type 2 5α-reductase have been shown not to be associated with the inheritance of androgenetic alopecia. Polymorphism of the AR gene is associated with male-pattern baldness; however, the AR gene is located on the X chromosome and does not explain the relatively strong concordance of the degree of baldness in fathers and sons. No specific gene has been identified so far, though single gene mutations, such as abnormality of the AR, might be necessary, but not sufficient for the phenotype. We probably deal with a polygenic inheritance, dependent on a combination of mutations, for example, in or around the AR gene affecting the expression of the AR, and other genes controlling androgen levels. Interactions between such genes might account for the tissue-specific and developmental stage-specific expression of the AR that is necessary to explain the characteristic anatomic and temporal patterns of androgenetic alopecia. Other genes relevant to androgens, including those on the Y chromosome, might also be examined.

3.5.5 Role of Oxidative Stress

Recent studies on the evolution of androgenetic hair loss have focused on oxidative stress:

· Naito et al. analyzed the effect of the lipid peroxides on hair follicles and observed that the topical application of linolein hydroperoxides, one of the lipid peroxides, lead to the early onset of the catagen phase in murine hair cycles. Furthermore, they found that lipid peroxides induced apoptosis of hair follicle cells. They also induced apoptosis in human epidermal keratinocytes by upregulating apoptosis-related genes. These results indicate that lipid peroxides, which can cause free radicals, induce the apoptosis of hair follicle cells, and this is followed by early onset of the catagen phase.

· Bahta et al. cultured dermal hair papilla cells (DPC) from balding and non-balding scalp and demonstrated that balding DPCs grow slower in vitro than non-balding DPCs. Loss of proliferative capacity of balding DPCs was associated with changes in cell morphology, expression of senescence-associated beta-galactosidase, decreased expression of proliferating cell nuclear antigen and Bmi-1, upregulation of p16(INK4a)/pRb, and nuclear expression of markers of oxidative stress and DNA damage including heat shock protein-27, superoxide dismutase catalase, ataxia-telangiectasia-mutated kinase (ATM), and ATM- and Rad3-related protein. The finding of premature senescence of balding DPC in vitro in association with expression of p16(INK4a)/pRB suggests that balding DPCs are particularly sensitive to environmental stress.

3.5.6 Clinical Presentations

From the clinical point of view, male-pattern hair loss with its characteristic bitemporal recession of hair and balding vertex has been set apart from female-pattern hair loss with a rather diffuse thinning of the crown and intact frontal hairline, as originally characterized by Ludwig. While affected men predominantly present with the male pattern, the female pattern is more characteristic for women. Nevertheless, considerable overlap exists, the reason for which alternative classification schemes to the Hamilton–Norwood scale for male-pattern alopecia and the Ludwig scale for female-pattern alopecia have been proposed. Moreover, Venning and Dawber have found that 13 % of premenopausal women and 37 % of postmenopausal women, resp., present with the male pattern of androgenetic alopecia.

Again, there are further clinical subtypes of female-pattern hair loss depending on the scalp area involved.

Besides the classical Ludwig type with diffuse thinning of the centroparietal scalp and intact frontal hair line (Fig. 3.5a), there is the Olsen type with frontal thinning in the form of a Christmas tree with its base at the frontal hairline (Christmas tree pattern) (Fig. 3.5b), a more diffuse thinning of the hair, first described by Sulzberger and further characterized by Rushton as diffuse androgen-dependent alopecia in women (Sulzberger or Rushton type) (Fig. 3.5c), and a type localized to the vertex, or widow’s cap alopecia (Fig. 3.5d), with tendency to affect the older age group.

Fig. 3.5

(a–e) Androgenetic alopecia: (a) Female androgenetic alopecia, classical Ludwig pattern. (b) Female androgenetic alopecia, Olsen’s Christmas tree pattern (frontal). (c) Female androgenetic alopecia, diffuse type. (d) Female androgenetic alopecia of the widow’s cap type (vertex alopecia). (e, f) Premature alopecia in a 10-year-old girl, (e) frontal type, (f) with significant anisotrichosis on dermoscopic examination. (g, h) Monitoring treatment effect: decrease of diversity of hair shaft diameters. (g) Before and (h) after 6 months therapy with topical minoxidil

Androgenetic alopecia that is clinically manifest between the ages of 10 and 20 is called premature alopecia or alopecia praecox. In children before puberty it presents in both females and males exclusively with the female pattern (Fig. 3.5e, f).

Diversity of hair shaft diameter or anisotrichosis is diagnostic dermoscopic feature of androgenetic alopecia. It is best appreciated in a central hair part at low magnification and is very useful to detect the condition, particularly in women with female-pattern hair loss. Originally, Tosti et al. suggested that diversity of hair shaft diameter > 20 % is diagnostic of female androgenetic alopecia. Rakowska et al. proposed more sophisticated diagnostic criteria for diagnosis of female androgenetic alopecia based on trichoscopic imaging.

Major criteria were (1) ratio of more than four empty follicles in four images (at 70-fold magnification) in the frontal area, (2) lower average thickness in the frontal area compared to the occiput, and (3) more than 10 % of thin hairs (<0.03 mm in diameter) in the frontal area.

Minor criteria were (1) increased frontal to occipital ratio of single-hair pilosebaceous units, (2) vellus hairs, and (3) peripilar signs.

Fulfillment of two major criteria or of one major and two minor criteria allow diagnosis of female androgenetic alopecia with a 98 % specificity.

We performed a study to evaluate the value of trichoscopy as compared to the trichogram for the diagnosis of female androgenetic alopecia and found that trichoscopy is a valuable and superior method to the trichogram for diagnosis of female androgenetic alopecia in women, especially in early cases, with the highest yield irrespective of the suggested cutoff of 20 % diversity of hair shaft.

The severity of androgenetic alopecia can be assessed using a photographic scale that considers hair diameter and hair density. Ultimately, treatment effect can be assessed by monitoring the degree of hair shaft diameter normalization over time (Fig. 3.5g, h).

Peripilar signs are found in early androgenetic alopecia. Although they have been shown to be linked to perifollicular inflammation, the prognostic significance of these signs has not been elucidated as yet.

Empty follicles reflect the kenogen phase of the hair cycle. Kenogen frequency and duration are greater in androgenetic alopecia. The number of kenogen phases increased in parallel with vellus hairs and the diminished number of normal hair cycles, features that mark progression of androgenetic alopecia aggravation. Postmenopausal women with androgenetic alopecia often present small bald areas with numerous empty follicles, so-called focal atrichia.

Scalp pigmentation with a honeycomb pigment pattern is eventually observed on the scalp as a consequence of sun exposure. Photodamaged scalp skin may also show vessels that are dilated and tortuous.

3.5.7 Treatment

The aim of therapy is to increase hair coverage of the scalp and to retard progression of hair thinning.

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First-line treatment and treatment with the highest level of evidence for female androgenetic alopecia is topical minoxidil.

Minoxidil promotes hair growth through increasing the duration of anagen. It causes hair follicles at rest to grow and enlarges suboptimal follicles. While minoxidil was originally developed for treatment of hypertension, and this feature of the drug’s action is best understood, its mechanism of action on hair growth is poorly understood. Minoxidil is a potassium channel opener and vasodilator and has been reported to stimulate the production of VEGF in cultured dermal papilla cells. There is evidence that this effect is mediated by adenosine and sulfonylurea receptors, which are well-known target receptors for adenosine-triphosphate-sensitive potassium channel openers.

Topical solutions of 2 and 5 % minoxidil are available for treatment of androgenetic alopecia. Originally developed for treatment of androgenetic alopecia in men, topical minoxidil proved to be more effective in female androgenetic alopecia (Fig. 3.6a–c). In the original studies performed on women by Jacobs et al., the investigators observed that 44 % of patients in the 2 % minoxidil group achieved new hair growth compared with 29 % in the placebo group. DeVillez et al. determined that 13 % in the minoxidil-treated group had moderate growth and 50 % had minimal growth, compared to 6 and 33 %, respectively, in the placebo-treated group. Similarly, 60 % of patients in the 2 % minoxidil group reported new hair growth (20 % moderate, 40 % minimal) compared with 40 % (7 % moderate, 33 % minimal) in the placebo group. Clinical studies using hair counts as a primary endpoint reported a mean increase in hair growth of 15–33 % in the minoxidil-treated groups compared with 9–14 % in the vehicle control groups. Using hair weight as the endpoint, Price and Menefee found an increase of 42.5 % in hair weights in the minoxidil group compared to 1.9 % in the controls. In the most recent trial comparing 5 and 2 % minoxidil lotion, Lucky et al. found increases of 18 and 14 %, respectively, in mean non-vellus hair counts after 48 weeks treatment, compared to a 7 % increase in the placebo group. The increase in hair counts following treatment with topical minoxidil was noticeable within 8 weeks and peaked after 16 weeks. The 5 % topical minoxidil group demonstrated statistical superiority over the 2 % topical minoxidil group in the patient assessment of treatment benefit. Both concentrations of topical minoxidil were well tolerated by the women in this trial without evidence of systemic adverse effects. Ultimately, Blume-Peytavi et al. compared the efficacy of once daily 5 % minoxidil topical foam with twice daily 2 % minoxidil topical solution in women with androgenetic alopecia and demonstrated non-inferiority of once daily 5 % minoxidil topical foam to twice daily 2 % minoxidil topical solution for stimulating hair growth. Moreover, 5 % minoxidil topical foam was significantly superior to twice daily 2 % minoxidil topical solution in participants’ agreement, “the treatment does not interfere with styling my hair.” The authors concluded that once daily 5 % topical minoxidil foam is associated with both aesthetic and practical advantages.

Fig. 3.6

Successful treatment in female androgenetic alopecia: (a–c) With 5 % topical minoxidil twice daily in a 49-year-old woman, (a) before, (b) after 3 months, and (c) after 6 months treatment

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Iron deficiency is overestimated as a single cause of hair loss in women, as well as the role of antiandrogens in the treatment of female androgenic alopecia.

Traditionally, female androgenetic alopecia has been treated with iron supplementation and antiandrogen treatment.

Several studies have evaluated the relationship between iron deficiency and hair loss. The various observational studies that evaluated the association between decreased ferritin levels and hair loss have resulted in opposing conclusions. A critical appraisal of available data points to the fact that iron deficiency is probably overestimated as a single cause of hair loss in women. In our study of 181 women complaining of hair loss, we found no association between serum ferritin levels >10 μg/L and hair loss activity in women.

Since Hammerstein’s proposition of the use of antiandrogens to treat women with symptoms of hyperandrogenism, such as hirsutism, seborrhoea, and alopecia, antiandrogen therapy was established as a treatment of androgenetic alopecia in women. Typically, a high dosage reverse sequential therapy of 100 mg cyproterone acetate (CPA) on the 5th–14th days of the menstrual cycle and 40 mcg ethinyl estradiol (E2) on the 5th–25th days was used in severe cases, while low dosages of 2 mg CPA and 50 mcg of E2 preparations were used for light cases. More recently, to compare topical minoxidil 2 % and CPA in the treatment of female androgenetic alopecia, Vexiau et al. randomly assigned 66 women for 12 cycles into two groups, 33 received two local applications (2 mL day⁻¹) of topical minoxidil 2 % plus combined oral contraceptive and 33 received CPA 52 mg day⁻¹ plus E2 35 μg for 20 of every 28 days. The investigators found that minoxidil treatment was more effective in the absence of other signs of hyperandrogenism, hyperseborrhea, and menstrual cycle modifications when the Body Mass Index (BMI) was low, and when nothing argued in favor of biochemical hyperandrogenism, while CPA treatment was more effective when other signs were present and when the BMI was elevated, factors that favored a diagnosis of biochemical hyperandrogenism.

Spironolactone is yet another agent with antiandrogenic action considered in the treatment of female androgenetic alopecia. Spironolactone is a competitive inhibitor of aldosterone receptors that also blocks androgen receptors and increases metabolic clearance of testosterone. It has been widely used to treat hirsutism, but there are no controlled trials of its use in female androgenetic alopecia. Rushton and colleagues reported that women treated for 12 months with spironolactone showed less hair loss than an untreated group, while in an open uncontrolled case series of 80 women treated for 1 year with 200 mg spironolactone daily or CPA, Sinclair et al. found that 35 (44 %) showed improvement in hair growth as assessed by standardized photography.

Finasteride, an inhibitor of type 2 5α-reductase inhibits conversion of testosterone to DHT, resulting in decrease in serum and scalp DHT levels believed to be pathogenic in androgenetic alopecia. One milligram oral finasteride daily has been shown to be effective in prevention and treatment of hair loss in men, and has also proven to be effective in the aging male, though to a lesser degree and with a higher frequency of sexual adverse effects compared to men between 18 and 40 years. While oral finasteride has unanimously been shown to be effective in treatment of hair loss in men, its efficacy in women remains controversial.

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Due to teratogenicity for the male fetus, oral finasteride is contraindicated for use in premenopausal women.

In a double-blind, placebo-controlled, multicenter trial, Price et al. demonstrated that oral finasteride, 1 mg/day, taken for 1 year did not slow progression of hair loss or promote hair growth nor improve follicular counts in horizontal sections of scalp biopsies in postmenopausal women with androgenetic alopecia. One explanation might be that the different patterns of hair loss in the majority of women from that usually seen in men may be due to differences in the relative levels of 5α-reductase, aromatase, and androgen receptors in scalp hair follicles in women compared with those in men. Shum et al. reported 4 cases of hair loss with characteristics of both male and female-pattern hair loss in women with hyperandrogenism, in which finasteride improved the alopecia. Their patients differed from those in the trial reported by Price et al. in that the patients had increased androgen levels, and finasteride was used in a slightly higher dose (1.25 mg/day), and given for a longer period of time (24–30 months as opposed to 1 year). On the other hand, Carmina and Lobo did not find finasteride, 5 mg/day, to be effective in treatment of alopecia in hyperandrogenic women. In the so far largest series of 37 premenopausal women treated for 1 year with finasteride in doses of 2.5–5 mg daily; Iorizzo et al. showed some improvement in 62 % as assessed by global photography.

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Differences in response of women to oral finasteride have led to the suggestion that not all types of female hair loss have the same pathophysiology, that is, a distinction should be made between alopecia with early (premenopausal) or late (postmenopausal) onset and with or without hyperandrogenemia.

Nevertheless, up to date no predictive factor for response to finasteride treatment has been identified in women with female androgenetic alopecia.

Antiandrogen treatment is not without problems. Dose-related side effects of CPA, including weight gain, fatigue, loss of libido, mastodynia, nausea, headaches, and depression, are common. Spironolactone may cause breast soreness and menstrual irregularities. Finasteride is well tolerated and probably represents the safer option in postmenopausal and infertile women.

Estrogens are primarily marketed in a number of ways to address problems related to hypoestrogenism. According to the indication, oral, transdermal, and topical preparations are available. In an attempt to circumvent problems related to systemic hormonal treatments of female androgenetic alopecia, topical treatment with 17β- and 17α-estradiol have been introduced (Fig. 3.7a, b). 17α-estradiol (alfatradiol) represents a stereoisomer of 17β-estradiol (estradiol) with 100-fold lower estrogenic and twofold higher 5α-reductase inhibitory action. Unfortunately, efficacy studies bear a low level of evidence. Moreover, no literature exists comparing efficacy and safety of topical versus systemic estrogens. Ultimately, in a study involving 103 women comparing alfatradiol to minoxidil, Blume-Peytavi et al. found minoxidil to be more effective. In contrast to minoxidil, alfatradiol did not result in an increase of hair density or thickness.

Fig. 3.7

Successful treatment of female androgenetic alopecia: (a, b) with 0.025 % estradiol once daily in a 71-year-old woman, (a) before and (b) after 3 months treatment (With courtesy of Dr. S. Koch)

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There is growing evidence for the modes of action and efficacy of nutritional supplements on the basis of L-cystine and B vitamins for promoting hair growth.

Pharmacy aisles and Internet drugstores are full of vitamins promising full, thick hair for prices that range from suspiciously cheap to dishearteningly exorbitant. The fact is that unless hair loss is due to a vitamin deficiency, there’s only so much that vitamins can do to increase the size of individual hairs. This is because hair thickness is largely genetic. Nevertheless, there are external factors that influence hair health to a considerable degree, and vitamins can boost hair that is suffering from these problems.

In a double-blind, placebo-controlled study with 30 women suffering from telogen effluvium, we demonstrated that dietary supplement with L-cystine, medicinal yeast, and pantothenic acid (CYP complex) increased and normalized the mean anagen rates within 3 and 6 months, resp., and irrespective of presence of hair thinning in the vertex (androgenetic alopecia) or not, suggesting a beneficial effect of oral supplementation therapy as an adjunct to minoxidil therapy (Fig. 3.8a, b).

Fig. 3.8

Successful treatment of female androgenetic alopecia: (a, b) With CYP-complex-based oral supplementation, (a) before and (b) after 4 months of adding on to preexisting topical minoxidil

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Low-level laser therapy (LLLT) has recently emerged as a novel therapy for the treatment of hair loss. It has received considerable media attention and marketing budgets from companies that advertise the devices, but a reservation has been the paucity of independent, peer-reviewed studies that demonstrate its efficacy in this application.

In fact, the ability of lasers to induce hair growth was incidentally noted as early as 1967 when Mester and colleagues used low-level laser therapy (LLLT) to treat cancer in mice with shaved backs. Since then, hypertrichosis has been recognized to be a possible side effect of laser treatment. First described in 2002 with IPL therapy, this phenomenon has now been widely acknowledged to occur with an incidence rate ranging from 0.6 %–10 % with low fluences and all laser types. It is thought to be the result of suboptimal fluences that are too low to induce thermolysis, but high enough to stimulate follicular growth. Eventually, LLLT has been developed for treatment of pattern hair loss. The hypothesized mechanisms of action of LLLT are increased mitochondrial respiration, ATP synthesis, cell proliferation, decreased apoptosis and cell death, expression of VEGF, and increased blood flow.

The HairMax Laser Comb^® is a handheld Class 3R low-level laser therapy device that contains a single laser module that emulates 9 beams at a wavelength of 655 nm. The device uses a technique of parting the user’s hair by combs that are attached to the device. This improves delivery of distributed laser light to the scalp. The combs are designed so that each of the teeth on the combs aligns with a laser beam. By aligning the teeth with the laser beams, the hair can be parted and the laser energy delivered to the scalp of the user without obstruction by the individual hairs on the scalp.

In 2007, the device received 510(k) clearance from the FDA for the treatment of pattern hair loss for males and 2011 for females. This clearance means that the device is considered a moderate-risk medical device by the FDA and is thereby solely screened for safety, not efficacy.

The HairMax Laser Comb^® has been tested in a company-sponsored study of 110 male patients with the claim of significant increase in mean terminal hair density when compared to a sham device. Avram and Rogers conducted the first independent blinded study of LLLT and hair growth with 7 patients and found that on average, there was a decrease in the number of vellus hairs, an increase in the number of terminal hairs, and an increase in shaft diameter.

A consensus written by hair loss experts states that based on anecdotal experience, LLLT, particularly 650–900 nm wavelengths at 5 mW, may be an effective treatment option for patients. This group also found that even if no regrowth was appreciated, patients noted improvement in the texture and quality of hair.

From our own experience we share with the authors the opinion that LLLT represents a safe and promising treatment option for patients who do not respond to or are not tolerant to minoxidil. This technology appears to work better for some people (Fig. 3.9a–f) than for others. Predictive factors which will most benefit from low-level laser treatment are yet to be determined.

Fig. 3.9

Successful treatment of female androgenetic alopecia: (a–f) With LLLT, (a) before, after (b) 1 year topical 5 % minoxidil treatment, and (c) after 6 months adding on LLLT, with (d–f) corresponding dermoscopic findings. Note improvement of texture in hair from (b) to (c) and decrease of diversity of hair shaft diameters from (e) to (f) after adding on LLLT to preexisting topical minoxidil

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Ultimately, combination treatments with topical minoxidil, nutritional supplements, low-level laser therapy, and appropriate scalp care may act synergistic to enhance hair growth. The scientific rationale for such an approach is given, but there is a need for clinical studies to establish increase in efficacy of combination regimes and adjuvant treatments.

Autologous hair transplantation represents the only treatment that can produce substantial improvement in patients with advanced hair loss and can give satisfactory results, as long as the patient has a realistic expectation regarding the treatment results. Hairline design and evaluation of the donor and recipient areas as well as the discussion of graft numbers are basic parts of the hair transplant consultation. There are two donor hair harvesting techniques that are performed under local anesthesia: in one technique, a strip of scalp skin is taken from the occipital area, which then is divided into mini- or micrografts, each containing one to four hairs. The grafts are then planted into tiny slits in the desired recipient area. The other technique is follicular unit extraction (FUE): Multiple follicles are harvested with small 1-mm punches and planted in the target area, avoiding the occipital linear scar of the strip technique. However, FUE is more labor intensive and therefore usually more expensive. A natural-looking result can be achieved with both procedures. One or two sessions usually provide a good coverage of a balding recipient area. Final results are usually seen 6–8 months after the surgery.

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Hair transplantation is most appropriate in women with pronounced hair loss of limited extent, for example, the frontal Olsen or Christmas tree pattern, who retain good hair density in the donor site. Hair transplantation is ideally combined with medical treatment to prevent further hair loss and to improve hair growth, density, and texture.

Evolving therapies are PGF2α (latanoprost) and prostamide F2α analogues (bimatoprost), mesotherapy, platelet-rich plasma (PRP), and hair follicle neogenesis/reprogramming.

In a randomized double-blind placebo-controlled pilot study to assess the efficacy of a 24-week topical treatment by latanoprost 0.1 % on hair growth in healthy androgenetic alopecia, latanoprost significantly increased hair density (terminal and vellus hairs) at 24 weeks compared with baseline and the placebo-treated area.

The optimal concentration for bimatoprost is still unknown; phase II clinical trials are in progress and can be followed on www.clinicaltrials.gov.

Mesotherapy has received a lot of publicity in the media and Internet, also about its possible role in androgenetic alopecia. However, the subject is controversial in view of lack of documented evidence. Moreover, multifocal scalp abscess with subcutaneous fat necrosis and cicatricial alopecia as a complication of scalp mesotherapy have been reported.

PRP is blood plasma that has been enriched with platelets. As a concentrated source of autologous platelets, PRP contains and releases through degranulation several different growth factors and other cytokines. These include PDGF, TGFβ, FGF, IGF-1 and 2, VEGF, EGF, IL-8, and KGF. The use and clinical validation of PRP is still in the early stages. Results of basic science and preclinical trials have yet to be confirmed in large-scale controlled clinical trials.

Developments on the field of hair follicle neogenesis and reprogramming can be followed on the respective commercial websites: www.histogen.com, www.aderansresearch.com, www.replicel.com, www.follicabio.com.

3.6 Menopause

Menopause is based on the cessation of hormone production by the ovaries, in this case of the hormones which make reproduction possible and may influence sexual behavior. The resultant decreased levels of circulating estrogen impact the entire cascade of a woman’s reproductive functioning, from brain to skin. Estrogens clearly have an important function in many components of human skin including the epidermis, dermis, vasculature, hair follicle, sebaceous, eccrine, and apocrine glands, having significant roles in skin aging, pigmentation, hair growth, and sebum production.

The typical age range for the occurrence of menopause is between the age of 45 and 55. The average age of menopause varies according to geographic location. In the Western world, the average age of menopause is 51 years; in some developing countries, such as India and the Philippines, the median age of natural menopause is earlier, at 44 years.

Dermatologic problems postmenopausal women encounter include atrophy, dryness, pruritus, loss of resilience and pliability, easily traumatized skin, dry hair, and alopecia. Postmenopausal women show an increased tendency towards male-pattern hair loss (Fig. 3.10). Those effects are currently understood to be due to low estrogen levels.

Fig. 3.10

Postmenopausal woman with male-pattern hair loss

3.6.1 Postmenopausal Frontal Fibrosing Alopecia

Postmenopausal frontal fibrosing alopecia represents a peculiar condition predominantly, but not exclusively affecting women in the postmenopause. Originally reported by Kossard, postmenopausal frontal fibrosing alopecia presents with a symmetric, marginal alopecia along the frontal and frontal–temporal hairline, often with concomitant thinning or complete loss of the eyebrows (see Fig. 2.10). Affected women typically present with the complaint of asymptomatic, progressive recession of their frontal hairline. The affected scalp skin is pale and smooth with loss of follicular orifices; often perifollicular erythema and follicular keratinization are observed marking the underlying inflammatory process.

We and others have observed that loss of eye lashes, and peripheral body hair, as well as extension beyond the frontal hair margin is not uncommon. Consequently, the process of inflammatory scarring alopecia is generalized rather than localized only to the frontal scalp and eyebrows.

Histopathologic examination shows a reduced number of hair follicles, which have been replaced by fibrous tracts, and a perifollicular, lymphocytic, lichenoid infiltrate that is typical of lichen planopilaris.

Since Kossard’s original description in 1994, the number of cases of postmenopausal frontal fibrosing alopecia has exploded exponentially worldwide, while its etiology remains obscure. Hormone replacement therapy does not appear to alter the course and progression of this condition.

3.6.2 Treatment

With respect to menopause and hormonal substitution therapy, the focus tends to be on the issues recently covered by the Women’s Health Initiative. Consequently, many women have become reluctant towards systemic estrogen substitution therapy. Topical estrogen supplementation with estradiol has been suggested to be of some benefit. Unfortunately, these studies are relatively small. Also no literature exists comparing efficacy and safety of topical versus systemic estrogens in postmenopausal women.

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In postmenopausal women with androgenetic alopecia, hormone replacement therapies with progestogens that possess net androgenic activity, such as norethisterone, levonorgestrel, or tibolone, should be avoided, since they may precipitate alopecia and often with a male pattern.

Topical minoxidil remains first-line and mainstay therapy of female androgenetic alopecia, also in menopause, retaining its efficacy and safety profile (Fig. 3.11a–c).

Fig. 3.11

(a–c) Successful treatment of pattern hair loss in 84-year-old woman with 2 % topical minoxidil twice daily, (a) before, (b) after 3 months, and (c) after 6 months treatment

Thai and Sinclair were the first to report successful oral finasteride treatment of androgenetic alopecia in a postmenopausal woman with androgen levels within normal values. We also reported successful treatment of androgenetic alopecia with 2.5 or 5 mg/day oral finasteride in 5 normoandrogenic, postmenopausal women. Improvement with growth of hair was observed as early as 6 months of therapy, irrespective of the pattern of hair loss (Fig. 3.12a–c). Efficacy was evaluated by patient and investigator assessments and review of photographs taken at baseline and at months 6, 12, and 18 by an expert panel. Finasteride treatment improved scalp hair by all evaluation techniques. The patients’ self-assessment demonstrated that finasteride treatment decreased hair loss, increased hair growth, and improved appearance of hair. These improvements were confirmed by investigator assessment and assessments of photographs. No adverse effects were noted.

Fig. 3.12

(a–c) With 5 mg oral finasteride once daily in a 60-year-old woman allergic to minoxidil, (a) before, after (b) 6 months, and (c) 12 months treatment

3.7 Effect of Cigarette Smoking and UV Radiation

As the rest of the skin, the scalp and hair are exposed to noxious environmental factors. While cigarette smoking and UV radiation are well appreciated as major factors contributing to extrinsic aging of the skin, their effect on the condition of hair and the natural course of androgenetic alopecia have only later attracted the attention of the medical community.

3.7.1 Effect of Cigarette Smoking on Hair

Besides being the single most preventable cause of significant cardiovascular and pulmonary morbidity and an important cause of death in the general population, tobacco smoking has been associated with various adverse effects on the skin. Premature skin aging has attracted the attention of the medical community only since the 1960s, although a relation between smoking and skin complexion was first suggested as early as 1856. The facial features, designated smoker’s face, were originally defined by Model as one or more of the following: (a) wrinkles typically radiating at right angles from the upper and lower lips or corners of the eyes (crow’s feet), deep lines on the cheeks, or numerous shallow lines on the cheeks and lower jaw; (b) a gauntness of facial features with prominence of the underlying bony contours, in some cases associated with a leathery, worn, or rugged appearance; (c) an atrophic, slightly pigmented gray appearance of the skin; and (d) a plethoric, slightly orange, purple, and red complexion different form the purply blue color of cyanosis or the bloated appearance associated with alcoholism. In a survey of 116 patients attending a general medical outpatient clinic (for other than dermatologic conditions), Model found that smoker’s face was present in 46 % of current smokers, whereas 8 % of past smokers and no nonsmokers had smoker’s face. Others have also addressed the topic of smoking as a risk factor for facial wrinkling and come to similar conclusions.

The mechanisms by which smoking causes wrinkling are believed to be multifactorial and related to effects of cigarette smoke on the microvasculature, cutaneous collagen, and elastic tissue, to prooxidant effects of smoking, and increased hydroxylation of estradiol, as well as inhibition of the enzyme aromatase, which converts androgens to estrogens, creating a relative hypoestrogenic state. Cigarette smoke has been shown to increase plasma neutrophil elastase activity, which may also contribute to abnormal skin elastin, and matrix metalloproteinase (MMP)-1 (collagenase) expression was shown to be increased in skin of smokers, which may contribute to degradation of collagen. Expression of both MMP-1 and MMP-3 has been shown to be induced in cultured human fibroblasts in a dose-related manner by cigarette smoke extracts, while the expression of tissue inhibitors of metalloproteinases (TIMPPs) was not influenced. The histologic features associated with smoking have not been studied as extensively, but have demonstrated increased elastosis.

Given the public’s overwhelming quest for a young and pleasing appearance, the consensus is that education about the link between cigarette smoking and skin aging could motivate young people not to smoke or to quit smoking.

Alike the skin, the hair is subject to intrinsic or physiologic aging and extrinsic or accelerated aging due to external factors. Intrinsic factors are related to individual genetic and epigenetic mechanisms with interindividual variations. Prototypes are familial premature graying, and androgenetic alopecia. Extrinsic factors include exposure to tobacco smoke.

In 1996, Mosley and Gibbs reported in patients visiting a general surgical outpatient clinic in the United Kingdom for the first time a significant relationship between smoking and premature gray hair in both men and women, and between smoking and baldness in men. Since the number of alopecia in women was very small, no corresponding calculation could be carried out for hair loss in women.

Subsequently, our observation of strikingly dissimilar androgenetic alopecia in a 52-year-old monozygotic male twin pair led to further speculations on the possibility of an association between smoking and hair loss, since studies on the degree of alopecia among monozygotic twins aged over 50 have shown that intrapair differences are negligible in 92 %, slight in 8 %, and striking in none. A salient feature differing the twin brothers in their personal histories was that the balding brother admitted to long-standing, heavy cigarette smoking, while the other was a nonsmoker. A succeeding study failed to confirm this association.

Eventually, a population-based cross-sectional survey among Asian men 40 years or older showed statistically significant positive associations between moderate or severe androgenetic alopecia and smoking status, current cigarette smoking of 20 cigarettes or more per day, and smoking intensity. The odds ratio of early-onset history for androgenetic alopecia grades increased in a dose–response pattern. Risk for moderate or severe androgenetic increased for family history of first-degree and second-degree relatives, as well as for paternal relatives. A reservation to be made is the role of negative psychological effects of androgenetic alopecia on self-esteem and peculiarities of psychological adjustment. Although in this study data were collected with respect to age at onset of androgenetic alopecia, and age at start of smoking, there is no information on the temporal relationship of these with respect to the question, whether smoking contributes to the development of androgenetic alopecia or alternatively represents a form of behavioral coping to the impairment in physical appearance resulting from alopecia.

The mechanisms by which smoking accelerates hair loss have not been examined, but it is likely that they are similar to the effects on the skin.

· The cutaneous microvasculature is constricted by acute and long-term smoking. Evidence of the consequence of impaired circulation and wound healing is a higher complication rate of hair restoration surgery in smokers versus nonsmokers.

Besides inducing local ischemia, the decreased capillary blood flow in the dermal papilla of the hair follicles may focally shunt more toxic substances. Cigarette smoke contains over 4,800 chemicals; many of which are known to be toxic to cells, and 69 are known to cause cancer. Apart from cancer, smoking is also a major risk factor in chronic obstructive pulmonary disease, heart disease, and cerebrovascular insult and other disorders such as slowed healing of wounds, impotence, infertility, and peptic ulcer disease. Smoke genotoxicants metabolized in hair follicle cells may cause DNA damage through the production of DNA adducts, and smoking-associated mitochondrial DNA mutations have been shown in human hair follicles, though the relevance of these for hair follicle pathology is as yet unknown. Both nicotine and cotinine are detected in hair samples of smokers.

Since substantial extracellular matrix remodeling is involved in the hair follicle growth cycle, especially during catagen-associated hair follicle regression, it is conceivable that cigarette smoke-induced imbalance in the intra- and perifollicular protease/antiprotease systems controlling tissue remodeling may also affect the hair follicle growth cycle.

Smoking-induced oxidative stress and a disequilibrium of antioxidant systems may lead to the release of pro-inflammatory cytokines from follicular keratinocytes, which by themselves have been shown to inhibit the growth of isolated hair follicles in culture. Moreover, adjacent fibroblasts are fully equipped to respond to such a pro-inflammatory signal. On the occasion that the causal agent persists, sustained microinflammation of the hair follicle is the result, together with connective tissue remodeling, where again collagenases play an active role and are believed to contribute to perifollicular fibrosis.

The fact that cigarette smoke-associated hair loss is of the androgenetic type indicates that genetic factors contribute. On the other hand, a local relative hypoestrogenic state induced by cigarette smoking due to increased hydroxylation of estradiol and inhibition of the enzyme aromatase may also contribute to an increase of androgen-dependent hair thinning.

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Variances between individuals also may result from patterns of conduct, in as much as persons exposed to one risk factor (smoking) are often exposed to others as well, such as intake of androgens or their precursors (such as DHEA in female antiaging regimens) or of progestins with androgenic activity (in oral contraceptives and hormone replacement therapy), excessive ultraviolet light exposure, and stress, all of which have been implicated in one way or another in the pathogenesis of alopecia and associated conditions of the scalp.

3.7.1.1 Treatment

Interestingly, a recent experiment demonstrated that C57BL/6 mice exposed to cigarette smoke developed hair loss, while no alopecia occurred in sham-exposed mice. Smoke-exposed mice had extensive atrophy of the epidermis, reduced thickness of the subcutaneous tissue, and scarcity of hair follicles with massive apoptosis in the hair bulbs at the edge of alopecic areas. This effect was prevented by the oral administration of N-acetylcysteine, an analogue and precursor of L-cysteine and reduced glutathione, as well as by L-cystine, the oxidized form of L-cysteine, which is a key hair component, in combination with vitamin B6, which plays a role in L-cystine incorporation in hair cells. The effect may be related to the glutathione-related detoxification system.

The appearance of hair plays an important role in people’s overall physical appearance and self-perception. The well-recognized psychological effects of androgenetic alopecia on affected women, and our society’s veneration of youth and its attributes, seem to offer a good opportunity for prevention or cessation of smoking.

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Increasing public awareness of the association between smoking and hair loss would seem more effective than the link between smoking and facial wrinkles, since the latter can be effectively counteracted by current cosmetic dermatologic procedures, while treatment options for androgenetic alopecia are limited.

3.7.2 Effect of UV Radiation on Hair

While the consequences of sustained ultraviolet radiation (UVR) on unprotected skin are well appreciated, mainly photocarcinogenesis and solar elastosis, the effects of UVR on the evolution of androgenetic alopecia have largely been ignored. However, some clinical and morphological observations, as well as theoretical considerations, suggest that UVR has some negative effect. Since all of these disparate disorders of the balding scalp share the common feature that under some circumstances they are induced or exacerbated by exposure to sunlight, it has been proposed that androgenetic alopecia is a photoaggravated dermatosis and demands adequate photoprotection.

The number of recognized photosensitive dermatoses that localize to the scalp is essentially limited to light-exacerbated endogenous eczema, dermatomyositis, and cutaneous lupus erythematosus. Patients with atopic or seborrheic dermatitis occasionally report nonspecific exacerbation of their condition following sun exposure, also on the scalp, where at times it may be difficult to differentiate from exacerbation of itch through heat-induced sweating. A high prevalence of seborrheic dermatitis has been described on the scalp in sun-exposed mountain guides in Austria, Switzerland, and Germany.

Besides these, erosive pustular dermatosis of the scalp is observed as a distinct disorder peculiar to the balding scalp. Erosive pustular dermatosis of the scalp was first described by Burton and subsequently delineated by Pye, Peachey, and Burton as a distinctive clinical entity producing chronic extensive pustulation confined to the scalp of elderly individuals and leading to erosion and scarring alopecia. A high incidence of antecedent local trauma strongly suggests that scalp injury may be important in initiating the dermatosis in a susceptible elderly person with atrophic skin changes of the scalp, particularly due to prolonged exposure of long-standing androgenetic alopecia to UVR. No recognized cause of pustulation is present, and the histology is nonspecific. Response to antibiotics is poor, but the condition is suppressed by potent topical steroids, suggesting an inflammatory rather than an infective etiology. The condition has been observed following contusion, laceration, blistering sunburn, shingles, synthetic fiber implantation, craniotomy, and skin grafting of the scalp, as well as following treatment of solar keratoses with 5 % topical fluorouracil cream, cryotherapy, topical tretinoin, and soft x-ray therapy. Response to therapy has been variable, with best responses reported to potent topical steroids, and more recently to topical 0.1 % tacrolimus. Anecdotal reports describe partial response to nimesulide, a phenoxymethane sulfonanilide that inhibits the respiratory burst of human granulocytes. Long-term follow-up is advised, since neoplastic change has been reported.

Terrestrial solar UVR ranges from approximately 290–400 nm. UVB (290–315 nm) reaches the upper dermis only, while UVA (315–400 nm) penetration into the dermis increases with wavelength. The two most important chronic effects of UVR on the skin and bald scalp are photocarcinogenesis and solar elastosis. The mechanisms by which UVR plays a role in the development of skin cancer are varied and represent a multistep process involving alterations in DNA structure, resulting from purine photoproducts, cytosine photohydrates, single strand breaks, and sister chromatid exchange, as well as from reactive oxygen species that are generated during exposure of cells to UVR. Theoretically, any alteration capable of causing a mutation in specific target genes could contribute to carcinogenesis, since there is a close correlation between mutation and transformation by UVR. Recent progress has been made in identifying specific genes that control cellular growth that may be involved in photocarcinogenesis. Also, UVR induces deviations of tumor immunosurveillance mechanisms that eventually aid the survival and progressive growth of UVR-induced malignancies. Finally, it has been found that telomerase activity plays a crucial role in the immortalization of human cells: Telomerase activity is found in plucked hair follicles, which is associated with the presence of stem cells in the follicle, and is found in a high percentage of skin tumors. Evidence of UV-associated activation of telomerase in human skin further suggests that telomerase activation is involved in skin photocarcinogenesis.

Actinic keratosis is the most common epidermal precancerous lesion resulting from chronic UVR exposure, usually on sun-exposed body regions of middle-aged or older people, including the balding scalp or bald scalp area. It presents as a skin-colored to reddish, ill-defined macule with a dry adherent scale.

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Actinic keratoses of the scalp are often multiple, and although usually asymptomatic, the patient may note mild local tenderness. At times multiple, confluent lesions of the centroparietal scalp with androgenetic alopecia may be misinterpreted as refractory seborrheic eczema of the scalp.

In these cases, topical therapy with imiquimod proves to be effective, while sparing the remaining hair.

Histopathologically, elastosis is regularly found in scalp biopsies, especially in alopecic conditions, but so far has largely been ignored. Up to date, no controlled study has been performed on the degree of scalp elastosis in relation to the pace of development, duration, or grade of androgenetic alopecia, though it would seem to be a good marker for exposure to UVR penetrating the skin. Interestingly, UVB irradiation has been found to stimulate the synthesis of elastic fibers by modified epithelial cells surrounding the hair follicle and sebaceous glands in mice.

Camacho et al. reported a peculiar type of telogen effluvium following sunburn of the scalp after 3–4 months in women with hairstyles that left areas of scalp uncovered during prolonged sun exposure. The clinical features were increased frontovertical hair shedding along with a trichogram that disclosed an increase of telogen hairs and dystrophic hairs. In women the hairs on the frontal region appeared unruly, and the frontovertical alopecia showed loss of the frontal hair implantation line. The pathomechanism of this type of telogen effluvium is not clear. It has been proposed that the columns of the cells in the hair shaft act as an efficient fiber-optic type system, transmitting UV light downward into the hair follicle. Morphologically, the keratinocytes within the hair shaft are arranged in compressed linear columns that resemble the coaxial bundles of commercial fiber-optic strands. Thus, hair follicular melanocytes located in the region of the hair matrix may function as UV biosensors and respond to photic inputs. Depending on the quantity of UVR exposure, it is conceivable that also photodamage may occur at this site, resulting in telogen effluvium.

3.7.2.1 Treatment

As a consequence of increased leisure time with a growing popularity of outdoor activities and holidays in the sun, awareness of sun protection has become important.

Topically applied chemicals that act as sun protectors are widely utilized and offer the most convenient means of protecting the glabrous skin against acute (sunburn) and chronic pathologic effects of UVR. Out of cosmetic reasons, their use on the hair-bearing scalp is problematic, unless complete baldness is present. Although hats provide the best protection of the scalp from UVR, not all patients find it convenient or acceptable for this purpose.

While protection of the hair against photodamage has been extensively studied, there are no data on photoprotection of the hair-bearing scalp: It has been found that hair dyes may protect hair against photodamage; recent experimental work indicates that cinnamidopropyltrimonium chloride, a quaternized UV absorber, delivered from a shampoo system, is suitable for photoprotection of hair, while simultaneously providing an additional conditional benefit on hair; and solid lipid nanoparticles have been developed as novel carriers of UV blockers for the use on skin and hair, while offering photoprotection on their own by reflecting and scattering UV radiation.

Finally, systemic photoprotection has been the focus of more recent investigation, in as much as this would overcome some of the problems associated with the topical use of sunscreens: Preclinical studies illustrate photoprotective properties of supplemented antioxidants, particularly beta-carotene (pro-vitamin A), α-tocopherol (vitamin E), and L-ascorbate (vitamin C). However, clinical evidence that these prevent, retard, or slow down solar skin damage is still impending. The same applies to topical melatonin, which has been found to suppress UV-induced erythema and UV-induced reactive oxygen species in a dose-dependent manner. Nevertheless, these results suggest the probable utility of combining these compounds with known sunscreens to maximize photoprotection.

3.8 Hair Aging

The study of hair aging focuses on two mainstreams of interest: On one hand, the aesthetic problem of aging hair and its management, in other words everything that happens outside the skin, and on the other hand, the biological problem of aging hair, in terms of microscopic, biochemical (hormonal, enzymatic), and molecular changes, in other words the secret life of the hair follicle in the depth of the skin.

Hair length, color, and style play an important role in people’s physical appearance and self-perception. Civilized mankind’s ancient preoccupation with hair is heightened as today’s increasing life expectancy fuels the desire to preserve youthfulness. This attention reflects a hair care market that is a multibillion dollar enterprise. The development of safe and effective means for the treatment of age-related hair changes indicates strategies for maintenance of healthy and beautiful hair in the young as well as the old.

Eventually, basic scientists interested in the biology of hair growth and pigmentation have exposed the hair follicle as a highly accessible and unique model that offers important opportunities also to the gerontologist for the study of aging. Its complex multicell type interaction system involving epithelium, mesenchyme, and neuroectoderm and its unique cyclical activity of growth, regression, rest, and regrowth provide the investigator with a range of stem, differentiating, and mitotic and post-mitotic terminally differentiated cells, including cells with variable susceptibility to apoptosis, for study. A number of intrinsic and extrinsic modulating factors for hair growth and pigmentation have been identified and are being further tested in vitro.

Aging is a complex process involving various genetic, hormonal, and environmental mechanisms. As the rest of the skin, the scalp and hair are subject to intrinsic or chronologic aging and extrinsic aging due to environmental factors. Both occur in conjunction with the other and are superimposed on each other. Intrinsic factors are related to individual genetic and epigenetic mechanisms with interindividual variation. Examples are familial premature graying and androgenetic alopecia. Extrinsic factors include ultraviolet radiation (UVR), smoking, and nutrition.

Experimental evidence supports the hypothesis that oxidative stress plays a major role in the aging process. As early as 1956, Harman et al. first proposed this free-radical theory of aging. Today it is one of the most widely accepted theories used to explain mechanisms underlying the aging process. Free radicals are highly reactive molecules with unpaired electrons that can directly damage various cellular structural membranes, lipids, proteins, and DNA. The damaging effects of these reactive oxygen species are induced internally during normal metabolism and externally through exposure to various oxidative stresses from the environment. The body possesses endogenous defense mechanisms, such as anti-oxidative enzymes (superoxide dismutase, catalase, glutathione peroxidase) and nonenzymatic anti-oxidative molecules (vitamin E, vitamin C, glutathione, ubiquinone), protecting it from free radicals by reducing and neutralizing them. With age, the production of free radicals increases, while the endogenous defense mechanisms decrease. This imbalance leads to the progressive damage of cellular structures, presumably resulting in the aging phenotype.

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The aging phenotype of hair manifests as decrease of melanocyte function or graying and decrease in hair production or alopecia.

3.8.1 Graying

Hair graying (canities) is a natural age-associated feature. The hair graying trait correlates closely with chronological aging and occurs to varying degrees in all individuals.

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The normal incidence of hair graying is 34 ± 9.6 years in Caucasians and 43.9 ± 10.3 years in Africans, and, by 50 years of age, 50 % of people have 50 % gray hair.

This graying incidence appears irrespective of sex and hair color. In men graying usually begins at the temples and in the sideburns. Women will usually start around the perimeter of the hairline. Gradually, the gray works its way back through the top, sides, and back of the hair.

Although graying is understood as a loss of pigment in the shaft, its cellular and molecular origins are incompletely understood. Theories for the gradual loss of pigmentation include exhaustion of enzymes involved in melanogenesis, impaired DNA repair, loss of telomerase, antioxidant mechanisms, and anti-apoptotic signals.

The color of hair mainly relies on the presence or absence of melanin pigment. Skin and hair melanins are formed in cytoplasmic organelles called melanosomes, produced by the melanocytes, and are the product of a complex biochemical pathway (melanogenesis) with tyrosinase being the rate-limiting enzyme. So far, the process of hair graying has been attributed to the loss of the pigment-forming melanocytes from the aging hair follicle. The net effect of this reduction is that fewer melanosomes are incorporated into cortical keratinocytes of the hair shaft. In addition, there appears also to be a defect of melanosome transfer, as keratinocytes may not contain melanin despite their proximity to melanocytes with remaining melanosomes. This defect is further corroborated by the observation of melanin debris in and sometimes around the graying hair bulb. This anomaly is due to either defective melanosomal transfer to the cortical keratinocytes or melanin incontinence due to melanocyte degeneration. Eventually, no melanogenic melanocytes remain in the hair bulb. This decrease of melanin synthesis is associated with a decrease in tyrosinase activity. Ultrastructural studies have shown that remaining melanocytes not only contain fewer melanosomes but the residual melanosomes may be packaged within autophagolysosomes. This removal of melanosomes into autophagolysosomes suggests that they are defective, possibly with reactive melanin metabolites. This interpretation is supported by the observation that melanocytes in graying hair bulbs are frequently highly vacuolated, a common cellular response to increased oxidative stress. Therefore, by analogy with the free-radical theory of aging, a free-radical theory of graying has been proposed.

The extraordinary melanogenic activity of pigmented bulbar melanocytes, continuing for up to 10 years in some hair follicles, is likely to generate large amounts of reactive oxygen species via the hydroxylation of tyrosine and the oxidation of DOPA to melanin. If not adequately removed by an efficient antioxidant system, an accumulation of these reactive oxidative species will generate significant oxidative stress. It is possible that the antioxidant system becomes impaired with age leading to damage to the melanocyte itself from its own melanogenesis-related oxidative stress. Since mutations occur at a higher rate in tissue exposed to high levels of oxidative stress, and these accumulate with age, the induction of replicative senescence with apoptosis is likely to be an important protective mechanism against cell transformation.

Wood et al. have recently demonstrated for the first time that human white scalp hair shafts accumulate hydrogen peroxide (H2O2) in millimolar concentrations and almost absent catalase and methionine sulfoxide reductase (MSR) protein expression in association with functional loss of methionine sulfoxide repair in the entire gray hair follicle. Accordingly, methionine sulfoxide formation of methionine residues (Met), including Met 374 in the active site of tyrosinase, the key enzyme in melanogenesis, limits enzyme functionality, which eventually leads to loss of hair color. While the entire hair follicle is subject to H2O2-mediated stress, it is tempting to assume that, besides tyrosinase and MSR, other proteins and peptides, including anti-apoptotic Bcl-2 protein, are targets for oxidation, which in turn could explain melanocyte apoptosis in the gray hair follicle. Moreover, H2O2-mediated oxidation has been documented for many other important regulators of pigmentation, including the proopiomelanocortins α-melanocyte-stimulating hormone (MSH) and β-endorphin, the prohormone convertases, and the synthesis and recycling of the ubiquitous cofactor 6-tetrahydrobiopterin. Although as yet little published data is available on the hair follicle melanocyte stem cell population, it is tempting to speculate that these cells may well also be target to oxidation. Since the discovery of unpigmented melanocyte stem cells located within the hair follicle, the question has arisen whether the process underlying hair graying arises specifically from changes in differentiated, pigmented melanocytes or the unpigmented progenitors which provide them. Utilizing melanocyte-tagged transgenic mice and aging human hair follicles, Nishimura et al. have recently demonstrated that hair graying may be caused by defective self-maintenance of melanocyte stem cells, and not of differentiated melanocytes. This process was dramatically accelerated with Bcl-2-deficiency, which causes selective apoptosis of melanocyte stem cells.

The rate at which an individual turns gray depends on genetics. It is not uncommon to observe kinships with marked early graying throughout.

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Hair is said to gray prematurely if it occurs before the age of 20 in Caucasians and before 30 in Africans.

While premature canities more commonly appear without underlying pathology, presumably inherited in an autosomal dominant manner (familial premature graying), it has been linked to a similar cluster of autoimmune disorders observed in association with vitiligo, that is, pernicious anemia and autoimmune thyroid disease, and several rare premature aging syndromes, such as Hutchinson–Gilford and Werner’s syndrome. In dystrophia myotonica of Curschmann–Steinert, the onset of gray hair may precede the myotonia and muscle wasting.

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Reports linking cigarette smoking with premature gray hair have drawn on one hand the attention to the role of oxidative stress on hair growth and pigmentation and on the other to canities as a marker for the general health status.

A possible explanation of the observation may be that smoking-related diseases increase aging in general, including pigmentation. However, more direct effects, for example, via smoke genotoxin-induced apoptosis, may also be involved. Whether canities, premature or otherwise, is a predictor or risk marker for disease remains controversial, mainly due to poor epidemiologic study design. Moreover, if it exists at all, it is more likely to reflect associated genetic effects rather than direct linkage.

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Anecdotal evidence indicates that gray hair becomes coarser and less manageable than pigmented hair.

Gray hair is said to often fail to hold a temporary or permanent set and to be more resistant to incorporating artificial color; both of which suggest changes to the underlying substructure of the hair fiber. Gray hair has been found to have increased sensitivity to weathering, increased cysteic acid residues and decreased cystine, and increased fiber reactivity to reducing and oxidizing agents. Moreover, gray hair is more sensitive to UVR. Photochemical impairment of the hair includes degradation and loss of hair proteins as well as degradation of hair pigment. UVB radiation is responsible for hair protein loss and UVA radiation is responsible for hair color changes. Absorption of radiation in photosensitive amino acids of the hair and their photochemical degradation is producing free radicals. They have adverse impact on hair proteins, especially keratin, while melanin can partially immobilize free radicals and block their entrance in keratin matrix.

Given the close interaction of melanin-transferring melanocytes with hair shaft-forming pre-cortical keratinocytes, it is conceivable that other functions of these cell types are affected by this activity. One possibility is that melanin transfer decreases keratinocyte turnover and increases keratinocyte terminal differentiation. Indeed, white beard hair has been shown to grow up to four times the rate of adjacent pigmented hair. In this way, aging hair follicles may reprogram their matrix keratinocytes to increase production of medullary, rather than cortical, keratinocytes. In fact the medulla is often enlarged and collapsed, forming a central cavity in gray and white hairs. An evolutionary basis for this increased medullation in senile white hair may reflect the enhanced insulation provided by these hairs which would confer an important benefit for temperature regulation. In this way, it may compensate for the loss of sunlight-absorbing and thus heat-trapping properties of melanized dark hair.

3.8.2 Possibilities and Limitations for Reversal of Age-Related Pigment Loss

Reports of spontaneous repigmentation of white hair are very scant in the medical literature, though this phenomenon may not be as rare as assumed. In fact, it is not too uncommon to see spontaneous repigmentation along the same individual hair shaft in early canities. Moreover, melanocytes taken from gray and white hair follicles can be induced to pigment in vitro.

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The most dramatic cases of return of normal hair color from gray are probably examples of pigmented hair regrowth following alopecia areata.

The reported repigmentation of gray hair in association with Addison’s disease has also been connected to a mechanism similar to that in alopecia areata or vitiligo, in view of the known association between these diseases. Alternatively, it may be explained through the effect of elevated levels of MSH, which also applies to darkening of skin and hair in Nelson’s syndrome and ectopic ACTH syndrome. Since the stimulation of pigment formation may also affect the hair, a conspicuous darkening of the hair should suggest the possibility of these disorders.

Temporary hair darkening has been reported after ingestion of large doses of p-aminobenzoic acid (PABA): Sieve gave 100 mg three times daily to 460 gray-haired individuals and noted a response in 82 %. Darkening was obvious within 2–4 months of starting treatment. The hairs turned gray again 2–4 weeks after stopping therapy. The mechanism of action has remained unclear. A major drawback is gastrointestinal side effects. For this reason, PABA is usually incorporated in smaller doses in commercially available oral dietary supplements for hair growth and color.

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Darkening of hair has been observed in the course of treatment of androgenetic alopecia with the topical hair growth-promoting agent minoxidil. The mode of action is probably prolonged anagen and follicular enlargement, enhancing normal melanogenesis.

In the absence of another way to reliably reverse hair graying, hair colorants have remained the mainstay of recovering lost hair color, reaching back as far as to the ancient Egyptians who colored their hair with henna and indigo and the ancient Romans who used lead combs dipped into vinegar.

Possibilities for prevention or reversal of senile graying of human hair are the subject of current intense research into the underlying biology of hair pigmentation and its derangements, respectively. Since reactive oxygen species have been implicated in hair follicle melanocyte apoptosis and DNA damage, and under in vitro conditions, Met oxidation of tyrosinase could be shown to be prevented by L-methionine, it will be interesting whether L-methionine could be useful for intervention or reversal of the hair graying process.

There is also an increasing interest in the hair follicular route for delivery of active compounds affecting the hair. Research activities also focus on topical liposome targeting for melanins, genes, and proteins selectively to hair follicles for therapeutic and cosmetic modification of hair.

Finally, tissue engineering with cells of hair follicular origin with stem cell properties represents yet another line of research in the quest of new treatments for loss of pigmentation. Advances in the identification and characterization of stem cell populations have led to substantial interest in understanding the precise triggers that would operate to induce activation of quiescent stem cells. Melanocyte stem cells that reside in the bulge region of murine hair follicles are characterized by reduced expression of the microphthalmia-associated transcription factor (Mitf) and its target genes implicated in differentiation. As Mitf is implicated in control of proliferation, Saha et al. explored the possibility that inducing Mitf expression via lipid-mediated activation of the p38 stress-signaling pathway may represent a repigmentation strategy. They isolated from placental extract a C18:0 sphingolipid able to induce Mitf and tyrosinase expression via activation of the p38 stress-signaling pathway. Strikingly, in age-onset gray-haired C57BL/6J mice that exhibit decaying Mitf expression, topical application of placental sphingolipid led to increased Mitf in follicular melanocytes and fresh dense black hair growth.

3.8.3 Rare Premature Aging Syndromes

From a clinician’s perspective, age-dependent progressive hair loss occurs in the following fundamentally different settings: as a symptom of one of the rare premature aging syndromes (progerias), as a consequence of androgenetic alopecia, or with onset of senescence.

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Scientists are particularly interested in the premature aging syndromes because these might reveal clues about the normal process of aging.

Hutchinson–Gilford progeria and Werner’s syndrome are repeatedly given as examples of premature aging and as evidence for the genetic basis of aging. However, the analogy of these syndromes with physiologic aging has been challenged. These pathologic conditions should rather be viewed as deviations from normal development. Since the mesenchymal tissue is severely affected in both diseases, and the inductive phenomena necessary for the differentiation and development of the different organs take place through the interaction of connective tissue with other tissues, it is conceivable that defects in the connective tissue lead to a variety of deviations in the whole organism. Symptoms of accelerated aging of the hair include premature loss and graying of hair.

Nevertheless, these rare syndromes and others with premature hair loss, such as myotonic dystrophy Curschman–Steinert and the Laron syndrome, give insights into the roles of telomeres, mitochondrial function, human growth hormone (HGH), and insulin-like growth factor 1 (ILGF1) for the growth and aging of hair.

3.8.4 Senescent Alopecia

Senile involutional or senescent alopecia has been defined as non-androgen-dependent hair thinning found in those over 60 years of age. Much like androgenetic alopecia, it involves a progressive decrease in the number of anagen follicles and hair diameter. It frequently occurs together with androgenetic alopecia, further complicating its delineation from the latter.

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Recent data comparing androgenetic alopecia and senescent alopecia using microarray analysis have identified significant differences in the gene expression patterns suggesting they represent different entities.

In androgenetic alopecia, genes required for anagen onset (Wnt-beta-catenin, TGF-alpha, TGF-beta, Stat-3, Stat-1), epithelial signal to dermal papilla (PPARd, IGF-1), hair shaft differentiation (Notch, Msx2, KRTs, KAPs), and anagen maintenance (Msx2, Activin, IGF-1) were downregulated, and genes for catagen (BDNF, BMP2, BMP7, VDR, IL-1, ER) and telogen induction and maintenance (VDR, RAR) were upregulated. In senescent alopecia, genes involved in epithelial signal to dermal papilla (FGF5), actin cytoskeleton (DST, ACTN2, TNNI3, PARVB), and mitochondrial function (JAK2, PRKD3, AK2, TRAP1, TRIO, ATP12A, MLL4, STK22B) were downregulated, while oxidative stress and inflammatory response genes were upregulated.

Eichmüller et al. proposed that senescent alopecia may result from cumulative physiological degeneration of selected hair follicles. In healthy murine skin they described clusters of perifollicular macrophages as perhaps indicating the existence of a physiological program of immunologically controlled hair follicle degeneration by which malfunctioning follicles are removed by programmed organ deletion. On the other hand, Price et al. did not identify any dropout of follicles in senescent alopecia upon staining biopsies for elastin, whereas there was less 5α-reductase enzyme activity in comparison to androgenetic alopecia.

In their study on aging and hair cycles over an exceptionally long duration of 8–14 years, Courtois et al. found a reduction in the duration of hair growth and in the diameter of hair shafts and a prolongation of the interval separating the loss of a hair in telogen and the emergence of a replacement hair in anagen (latency phase). These phenomena resemble those observed in the course of androgenetic alopecia, although their development is less marked, suggesting androgenetic alopecia a premature aging phenomenon. This aging process was evidenced by a reduction in the number of hairs per unit area and deterioration in the quality of scalp hair. The reduction in density was manifested to different degrees in different individuals. It amounted to less than 10 % in 10 years in the individuals with the least alopecia and was much more pronounced in the balding subjects. The maximal length of hair diminished as the subjects aged, in parallel the hairs became finer. However, among non-balding subjects, there was a tendency for the proportion of thicker hairs to increase. Finally, aging did not appear to follow a perfectly regular course over time. Periods of stability, or even partial remission, alternated with periods of more marked evolution, reflecting perhaps the influence of individual factors such as the subject’s general health, lifestyle, and risk factors for accelerated aging.

3.8.5 Possibilities and Limitations for Reversal of Age-Related Hair Loss

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Current available treatment modalities with proven efficacy for treatment of female androgenetic alopecia may also be used in women aged 60 years or more with thinning hair.

However, topical minoxidil has not been studied in the specific perspective of aging and senescent alopecia. In an analysis of clinical trial data in 630 females, Rundegren compared a therapeutic benefit of topical minoxidil solution with age and duration of hair loss: Age was found to be the denominator for predicting treatment success. Younger subjects experienced better efficacy than older subjects, although clear treatment effects were noted also in the older age group. In contrast, no correlation was showed with duration of hair loss.

In their study of 1 mg oral finasteride for treatment of androgenetic alopecia in postmenopausal women, Price et al. implied that the older age of the women enrolled in the clinical trial may have contributed to the lack of improvement with finasteride, since they assumed that women in the later decades of life develop senescent scalp thinning which is not 5α-reductase or DHT dependent. On the other hand, oral finasteride, 1 mg/day, has been shown to be effective in men of older age.

In a double-blind, placebo-controlled study with 30 women suffering from telogen effluvium, we demonstrated that dietary supplement with L-cystine, medicinal yeast, and pantothenic acid (CYP complex) increased and normalized the mean anagen rates within 3 and 6 months, resp., and irrespective of patient age (senescent alopecia), suggesting a beneficial effect of oral supplementation therapy as an adjunct to minoxidil therapy.

Finally, in the course of hormonal antiaging protocols containing recombinant human growth hormone (hGH) at the Palm Springs Life Extension Institute, Chein reports improvement of hair thickness and structure in 38 % of patients, in some cases darkening of hair, and in few increased hair growth. It is noteworthy that in primary growth hormone insensitivity (Laron syndrome), hair growth and hair structure have been shown to be impaired, underscoring the interest in studying the premature aging and related syndromes for a deeper insight into the basis of the hair aging process. The effect of hGH is presumably mediated by IGF-1 on the hair follicle.

3.9 Alopecia with Scarring Phenomena

The limited success rate of treatment of androgenetic alopecia with minoxidil and finasteride means that further pathogenic pathways may be taken into account. On histologic examination of scalp biopsies, the miniaturization of terminal hairs is frequently associated with perifollicular lymphocytic infiltration, and eventually fibrosis. Therefore, it is conceivable that the role of this microscopic follicular inflammation causing fibrosis below the shortened balding follicle has been underestimated, though it seems likely that this would prevent the follicle to reform a terminal hair follicle.

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The implication of microscopic follicular inflammation in the pathogenesis of androgenetic alopecia has emerged from several independent studies.

An early study referred to an inflammatory infiltrate of activated T cells and macrophages in the upper third of the hair follicles, associated with an enlargement of the follicular dermal sheath composed of collagen bundles (perifollicular fibrosis), in regions of actively progressing alopecia. Horizontal section studies of scalp biopsies indicated that the perifollicular fibrosis is generally mild, consisting of loose, concentric layers of collagen that must be distinguished from cicatricial alopecia.

Bernard et al. proposed the term follicular microinflammation, because the process involves a slow, subtle, and indolent course, in contrast to the inflammatory and destructive process in the classical inflammatory scarring alopecias.

3.9.1 Androgenetic Alopecia with Histological Evidence of Follicular Inflammation and Fibrosis

The significance of follicular microinflammation and fibrosis in androgenetic alopecia remains controversial.

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However, morphometric studies in male patients with androgenetic alopecia treated with topical minoxidil showed that 55 % of those with microinflammation had regrowth in response to treatment, in comparison to 77 % in those patients without inflammation and fibrosis.

An important question is how the inflammatory reaction pattern is generated around the individual hair follicle. Inflammation is regarded a multistep process which may start from a primary event. The observation of a perifollicular infiltrate in the upper follicle near the infundibulum suggests that the primary causal event for the triggering of inflammation might occur near the infundibulum. On the basis of this localization and the microbial colonization of the follicular infundibulum with Propionibacterium spp., Staphylococcus spp., Malassezia spp., or other members of the transient flora, one could speculate that microbial toxins or antigens could be involved in the generation of the inflammatory response. The production of porphyrins by Propionibacterium spp. in the pilosebaceous duct has also been considered to be a possible cofactor of this initial pro-inflammatory stress.

Alternatively, keratinocytes themselves may respond to chemical stress from irritants, pollutants, and UV irradiation by producing radical oxygen species and nitric oxide and by releasing intracellularly stored IL-1alpha. This pro-inflammatory cytokine by itself has been shown to inhibit the growth of isolated hair follicles in culture. Moreover, adjacent keratinocytes, which express receptors for IL-1, start to engage the transcription of IL-1 responsive genes: mRNA coding for IL-1beta, TNFalpha, and IL-1alpha and for specific chemokine genes, such as IL-8, and monocyte chemoattractant protein-1 (MCP-1) and MCP-3, themselves mediators for the recruitment of neutrophils and macrophages, have been shown to be upregulated in the epithelial compartment of the human hair follicle. Besides, adjacent fibroblasts are also fully equipped to respond to such a pro-inflammatory signal. The upregulation of adhesion molecules for blood-borne cells in the capillary endothelia, together with the chemokine gradient, drive the transendothelial migration of inflammatory cells, which include neutrophils through the action of IL-8, T cells, and Langerhans cells at least in part through the action of MCP-1. After processing of localized antigen, Langerhans cells, or alternatively keratinocytes, which may also have antigen presenting capabilities, could then present antigen to newly infiltrating T lymphocytes and induce T-cell proliferation. The antigens are selectively destroyed by infiltrating macrophages or natural killer cells.

On the occasion that the causal agents persist, sustained inflammation is the result, together with connective tissue remodeling, where collagenases, such as matrix metalloproteinase (also transcriptionally driven by pro-inflammatory cytokines) play an active role. Collagenases are suspected to contribute to the tissue changes in perifollicular fibrosis.

3.9.2 Fibrosing Alopecia in a Pattern Distribution

Alopecia in a pattern distribution is a common event associated with androgenetic hair loss and aging. Although it is regarded as a pathologic process by some physicians and many affected patients, by others it is considered a genetically determined physiologic event in the lives of most men and women. The same controversy applies to the histological finding of inflammatory cells in the vicinity of the upper hair follicle in androgenetic alopecia inasmuch as it remains uncertain whether this phenomenon is still a physiologic event or already reflects a pathologic process. Clinically, androgenetic alopecia is usually a non-inflammatory and non-scarring process that eventually leads to permanent hair loss of the affected scalp.

In our original description of fibrosing alopecia in a pattern distribution, patients displayed progressive scarring alopecia in a pattern distribution (Fig. 3.13a). Close clinical examination reveals obliteration of follicular orifices, perifollicular erythema (Fig. 3.13b), and follicular keratosis limited to the area of androgenetic hair loss (Fig. 3.13c). Histological findings of androgenetic alopecia, that is, increased numbers of miniaturized hair follicles with underlying fibrous streamers, are evident in the majority of patients and associated with a perifollicular lymphocytic infiltrate. A pattern of follicular interface dermatitis targeting the upper follicle is found in early lesions, whereas perifollicular lamellar fibrosis and the presence of selectively fibrosed follicular tracts characterize late lesions.

Fig. 3.13

(a–c) Fibrosing alopecia in a pattern distribution. (a) Patterned scarring alopecia, (b) follicular erythema, (c) follicular keratosis

The pattern distribution and histological findings share features with Kossard’s postmenopausal frontal fibrosing alopecia. The clinical presentation in these women might mimic male-pattern alopecia because it produces frontal recession of the hairline, but it is associated with clinical evidence of scarring. Kossard et al. later interpreted this type of alopecia as a frontal variant of lichen planopilaris on the basis of histopathologic and immunohistochemical studies.

Considerable overlap exists among postmenopausal frontal fibrosing alopecia, lichen planopilaris, and fibrosing alopecia in a pattern distribution: Postmenopausal frontal fibrosing alopecia has been described in association with lichen planus elsewhere (oral cavity), and we observed postmenopausal frontal fibrosing alopecia-type changes in patients with fibrosing alopecia in a pattern distribution.

Remarkably, in healthy murine, skin clusters of perifollicular macrophages have been described as perhaps indicating the existence of a physiological program of immunologically controlled hair follicle degeneration by which malfunctioning follicles are removed by programmed organ deletion. Various forms of clinically perceptible, permanent alopecia might represent pathological exaggeration of this type of programmed organ deletion, resulting in a lichenoid tissue reaction pattern and true scarring alopecia. Further studies are required in patients with fibrosing alopecia in a pattern distribution to elucidate a presumable role of androgenetic factors in addition to that of the lymphohistiocytic infiltrate, perifollicular lamellar fibrosis, and apoptosis-mediated follicular regression.

An important question to be addressed in further studies is how the lichenoid tissue reaction pattern is generated around the individual androgenetic hair follicle. Follicles with some form of damage or malfunction might express cytokine profiles that attract inflammatory cells to assist in damage repair or in the initiation of apoptosis-mediated organ deletion. Alternatively, an as yet unknown antigenic stimulus from the damaged or malfunctioning hair follicle might initiate a lichenoid tissue reaction in the immunogenetically susceptible individual. The possible role of microbial antigens or superantigens in this context remains to be elucidated.

3.9.3 Targeting the Inflammatory Component in Androgenetic Alopecia

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So far, the inflammatory component has not been included in treatment protocols for androgenetic alopecia.

No treatment has convincingly been found to significantly alter the course of frontal fibrosing alopecia, in part due to the patients’ delay in consulting a physician for the condition or the doctor’s delay in making the diagnosis. Basically, frontal fibrosing alopecia is very much treated in the same way as lichen planopilaris (see Table 3.4). Regrowth of eyebrow can be induced with intralesional triamcinolone acetonide.

Table 3.4

Inflammatory scarring alopecias. Recommended treatment regimens

Lichen planopilaris

Topical clobetasol propionate first month twice daily, 3 months daily, thereafter every second day, in combination with

Oral doxycycline 100–200 mg daily for 3–6 months

If unsuccessful, may be combined with oral hydroxychloroquine 200 mg daily

If unsuccessful, oral cyclosporine A 3–5 mg/kg body weight daily for 4 months, may be combined with

Surgical reduction of patches of scarring alopecia (under immunosuppressive therapy with oral cyclosporine A: Fig. 3.18a, b)

Trial with low-dose excimer 308-nm laser

Chronic cutaneous lupus erythematosus

Intralesional triamcinolone acetonide 10 mg/mL every 4 weeks, in combination with

Oral hydroxychloroquine, first 4 weeks 2 × 200 mg daily, thereafter 200 mg daily (Fig. 3.19a–c)

May be combined with 1,200 IU vitamin E and 500 mg vitamin C daily (in smokers)

Photoprotection

Folliculitis decalvans

Oral fusidic acid 3 × 500 mg daily for 3 weeks, in combination with

Oral zinc gluconate 30 mg daily for months (Fig. 3.20a–c)

Oral rifampicin 450 mg twice daily in combination with oral flucloxacilline 500 mg four times daily for 2 weeks and thereafter every 3 months for 5 days

Oral rifampicin 300 mg twice daily in combination with oral clindamycin 300 mg twice daily during 10 weeks

Daily antiseptic shampoo treatment with 0.2–2 % chlorhexidine gluconate

Surgical reduction of patches of scarring alopecia or selective punch excision of hair tufts may be taken into consideration (during oral antibiotic treatment)

Central centrifugal cicatricial alopecia (black women)

Compound of topical 5 % minoxidil and 0.2 % triamcinolone acetonide, first month twice daily, thereafter once daily, thereafter every second day alternating with topical 5 % minoxidil, in combination with

Oral doxycycline 100–200 mg daily for 3–6 months (Fig. 3.21a, b)

Avoid traction, chemicals, and heat

Tinea capitis (children)

Systemic antimycotic treatment, in case of endotrich infection with Trichophyton spp. with oral terbinafine 6 mg/kg body weight per day for 2–4 weeks, in case of exotrich infection with Microsporum spp. with oral itraconazole 5 mg/kg body weight per day for 4–6 weeks, in combination with

Topical antimycotic treatment, either as shampoo (selenium disulfide, ketoconazole, or povidone iodine) or topical antimycotic agent (ciclopiroxolamine, an imidazole, or terbinafine)

May combine oral prednisone 1 mg/kg body weight per day for 1–2 weeks in case of deep inflammatory tinea (Kerion)

Combine with oral antibiotic, preferably an oral macrolide antibiotic, if secondary pathogenic bacterial infection is present

Check for carrier status for sanitation of family members or pets, depending on anthropophilic or zoophilic fungal agent, resp., detected in mycologic culture

Table 3.5

Causes for dystrophic anagen effluvium

Antineoplastic drugs (chemotherapy-induced alopecia)

X-ray (radiation-induced alopecia)

Environmental or occupational exposure to toxins (toxic alopecia)

Immunologic injury (alopecia areata)

Early treatment of fibrosing alopecia in a pattern distribution with a compound of 5 % topical minoxidil and 0.2 % triamcinolone acetonide may be quite rewarding. The addition of 5 mg oral finasteride or 0.5 mg oral dutasteride in postmenopausal women is optional, as well as the addition of an oral anti-inflammatory agent, such as hydroxychloroquine or doxycycline (Fig. 3.14a–d).

Fig. 3.14

(a–d) Successful treatment of fibrosing alopecia in a pattern distribution with a topical compound of 5 % minoxidil and 0.2 % triamcinolone acetonide and oral hydroxychloroquine 200 mg daily, (a) before, after (b) 3 months, (c) 6 months, and (d) 12 months treatment

Dissecting the molecular controls of immune-mediated, physiological hair follicle degeneration by apoptosis-mediated organ deletion could provide insights into how progression of some forms of permanent alopecia might be halted, which can be suppressed with only limited success by current treatment modalities. This could also hold true for further studies in androgenetic alopecia with inflammatory phenomena and fibrosis.

3.9.4 Inflammatory Scarring Alopecias

Written documents of the importance of making a distinction of scarring from non-scarring alopecia are as old as the Old Testament (Leviticus 13:40–42):

If a man’s hair has fallen from his head, he is bald but he is clean.

And if a man’s hair has fallen from his forehead and temples,

he has baldness of the forehead but he is clean.

But if there is on the bald head or the bald forehead a reddish-white diseased spot, it is leprosy breaking out on his bald head or his bald forehead. In that case the priest shall examine him

(Comment: Biblical leprosy or tzaraath, תערצ, does not refer to what we call Hansen’s disease today, but to any form of terrible skin disease.)

The scarring alopecias are both a diagnostic and therapeutic challenge to the practitioner. The irreversibility and the possible important cosmetic consequences of scarring alopecia demand special diagnostic attention in order to promptly attain a precise diagnosis and specific treatment.

Loss of follicular orifices in an area of alopecia points to a permanent loss of hair, either due to permanent damage to essential parts of the hair follicle or destruction of the entire hair follicle. Where there is no obvious physical/chemical injury or acute infectious etiology, clinical differential diagnosis of scarring alopecia is often difficult. The clinical inspection is of limited usefulness in establishing a diagnosis. Overlapping features may blur the distinction between different diseases; moreover, these share the common final pathway of replacement of follicle by fibrous tissue. Finally, there is no characteristic biological marker for most entities. Accurate diagnosis based on a careful patient history, clinical examination, microbiological studies, and scalp biopsy is a prerequisite to therapy.

Problems inherent to scalp biopsies are a reluctance of many practitioners in performing them and a lack of familiarity of many pathologists with scalp histopathology. Ultimately, it must be borne in mind that the hair follicle and its derangements are complex and dynamic. A biopsy gives only a momentary snapshot of the underlying pathology.

Scarring alopecias may be due to hereditary or developmental defects. Examples of these rare conditions are aplasia cutis congenita, organoid nevi, hereditary epidermolysis bullosa, alopecia ichthyotica, and the follicular keratosis syndromes.

More frequently they are due to acquired, irreparable destruction of critical hair follicle structures (follicular sheath, stem cells, follicular papilla, and their interaction), or of the whole hair follicle. The acquired scarring alopecias are further differentiated into primary and secondary scarring alopecias:

· Primary scarring alopecia is due to preferential destruction of the follicle. Well-defined, chronic inflammatory diseases of the scalp amenable to specific therapies are differentiated microscopically from a morphologic point of view on the basis of the pattern of inflammation and the type of inflammatory cell that predominates (see Table 3.3).

· In a study of 136 scalp biopsies obtained for histopathology and direct immunofluorescence studies, we found lichen planopilaris (28 %), folliculitis decalvans (23 %), chronic cutaneous lupus erythematosus (21 %), and pseudopelade of Brocq (10 %) to be the most prevalent:

· Lichen planopilaris is the most common cause of scarring alopecia in the adult. It presents with pruritic central or multifocal alopecic patches with follicular hyperkeratosis and erythema at the hair-bearing margin (Fig. 3.15a). Histopathology reveals a lymphocytic primary scarring alopecia. Non-scalp involvement (mucous membranes, glabrous skin, nails) may be present. The Lassueur–Graham Little–Piccardi syndrome is considered a disseminated variant, Kossard’s frontal fibrosing alopecia and Zinkernagel and Trüeb’s fibrosing alopecia in a pattern distribution as patterned variants of lichen planopilaris.

Fig. 3.15

(a–c) Primary scarring alopecias: (a) Lichen planopilaris. (b) Cutaneous lupus erythematosus. (c) Folliculitis decalvans

· Chronic cutaneous or discoid lupus erythematosus presents as symptomatic, erythematous scaly plaques with follicular plugs, telangiectases, atrophy, and depigmentation with time (Fig. 3.15b). In contrast to lichen, planopilaris activity tends to be in the center of alopecic patches. Histopathology again reveals a lymphocytic primary scarring alopecia. Non-scalp involvement may be present, since lupus erythematosus may represent a systemic autoimmune inflammatory disease.

· Folliculitis decalvans represents a chronic and recurrent pustulofollicular scalp infiammation resulting in scarring alopecia. It usually presents in the central scalp area with exsudative crusted areas and grouped follicular pustules at the hair-bearing margin with centrifugal progression (Fig. 3.15c). Invariably pathogenic strains of Staph. aureus can be detected. Very rarely there may be an association with immune deficiency. Histopathology reveals a neutrophilic primary scarring alopecia.

· Pseudopelade as first described by Brocq in 1888 and redefined by Bergner and Braun-Falco presents with asymptomatic, noninflamed, ivory-white- or flesh-colored small oval-round, reticulate, or large, irregular patches of the central scalp area (see Fig. 2.9). Non-scalp involvement is absent. It is considered a lymphocytic primary scarring alopecia with selective destruction of hair follicles. It is clinically and histologically indistinguishable from end-stage lichen planopilaris.

· Secondary scarring alopecia results from events outside the follicle, which eventually impinge upon and eradicate the follicle. These include physical or chemical injury, infectious diseases (fungal, bacterial, viral), granulomatous disease (sarcoidosis: Fig. 3.16a, necrobiosis lipoidica/Miescher’s granulomatosis disciformis progressiva: Fig. 3.16b) or neoplastic processes (primary or metastatic solid tumors, malignant lymphoma), and autoimmune diseases, such as circumscribed scleroderma in the young (Fig. 3.16c) and cicatricial pemphigoid (Fig. 3.16d) or necrotizing temporal arteritis in the elderly (Fig. 3.16e).

Fig. 3.16

(a–e) Secondary scarring alopecias: (a) Sarcoidosis. (b) Necrobiosis lipoidica (Miescher’s granulomatosis disciformis progressive). (c) Circumscribed scleroderma (en coup de sabre). (d) Cicatricial pemphigoid (Brunsting–Perry syndrome). (e) Temporal arteritis (Horton’s disease)

· Finally, pseudopeladic state of Degos (1954) represents the nonspecific end stage of a variety of at least 60 types of primary or secondary cicatricial alopecias, whereby: Pseudopelade of Brocq(1905) probably represents the end stage or a variant of lichen planopilaris, Sperling’s central centrifugal scarring alopecia (2000) with its predilection for African–Americans and close relationship to LoPresti’s hot comb alopecia (1968) a USA-specific perspective of Degos’ pseudopeladic state due to peculiarities of African–American hair grooming habits and hair anatomy, and Alopecia parvimaculata Dreuw (1911) possibly the pediatric variant of Degos’ pseudopeladic state.

The relationship of the different groups of scarring alopecia is graphically summarized in Fig. 3.17.

Fig. 3.17

Overview of scarring alopecias. Abbreviations: LPP lichen planopilaris, CCLE chronic cutaneous lupus erythematosus, FD folliculitis decalvans, DC dissecting cellulitis, KFSDkeratosis follicularis spinulosa decalvans, FSD folliculitis spinulosa decalvans, FK folliculitis keloidalis, FN folliculitis necrotica, EPD erosive pustular dermatosis

Fig. 3.18

Successful treatment of scarring alopecias: (a, b) Lichen planopilaris. Surgical reduction of patch of scarring alopecia under immunosuppressive therapy with oral cyclosporine A (Courtesy of Dr. B. Banholzer)

Fig. 3.19

Successful treatment of scarring alopecias: (a–c) Chronic cutaneous lupus erythematosus. Treatment with oral hydroxychloroquine and intralesional triamcinolone acetonide, (a) before, (b) after 3 months, and (c) after 6 months of treatment

Fig. 3.20

Successful treatment of scarring alopecias: (a–c) Folliculitis decalvans. Treatment with oral fusidic acid, oral zinc gluconate, and daily antiseptic washings with a shampoo containing 2 % chlorhexidine gluconate, (a) before, (b) after 1 month, and (c) with a wig

Fig. 3.21

(a, b) Central centrifugal cicatricial alopecia. Treatment with 100 mg oral doxycycline and a compound of topical 5 % minoxidil and 0.2 % triamcinolone acetonide, avoidance of traction, chemicals, and heat, (a) before and (b) after 2 months treatment

3.9.5 Treatment

The goal of therapy is mostly to halt further progression. Problems related to the treatment of the scarring alopecias include patients’ delay, when irreversible scarring has already occurred. Since the causes are mostly unknown, therapy has remained empiric and nonspecific. Published data on recommended therapies have usually low levels of evidence. Recommended treatment regimens for the most prevalent among the infiammatory scarring alopecias in women are summarized in Table 3.4.

Management of less well-classified entities, such as pseudopelade of Brocq, alopecia parvimaculata of Dreuw, and pseudopeladic state of Degos, is problematic, since the etiologies are varied or not understood and hair loss is permanent. Where end-stage fibrosis is established, surgical treatment or prosthetic help is taken into consideration.

With the expanding knowledge of the biology of hair growth and immunological phenomena of the hair follicle, there is hope for the feasibility of therapeutic interventions that interfere early in the course of the pathogenetic processes ultimately leading to permanent hair loss.

3.9.6 Alopecia Neoplastica

A type of secondary scarring alopecia of particular relevance to female alopecia is alopecia neoplastica, since cutaneous metastasis of breast carcinoma represents the single most frequent tumor underlying alopecia neoplastica.

By definition, alopecia neoplastica is hair loss secondary to a visceral malignancy that has metastasized to the scalp. In an observation of 25 women with alopecia neoplastica, breast cancer was the primary malignancy in 84 % of patients. Other primary tumors whose metastases presented as neoplasm-related hair loss were gastric carcinoma, colon carcinoma, cervical carcinoma, and trophoblastic tumor. The clinical presentation may mimic alopecia areata (Fig. 3.22). The suspicion must remain high, and a scalp biopsy will reveal the diagnosis. At times, the diagnosis of alopecia neoplastica may antedate the diagnosis of the underlying malignancy.

Fig. 3.22

Alopecia neoplastica (cutaneous metastasis of breast carcinoma)

3.10 Traumatic Alopecia

Traumatic alopecia is classified with respect to the type of trauma, localization, and pattern within the hairy scalp. With respect to the type of trauma, it has been classified into cosmetic traumatic alopecia, accidental traumatic alopecia, and trichotillomania. Depending on the stress on hair through hairdressing customs, there is a wide variety in cosmetic traumatic alopecia. The localization of traction alopecia may be marginal or non-marginal, and, depending on the traction lines on the scalp, frontomarginal and ophiasiform patterns of marginal traction alopecia may be differentiated, respectively, linear and patchy types of non-marginal traction alopecia.

3.10.1 Traction Alopecia

Traction alopecia is defined as hair loss resulting from either prolonged or repetitive pulling force to the hair. Clinically, traction alopecia most often affects the frontal and temporal scalp areas. However, it has been extensively reported in the literature to occur on many different regions of the scalp, depending on an individual’s hair grooming practices, which may or may not be related to the ethnic or cultural background.

The condition was originally described in female subjects in Greenland who developed hair loss along the hairline from wearing tight ponytails. In 1958, Slepyan reported alopecia in American girls wearing ponytails and stated that the patches of baldness need not be limited to the margins of the scalp, since alopecia may occur along any line of traction. Traction alopecia is also seen occasionally in long-haired people who use barrettes to keep the hair out of their faces.

The more recent literature has focused on traction alopecia from African hair-braiding styles (Fig. 3.23a). It has been pointed out that in African females, the likelihood of developing traction alopecia increases when traction is applied to chemically processed hair.

Fig. 3.23

Traction alopecia: (a) Resulting from African hair-braiding styles. (b) The fringe sign

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The risk of developing traction alopecia increases in the presence of androgenetic alopecia and with age.

With androgenetic alopecia, the hair seems to be less resistant to traction, while with age traction alopecia is likely to result from a longer history of the aforementioned hair practices.

Finally, the risk of developing traction alopecia is substantial in hair weaves that are worn to conceal hair loss, usually resulting from androgenetic alopecia. Hair weaving involves creating a braid around the head below the existing hairline, to which a hairpiece is attached. Since the hair of the braid is still growing, it requires frequent maintenance, which involves the hairpiece being removed, the natural hair braided again, and the piece tightly reattached. The tight braiding and snug hairpiece cause tension on the hair that is already at stake.

Traction alopecia generally does not present any diagnostic difficulties, provided the possibility is considered. Diagnostic challenges may be encountered if the clinical suspicion is not high or if no history of traction is obtained. Traction alopecia of the marginal hairline may be misdiagnosed as ophiasis pattern alopecia areata or frontal fibrosing alopecia, while the differential diagnosis of patchy alopecia includes alopecia areata or the inflammatory scarring alopecias.

The earliest clinical manifestation of continuous traction on hair is perifollicular erythema. Occasionally keratin cylinders may surround the hairs just above the scalp surface. Not infrequently, patients complain of localized dandruff with itching. Eventually the erythema around the follicles will evolve into folliculitis, and minute folliculopustules may become evident. In general, patients who develop any symptoms, including pain, pimples, stinging, or crusts with hairdressing are at increased risk of developing traction alopecia. The process gradually leads to loss of hair, which becomes irreversible after sustained traction. By the time the alopecia is evident, the scalp usually no longer shows inflammatory changes. Although the hair loss has become permanent, the skin does not have the quality common to the usual types of cicatricial alopecia, remaining soft and pliable. On close inspection there is a decrease in the density of follicular orifices.

In traction alopecia of the marginal hair line, Mirmirani et al. made the observation that the presence of retained hairs along the frontal and/or temporal rim, which they termed the fringe sign (Fig. 3.23b), may be a useful clinical marker seen in 85 % of women with the condition.

Treatment of traction alopecia depends on whether or not long-standing traction has resulted in permanent loss of hair. Accordingly, management of traction alopecia is divided into prevention and treatment of early and of long-standing disease.

Prevention is key in girls and involves educating parents on the importance of loosening the hairstyle. Brushing the affected area with the misbelief of stimulating hair growth should be avoided as well. In adults with early traction alopecia, the hairstyle should also be loosened. Moreover, chemicals or heat are to be avoided. Intralesional triamcinolone and oral tetracycline antibiotics may be beneficial in suppressing perifollicular inflammation, while added topical minoxidil may promote hair growth in some patients. Ultimately, with long-standing disease surgical procedures, such as hair transplants in the form of micrografting, mini-grafting, and follicular unit transplantation may be considered.

3.10.2 Chignon Alopecia

In 1931, Sabouraud first described, under the French designation alopécie du chignon, a type of alopecia associated with the wearing of a chignon. In contrast to marginal traction alopecia, chignon alopecia would occur occipitally where the bun rested on the scalp (Fig. 3.24). The cause appears to be traction and twisting of the hair necessary to form and maintain a bun. Sabouraud failed to recognize the traumatic origin of both alopécie liminaire frontale (marginal frontal alopecia) and alopécie du chignon.

Fig. 3.24

Chignon alopecia

We reported three women with localized alopecia of the occipital scalp associated with the wearing of a chignon. They had previously been uniformly misdiagnosed as having alopecia areata. Chignon alopecia should be ruled out when the diagnosis of persistent alopecia areata at the level of the lambda is considered. The typical patient is a woman over 40 years of age who has been wearing a chignon for a prolonged time. As illustrated in Sabouraud’s textbook on hair “Diagnostic et Traitement des Affections du Cuir Chevelu” (1932), frontomarginal traction alopecia may also result from the wearing of a chignon, since the frontomarginal scalp is the area in which the roots of the longest hairs are drawn taut in making the bun. Therefore, it is not unusual to encounter both frontotemporal and non-marginal occipital alopecia in the same patient, raising the index of suspicion for a traumatic origin of an occipital patch of baldness.

When the condition is long standing, there is follicular atrophy and fibrosis resulting in permanent alopecia. A distinctive histopathologic finding is perifollicular fibrosis extending into the subcutaneous fat.

The condition may be treated by scalp reduction surgery.

3.10.3 Postoperative Pressure Alopecia

Postoperative pressure alopecia represents yet another form of traumatic alopecia of localized to the occipital scalp. Patients typically complain of occipital pain and tenderness within 24 h of surgery. Signs observed within the first week after surgery may be focal swelling, edema, crusting, and ulceration. The hair loss is of the dystrophic anagen effluvium type, sets in between 2 and 3 weeks after surgery, and is complete within 28 days (Fig. 3.25).

Fig. 3.25

Postoperative pressure alopecia

Postoperative pressure alopecia has been originally reported after open cardiac surgery and certain gynecologic surgery and is now increasingly observed following lengthy plastic surgical procedures. It occurs after prolonged pressure on the scalp during general anesthesia with intubation, with the head fixed in one position, and understood to be due to pressure-induced ischemia.

Risk factors for hair loss and scarring include length of the anesthesia, prolonged endotracheal intubation, prolonged head immobilization, intraoperative use of the Trendelenburg position, and additional factors potentially aggravating ischemia of the scalp, such as severe hypotension, massive blood loss, and use of vasoconstrictors.

The single most important aspect of prevention of this complication of surgery is knowledge of its existence and pathophysiology. A prospective study that incorporated head repositioning every 30 min in cardiac surgical patients significantly reduced the incidence of alopecia from a prospectively determined value of 14 % to 1 %.

Fortunately, the condition is self-limiting in most cases with spontaneous regrowth of hair occurring within 3 months. In case of necrosis, ulceration, and scarring, the alopecia is permanent.

3.11 Trichotillomania and Related Disorders

It is a common experience among dermatologists that significant numbers of their patients have psychological overlays to their chief complaints. This particularly holds true for complaints related to conditions of the hair and scalp. The exact incidence in any particular dermatologic practice most likely depends on the dermatologist’s interest. However, even for those dermatologists who are not specially interested in the psychological aspects of dermatologic disease, some patients have such overt psychopathologic conditions, such as trichotillomania, factitial dermatitis, or delusions of parasitosis, that even the least psychologically minded dermatologist feels obliged somehow to address the psychological issues. Ideally, this would be accomplished simply through referral of the patient to a mental health professional.

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In reality, the majority of psychodermatologic patients are reluctant to be referred to a psychiatrist.

Many lack the insight regarding the psychological contribution to their dermatologic complaints; others fear the social stigmatization of coming under the care of a psychiatrist.

The dermatologist is often the physician designated by the patient to handle their chief complaint, even if the main disorder is a psychological one. Therefore, it is essential for dermatologists dealing with such patients to expand their clinical acumen and therapeutic armamentarium to effectively handle the psychodermatologic cases in their practice. To accomplish this goal, the following steps are required:

Any form of self-inflicted lesions, excluding injuries produced accidentally through physical or chemical cosmetic procedures, is aberrant. The most frequent form of deliberate harm to the scalp consists of plucking the hair. Hallopeau is given credit for describing the clinical syndrome of hair loss resulting from the repetitive pulling and plucking of one’s own hair. In 1889 he termed this syndrome trichotillomania. In 1902, Raymond referred to this syndrome as tic d’épilation, Sutton (in 1916) as trichorrhexomania, and Sabouraud (in 1936) as idiopathic trichoclasia. Besnier, in discussing Hallopeau’s case, noted associated trichophagy (the practice of eating hair) in an affected infant.

Other forms of self-inflicted injuries of the scalp include neurotic excoriations, excoriations resulting from delusion of parasitosis (Ekbom’s disease), and factitial dermatitis (Munchausen’s syndrome).

3.11.1 Trichotillomania

Trichotillomania involves the repetitive, uncontrollable pulling of one’s hair, resulting in noticeable hair loss. It represents a disorder of impulse control. The disorder usually begins between early childhood and adolescence. It occurs six to seven times more frequently in children than in adults, before the age of 6 males predominate, thereafter females.

Most commonly, scalp hair is pulled, resulting in ill-defined areas of incomplete hair loss. In the affected areas, there are different lengths of hair, short, longer, and normal. When the hair is pulled in the centroparietal area of the scalp, sparing the lateral margins and the nape of the neck, a tonsural pattern may result that has been termed tonsure trichotillomania (see Fig. 2.8a).

In younger children, trichotillomania results from a mild form of frustration in a climate of psychosocial stress and soon becomes a habitual practice.

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From puberty onwards, trichotillomania is related to more severe pathologic psychodynamics, and prognosis is more guarded, particularly tonsure trichotillomania in the female adolescent.

The most important differential diagnosis is alopecia areata. Trichotillomania in connection with alopecia areata may pose a special diagnostic challenge. It may result from scratching at the site of alopecia areata that is symptomatic with pruritus, initiating a habit-forming behavior. Alternatively, patients with a mental predisposition may artificially prolong the disfigurement as the hair on the bald patches of alopecia areata regrows, with the aim to maintain gratification of dependency needs, which were being met during alopecia areata.

Traumatic alopecia due to child abuse (battered child) is – though uncommon – yet another important differential diagnosis to take into consideration in a child with unexplained hair loss and other signs of physical trauma (Fig. 3.26).

Fig. 3.26

Traumatic alopecia due to child abuse (battered child). Note hematoma in the face

Associated features of trichotillomania may include excoriations of the scalp, nail biting (onychophagy), and eating hairs (trichophagy) with the risk of gastrointestinal obstruction by a mass of hair (trichobezoar), a complication that has been termed the Rapunzel syndrome.

Parents seldom notice their child’s behavior, and most of them do not believe that their child would pull out his or her own hair. Once the diagnosis is suspected, it is confirmed in the following way:

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Children with trichophagy should be screened for iron deficiency as part of their evaluation, since the association of pica – an unusual craving for nonfood items – and iron deficiency has been reported. The compulsive oral behavior characteristically resolved with the oral administration of therapeutic doses of iron. It must be kept in mind though that iron deficiency may either be a cause of trichophagy or result from gastrointestinal bleeding in the case of trichobezoar.

3.11.1.1 Treatment

The primary treatment approach for trichotillomania is habit reversal combined with stress management and behavioral contracting. Parents can help by recognizing the problem in its early stages and getting involved in its treatment. Treatment may involve self-monitoring of hair-pulling episodes as well as the feelings and situations that are most likely to lead to hair pulling. Youngsters are then systematically introduced to new behaviors; for example, squeezing a ball or tightening their fist whenever they feel the urge to pull at their hair. Relaxation training and other stress-reduction techniques may also be used, including reward charts that help track and monitor a child’s progress with the added incentive of earning small rewards for continued progress. In addition, cognitive therapy is found to be effective.

The younger the patient, the smaller the percentage of cases referred to a psychiatrist; the rest are treated by the dermatologist who applies his or her own psychiatric knowledge (liaison psychiatry). A proper follow-up is required to establish whether improvement has actually occurred. When the symptom is present in adolescents or adults, competent help from a psychiatrist should be sought.

In a dermatologic setting, a pharmacologic approach may be most feasible for patients who refuse to be referred elsewhere. Basically, the same pharmacologic agents are used for the treatment of trichotillomania as for obsessive–compulsive disorder: the older tricyclic antidepressants imipramine and clomipramine and the newer selective serotonin reuptake inhibitors (SSRIs) fluoxetine, fluvoxamine, sertraline, and paroxetine. Physicians using SSRIs for treatment of patients with obsessive–compulsive disorders or trichotillomania are cautioned that the duration of treatment is critical in determining adequate treatment. Improvement continues to occur when the drugs are taken beyond 8- or 12-week trials. A patient showing a partial response after 4–6 weeks would be expected to continue to improve during the following weeks. Cessation of pharmacotherapy results in a relapse on the majority of patients. Despite success with SSRIs, patients with obsessive–compulsive disorders tend to respond to medication with only partial symptom reduction, suggesting that obsessive–compulsive disorders may be a neurobiological heterogeneous disorder that may require alternative treatment options in the individual patient. For example, successful treatment of five adult trichotillomania patients with a combination of the SSRI escitalopram with the anticonvulsant topiramat was recently reported.

With regard to prognosis, two types of trichotillomania are generally recognized: a temporary localized infant and childhood pattern with a good prognosis (epilation tic) and a severe adult form typically occurring in young women, in which the affected area is more widespread and the prognosis is guarded (tonsure trichotillomania).

3.11.2 Neurotic Excoriations of the Scalp

The term neurotic excoriations refers to patients with self-inflicted excoriations of the scalp in the absence of an underlying specific dermatologic disease condition. The etiology is varied, and psychiatrically, patients with neurotic excoriations are not a homogenous group, each requiring an individual therapeutic approach.

The condition may occur at any time from childhood to old age, with the most severe and recalcitrant cases reportedly starting in the third to fifth decade.

Because the patients, by definition, can inflict lesions only on those areas of the body that can be reached, and because patients tend to excoriate areas that are easily accessible, the clinical distribution of lesions besides the scalp can give a clue to the diagnosis. The lesions may affect the scalp in an isolated manner, or may be associated with excoriations of the face, and/or of the upper trunk and extensor aspects of the arms. The excoriations may be initiated by minor irregularities of the skin surface, such as a keratin plug, insect bite, acne papule (acne excoriée), or irritated hair follicle, or may start de novo. There is a decreased threshold for itch with tendency to habitual or neurotic scratching. Picking activity may start inadvertently as the hand comes across on an irregularity of the skin, or it may occur in an organized and ritualistic manner, sometimes using an auxiliary instrument, such as the point of a knife. Tissue damage itself may again trigger itching, and the itch–scratch cycle may take on a life of its own. This activity typically takes place when the patient is unoccupied, and precipitating psychosocial stressors are usually present.

Neurotic excoriations occur across the spectrum of psychopathology. In mild and transient cases, it may be a response to stress, particularly in the younger patient, such as examination stress (thinker’s itch), mainly in someone with obsessive–compulsive personality traits. In the more severe and sustained cases, psychiatric evaluation may diagnose a generalized anxiety disorder (DSM-IV 300.02, ICD-10F41.1), depression (DSM-IV 300.4, ICD-10F34.1), or obsessive–compulsive disorder (DSM-IV 300.3, ICD-10F42.x).

The inflicted lesions are rather nonspecific. Varying in size from a few millimeters to several centimeters in the well-developed case, lesions are seen in all stages of evolution, from small superficial saucerized excoriations through deep scooped-out skin defects (Fig. 3.27a) to thickened hyperpigmented nodules and finally hypopigmented atrophic scars. Secondary bacterial infection may lead to regional lymphadenopathy. The histology is that of an excoriation with nonspecific inflammatory changes. Microbiological studies may reveal secondary bacterial infection, usually with Staph. aureus.

Fig. 3.27

Psychodermatologic presentations on the scalp: (a) Neurotic excoriations of the scalp. (b) Factitial dermatitis of the scalp. (c) Trichoteiromania. (d) Letter from a patient with overvalued ideas concerning her hair shedding

Since other dermatologic conditions can lead to similar lesions, clinicians must be careful not to make this diagnosis on the basis of the morphology of lesions alone. Specifically, pruritic skin conditions of dermatologic or other origin need to be excluded. Examples are atopic dermatitis, acne miliaris necroticans, chronic cutaneous lupus erythematosus, pemphigus vulgaris, pemphigoid, parasitic infestation, neurologic disorders, and other psychiatric disorders, such as cocaine intoxication, delusions of parasitosis, and factitial dermatitis.

Most importantly, one needs to confirm the diagnosis by ascertaining the presence of psychopathology through both clinical observation and direct patient questioning.

3.11.2.1 Treatment

Dermatologic treatment includes the prescription of nonirritating or sensitive shampoos, topical glucocorticoid-antibiotic cream preparations, and sedative antihistamines, such as hydroxyzine or doxepin, preferably given at nighttime. Cool compresses are soothing, provide hydration, and facilitate debridement of crusts. When followed by the application of an emollient, they reduce any contribution that xerosis makes to itching. When present, secondary bacterial infection must be treated appropriately, usually with a short course of oral antibiotics.

Psychiatric treatment includes nonpharmacologic and pharmacologic therapeutic options. In both, the choice of the appropriate technique or pharmacologic agent depends on the underlying mental disorder.

Although behavioral modification, cognitive psychotherapy, psychodynamic psychotherapy, and an eclectic approach have met with variable success, many patients who present to the dermatologist are reluctant to agree to the psychiatric nature of their skin disorder and lack insight into the circumstances that trigger the drive to excoriate. Unless the patient is managed in a liaison clinic where dermatologists and psychiatrists can confer, it is the dermatologist who will take the responsibility for treatment.

If the patient is suffering from excessive stress, there are specific and nonspecific approaches. Those individuals who can find specific, real-life solutions to the difficulties they report are the more fortunate ones. Many patients experience stress from work or home relationships for which there is no easy way out. For these patients, a nonspecific solution to the stress can still be beneficial. Among the nonspecific solutions to stress, there are nonpharmacologic and pharmacologic means. The nonpharmacologic means include exercise, biofeedback, yoga, self-hypnosis, progressive relaxation, and other techniques learned in stress-management courses. Some patients do not have time to take stress-management courses, and others have special difficulty benefiting from this type of approach, for example, those who are not psychologically minded. For these patients, cautious use of antianxiety agents may be an alternative. In general, there are two types of anxiolytics: a quick-acting benzodiazepine type that can be sedating and produce dependency, such as alprazolam, and a slow-acting non-benzodiazepine type that is not sedating and does not produce dependency, such as buspirone. Alprazolam differs from the older benzodiazepines such as diazepam and chlordiazepoxide because its half-life is short and predictable. Another advantage is that it has an antidepressant effect, whereas most other benzodiazepines generally have a depressant effect. Because of the possible risk of addiction with long-term use, the most prudent way of using alprazolam would be to restrict its use to 2–3 weeks. If the patient requires long-term therapy for anxiety, buspirone may be considered. However, it must be kept in mind that the effect of buspirone is usually not experienced by the patient for the first 2–4 weeks of treatment. Also, buspirone cannot be used on an as-needed basis. If buspirone does not work for a patient with chronic anxiety disorder, an alternative would be the use of low-dose doxepin. Even though doxepin is a tricyclic antidepressant, in low doses, it has been compared to benzodiazepines in terms of its anxiolytic effects. Sometimes, also a low dose of a low-potency antipsychotic agent such as thioridazine can be used.

Although there are a number of nonpharmacologic treatment options for depression, most dermatologists have neither the time nor the training to execute these treatment modalities. Nonetheless, it is advantageous to be conscious of these options, especially for those patients who agree to a referral to a mental health professional. Individual psychotherapy can be useful if there are definable psychological issues to be discussed, for example, frustrations at work, a maladaptive style in interpersonal relationships, and the presence of maladaptive views of oneself, such as unrealistic expectations or fear of failure. Other patients have neurobiological predispositions to depression, and their depressive episodes may not be associated with any identifiable psychosocial difficulties. For these patients, the use of specific psychopharmacologic agents may in fact correct the primary cause of their depression. There are a number of antidepressants to choose from for treatment of depression pharmacologically. Among the tricyclic antidepressants, again doxepin is probably the most suitable for treatment of depressed patients with neurotic excoriations. If the patient cannot tolerate the sedative side effect of doxepin, desipramine or one of the newer, nontricyclic antidepressants such as fluoxetine, sertraline, and paroxetine are alternatives.

Finally, for the obsessive–compulsive patient with neurotic excoriations, there are, once again, nonpharmacologic and pharmacologic therapeutic options. However, if the dermatologist were to follow a nonpharmacologic approach for patients who reject referral to a mental health professional, it would have to be a technique that is simple enough to perform in a dermatologic setting. One such technique is the invocation of a 1- or 5-minute rule, a simple behavioral technique to try to interrupt the progression from obsessive thoughts to compulsive behavior. The patient is asked to try to put an interval of 1–5 min between the occurrence of the obsessive thought and the execution of the compulsive behavior. Once the patient is successful in refraining for 1 min, the time is gradually increased to 5, 10, or even 15 min, and eventually, with such a long interruption between the obsessive thought and the compulsive behavior, one anticipates to break the natural progression from one to the other. In a dermatologic setting, the pharmacologic approach may be most feasible for patients who refuse to be referred elsewhere. Moreover, the recognition that serotonin pathways are involved and that the SSRI group of antidepressant agents reduces compulsive activity has made it more likely that the dermatologist will meet with success. Frequent short visits should be scheduled for supervision of the dermatologic regimen and for emotional support, and either clomipramine (an older antidepressant with extensive documentation about its anti-obsessive–compulsive efficacy in the medical literature) or one of the newer SSRIs (fluoxetine or fluvoxamine maleate) should be prescribed.

3.11.3 Factitial Dermatitis of the Scalp and Trichotemnomania

Factitial dermatitis (factitious disorder with physical symptoms: DSM-IV 300.19, ICD-10F68.1) is a condition in which the patient creates lesions on the skin to satisfy a psychological need of which he or she is not consciously aware; usually a need to be taken care of by assuming the sick role. Patients with factitious disorder or factitial dermatitis create the lesions for psychological reasons, and not for monetary or other discrete objectives as in the case of malingering (DSM-IV V65.2, ICD-10 Z76.5).

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Patients with factitial dermatitis knowingly fake symptoms but will deny any part in the process. They desire the sick role and may move from physician to physician in order to receive care.

They are usually loners with an early childhood background of trauma and deprivation. They are unable to establish close interpersonal relationships and generally have severe personality disorders. Unlike malingerers, they follow through with medical procedures and are at risk for drug addiction and for the complications of multiple operations. In the more severe form known as Munchausen syndrome or laparotomophilia migrans, a series of successive hospitalizations becomes a lifelong pattern.

Little is known about the etiology of factitious disorder. Besides the difficulties involved in making the diagnosis, the reluctance of these patients to undergo psychological testing and the heterogeneity in the details of cases published in the literature lie at the origin of this situation. Some clinicians have remarked that patients with factitious disorder often present traumatic events, particularly abuse and deprivation, and numerous hospitalizations in childhood, and as adults lack support from relatives and/or friends. The majority of patients suffer from borderline personality disorder. Because of emotional deficits in early life and a frequent history of physical or sexual abuse, patients have failed to develop a stable body image with clearly defined physical and emotional boundaries. For these patients, the factitial lesions serve many purposes: the excitement and stimulation ease the sense of emptiness and isolation, and skin sensation defines boundaries and helps establish personal and sexual identity, whereas the sick role gratifies dependency needs. In all reported series, females outnumber male patients from 3:1 to 20:1; onset is highest in adolescence and early adulthood, and a remarkably high number of patients work, or have a close family member working, in the health care field.

Factitial dermatitis of the scalp is only one aspect of the whole picture of factitious disease. The condition for which dermatologists are consulted often has already occasioned many visits to other physicians. The patient typically presents a bundle of normal investigative findings and a shopping bag filled with oral and topical medications. The lesions themselves are as varied as the different methods employed to create them; on the scalp there are usually ulcerations (Fig. 3.27b) or areas of cutoff hair (trichotemnomania). They are bizarre in shape and distribution and usually appear on normal skin. Though the possibilities are limitless, consistent is a hollow history – a term that refers to the patient’s vagueness and inability to give details of how the lesions evolved. Consistent also are the affect of both the patient and their family. Although the patient seems astonishingly unmoved by the lesions, the family is angry, accusatory, and critical of what they interpret as medical incompetence.

A number of dermatologic, neurologic, and mental disorders may share similar symptoms. Clinically the differential diagnostic considerations are determined by the morphology and cover the scope of clinical dermatology. Among the most important disorders affecting the scalp that have to be taken into consideration are necrotizing herpes zoster (shingles), temporal arteritis, angiosarcoma, neurotrophic ulcerations of the scalp, and neurotic excoriations of the scalp.

3.11.3.1 Treatment

The essential and probably most difficult step is to secure an enduring and stable patient–physician relationship. For achieving this goal most clinicians advocate a non-confrontational strategy reframing the factitious manifestation as a cry for help. An interesting approach is that of contract conference. In this approach the psychiatrist emphasizes the need for the patient to express him/herself in the common language of difficult relationships, feelings, and problems in living instead of the (factitious) language of illness. After that the patient and clinician can focus their efforts on resolving those real problems. Once a stable relationship is installed, the management of the disorder must be oriented to avoid unnecessary hospitalizations and medical procedures.

Another important issue in the management of this condition is recognition and adequate treatment of frequently associated disorders, such as personality disorders, depression, drug and/or alcohol abuse, and dependency.

Dermatologic treatment is symptomatic and determined by the clinical presentation. The uses of occlusive dressings are a diagnostic tool rather than an effective therapeutic intervention, since success is only of a temporary nature. Because of the patient’s intense emotional investment in their skin, it may be helpful to prescribe positive measures such as wet dressings, emollients, and other bland topicals to replace the prior destructive activity.

Some case reports focus on the use of pharmacological agents. A good response has been reported to the antipsychotic drug pimozide; other clinicians, because of the resemblance to the obsessive–compulsive disorder, advocate the use of clomipramine or the SSRIs fluoxetine and fluvoxamine maleate.

In the vast majority of patients, the condition remains chronic.

3.11.4 Trichoteiromania

Trichoteiromania is the term originally coined by Freyschmidt-Paul et al. in 2001 for breakage of hair by forcefully rubbing an area of the scalp. The typical clinical presentation is that of a bald patch with broken hairs (Fig. 3.27c). Subsequently, we reported four patients with trichoteiromania and further characterized them on the basis of clinical, morphological, and psychopathological criteria.

In contrast to trichotillomania, trichoteiromania has no diagnostic histopathologic features and a normal trichogram. Traumatic changes to the hair shaft are more conspicuous, with splitting at the ends of the hairs, giving the impression of white tips.

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The mental disorder underlying trichoteiromania varies among patients, though an underlying cutaneous sensory disorder, not explained through any specific dermato-logical disorder, is a common denominator in all cases.

While trichotillomania is considered to be an obsessive–compulsive disorder, the underlying mental disorder in trichoteiromania represents a more heterogeneous group, including anxiety, depression, or somatoform disorder.

In dermatology, the somatoform disorders consist of a heterogeneous pattern of differing clinical presentations based on a comparable emotional disorder; the characteristic of which is repeated presentation of physical symptoms in combination with a stubborn demand for medical examination, despite repeated negative results, and the physician’s assurance that the symptoms have no physical basis.

3.11.4.1 Treatment

Cooperation with the psychiatrist is indicated, as much as the management and prognosis of trichoteiromania again will depend on recognition of the underlying mental disorder and its specific psychotherapeutic and pharmacological treatment.

3.12 Imaginary Hair Loss (Psychogenic Pseudoeffluvium)

Patients with imaginary hair loss or psychogenic pseudoeffluvium are frightened of the possibility of going bald, or are convinced they are going bald without any objective findings of hair loss. Basically they suffer of what Cotterill has termed dermatologic nondisease. Although dermatologists are used to seeing patients with minor skin and hair problems in significant body areas that cause disproportionate anxiety and cosmetic distress, with dermatologic nondisease there is no dermatologic pathology.

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It is important to realize that imaginary hair loss only makes up for a minority of female patients complaining of hair loss and that patients with psychogenic pseudoeffluvium have varied underlying mental disorders.

The most common underlying psychiatric problems present are depressive disorder (DSM-IV 300.4, ICD-10F34.1) and body dysmorphic disorder (DSM-IV 300.7, ICD-10F45.2). The clinical spectrum is wide, and the majority of patients are at the neurotic end of the spectrum and merely have overvalued ideas about their hair, whereas a minority of patients are truly deluded and suffer from delusional disorder (DSM-IV 297.1, ICD-10F22.0). These patients lie at the psychotic end of the psychiatric spectrum. Those parts of the body that are important in body image are the focus of the preoccupation and concern. Female patients are more likely to be preoccupied with the condition of their hair.

True telogen effluvium resulting from androgenetic alopecia, chronic telogen effluvium, or from involutional alopecia must carefully be excluded.

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Differential diagnosis of psychogenic pseudoeffluvium is particularly challenging, since there is a considerable overlap between hair loss and psychological problems. Patients with hair loss have lower self-confidence, higher depression scores, greater introversion, as well as higher neuroticism and feelings of being unattractive.

A careful medical history, including medications, hormones, and crash diets, clinical examination of the hair and scalp (no alopecia, normal scalp), hair calendar (normal counts of hairs shed), trichogram (normal anagen and telogen rates), and laboratory workup (C-reactive protein, ferritin, basal thyroid-stimulating hormone, prolactin, estradiol, testosterone, and dehydroepiandrosterone sulfate or DHEA-S) should be performed to exclude real effluvium, and if necessary repeated.

It is important to question women who complain of excessive hair loss while no evidence of alopecia is evident on examination about depression and marital difficulties. In addition to the relentless complaint of hair loss, patients suffering from body dysmorphic disorder adopt obsessional, repetitive ritualistic behavior and may come to spend the majority of the day in front of a mirror, repeatedly checking their hair. Another aspect of this behavior is a constant need for reassurance about the hair, not only from the immediate family but also from the medical profession and from dermatologists in particular. These patients may become the most demanding types of patient to try to manage.

3.12.1 Treatment

The first step is to establish a good rapport with the patient. In trying to do so, it is important to recognize that patients with psychogenic pseudoeffluvium are expecting the clinician to treat them with respect as a trichologic patient, and not as a psychiatric case.

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The most effective approach to psychogenic pseudoeffluvium is to take the chief complaint seriously and give the patient a complete trichologic examination.

Patients with overvalued ideas may respond to a sympathetic and unpatronizing dermatologist.

Psychotherapy is aimed at any associated symptomatology of depression, regardless of whether there is a causal relationship between the psychiatric findings and the imagined hair loss, because it is possible that patients who are depressed perceive even normal hair shedding in an exaggerated manner.

Patients with anxiety related to the fear of hair loss may also benefit from anxiolytic therapy with alprazolam or buspirone.

Many different treatments have been advocated to treat patients with body dysmorphic disorder: A wide variety of psychotropic agents (including tricyclic antidepressants and benzodiazepines) and antipsychotic drugs (including pimozide and thioridazine) have been tried in this condition, with poor results. Although there have been no controlled clinical trials of treatment of patients with body dysmorphic disorder, preliminary data indicate that SSRIs, such as fluoxetine and fluvoxamine maleate, may be effective, though the effective dosage of the SSRI drugs needs to be higher than the dosage conventionally employed to treat depression and the duration of treatment is long term. Response to this group of drugs takes up to 3 months, and not all patients with body dysmorphic disorder will respond to treatment with SSRIs. In patients who fail to respond to SSRIs given for 3 months, it has been suggested to add either buspirone to the SSRIs, or if the patient has delusional body dysmorphic disorder, to add an antipsychotic agent such as pimozide.

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Patients with body dysmorphic disorder expect the solutions to their problems in dermatologic (trichotropic agents) or surgical terms (hair transplantation).

Accordingly, following an initial consultation, it is common for a patient with body dysmorphic disorder to be given dermatologic treatment, either various scalp applications or antiandrogen therapy for alopecia. After repeated consultations with the patient, the dermatologist realizes that he or she is dealing with dermatologic nondisease. The result is often a frustrated dermatologist and a patient who eventually defaults from follow-up. The long and tough consultations, repeated telephone calls, and constant need for reassurance can put a significant strain on the dermatologist involved. Finally, a minority of patients with dysmorphic body disorder are angry, and these patients can direct this anger not only at themselves but also at the attending physician, with reproachful letters (Fig. 3.27d), threats, and even physical violence. It is important not to reject these patients and treat them mechanistically but to adopt an empathetic approach.

The prognosis depends on the underlying psychopathology, its appropriate treatment, and the attending physician’s capability to reassure and guide the patient.

3.13 Trichodynia and Red Scalp

Trichodynia and red scalp are frequent complaints encountered in women otherwise complaining of hair loss. In contrast to the hair loss, the underlying pathomechanisms of trichodynia and red scalp are less understood, which is probably the main reason for the fact that these complaints are often either ignored by the physician or inadequately treated, usually under the presumption of a seborrheic dermatitis-like condition.

3.13.1 Trichodynia

The term trichodynia was proposed for discomfort, pain, or paresthesia of the scalp related to the complaint of hair loss.

Rebora found that 34.2 % of female patients, who had their hair consultation because of hair loss, complained of this phenomenon. In a subsequent survey, Grimalt et al. claimed that 22.1 % of their female patients reported trichodynia.

The cause of trichodynia is not understood, though it has been proposed that it is probably polyetiologic.

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The most prevalent speculations with respect to the pathogenesis of trichodynia are perifollicular inflammation, increased expression of neuropeptide substance P localized in the vicinity of hair follicles, and underlying psychiatric disorders.

Originally, trichodynia was reported to be more prevalent in female patients with chronic telogen effluvium and to a lesser extent in patients with androgenetic alopecia. Rebora et al. proposed the symptom to be distinctive for chronic telogen effluvium.

Our study on 403 patients (311 female, 92 male) whose main complaint was hair loss confirms the previously published findings in the literature that trichodynia affects a significant proportion of patients complaining of hair loss. The aim of our study was to assess the frequency of trichodynia in patients complaining of hair loss and its correlation with gender, age, and cause and activity of hair loss. In our series, we found that 17 % of patients complaining of hair loss, that is, 20 % of female and 9 % of male patients, reported hair pain, pain or discomfort of the scalp, not otherwise explained by presence of a specific dermatologic disease, such as psoriasis or eczema, or neurologic disorder, such as migraine equivalent.

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Statistical analysis failed to demonstrate any significant correlation between trichodynia, the extent of hair thinning, and hair loss activity quantified by the hair pull, daily hair count, wash test, and trichogram. It is noteworthy though that trichodynia typically increases the anxiety related to the patient’s preoccupation with hair loss or fear of hair loss.

As opposed to the suggestion of Rebora et al. that trichodynia would be typical for chronic telogen effluvium, in our series the symptom did not allow any discrimination with respect to the cause of hair loss and was found with similar frequencies in association with androgenetic alopecia, chronic telogen effluvium, or a combination of both.

The cause of trichodynia remains obscure. Rebora et al. proposed a possible role of perifollicular microinflammation. Hoss and Segal interpreted scalp dysesthesia as a cutaneous dysesthesia syndrome related to underlying psychiatric disorders, with affected individuals either suffering of depressive, generalized anxiety, or somatoform disorder. Hordinsky and collaborators found localization of the neuropeptide substance P in the scalp skin of patients with painful scalp suggesting a causal relationship between the presence of substance P and trichodynia. Substance P represents a neuropeptide involved in nociception and neurogenic inflammation.

We proposed that trichodynia probably is polyetiologic. Though only a small number of patients with trichodynia in our series showed telangiectasia of the scalp, this finding strongly correlated with presence of trichodynia. An interesting analogy is the observation of Lonne-Rahm et al. who found that patients with the telangiectatic variant of rosacea respond more frequently with stinging sensations to the topical application of 5 % lactic acid on the cheeks than patients with the papulopustular type of rosacea or normal controls. On the basis of these findings, they concluded that the blood vessels are of importance in stinging sensations and a connection exists between sensory or subjective irritation and cutaneous vascular reactivity. Also the observation of development of cutaneous allodynia during a migraine attack provides clinical evidence for the relation of vascular changes and pain.

In this context, it is interesting to note that substance P not only represents an important mediator of nociception and neurogenic inflammation but also exerts a potent vasodilatatory effect. The role of substance P and related substances (neuropeptides) in the pathogenesis of trichodynia, and especially its relation to the nervous system and emotional stress, needs further elucidation. By the virtue of their bidirectional effects on the neuroendocrine and immune systems, substance P and other neuropeptides may well represent key players in the interaction between the central nervous system and the skin immune and microvascular system. Such mechanisms would explain the noxious effects not only of external stimuli (mechanical, thermal, chemical) but also of emotional distress on cutaneous nociception through the release of neuropeptides, such as substance P. Interestingly, Paus and collaborators have recently demonstrated that stress-induced immune changes of the hair follicles in mice could be mimicked by injection of substance P in non-stressed animals and were abrogated by selective substance P receptor antagonism in stressed animals.

A higher prevalence of female patients might be connected to gender-related differences in pain perception, in as much as increase of pain perception in relation to anxiety scores has been found to be more pronounced in females. Trichodynia tends to affect the centroparietal area of the scalp, seemingly surprising since the pain threshold of the centroparietal scalp is otherwise considered to be higher.

3.13.1.1 Treatment

In the absence of any other specific morphologic changes of the scalp or correlation with quantitative parameters of hair loss, management of trichodynia remains empiric and empathetic, tailored to the individual patient’s needs. The therapeutic choice includes nonirritating shampoos, topical antipruritic or anesthetic agents, topical capsaicin, corticosteroids, tricyclic antidepressants, and gabapentin. The future role of antidepressants on the basis of selective substance P-inhibition (MK-869) for treatment of trichodynia will be interesting.

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As a general rule, topical overtreatment of the scalp is to be avoided. Most importantly, the patient needs to be reassured that trichodynia does not reflect hair loss activity, which may ease the patient’s anxiety and, in our experience, also may beneficially influence cutaneous nociception.

3.13.2 Red Scalp

Red scalp was first been described by Thestrup-Pedersen and Hjorth in 1987, and subsequently commented on by Moschella in 1992, who stated on the difficult problem of “diffuse red scalp disease which can also be itchy and burning. …. It is nonresponsive to any therapy including potent topical steroids or anti-seborrhoeic therapy.” Patients frequently report aggravation in the sun or report repeated episodes of sunburn of the scalp.

Grimalt et al. presented their findings in 18 patients with red scalp syndrome at the 2000 Annual Meeting of the European Hair Research Society: The majority were middle-aged females consulting for hair loss. By definition no specific dermatologic disease was found. The scalp redness was associated with androgenetic alopecia in 13 out of 18 patients, and three of 10 biopsies performed were compatible with a cicatricial alopecia (not otherwise specified). Some patients reported associated discomfort of the scalp. The most prevalent speculations with respect to the pathogenesis of scalp discomfort in the absence of a specific dermatologic disease are perifollicular inflammation and increased expression of the neuropeptide substance P in the vicinity of affected hair follicles.

In our published series of 403 patients complaining of hair loss examined for trichodynia, the dermatoscopic finding of scalp telangiectasia was found to strongly correlate with presence of trichodynia.

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An interesting analogy exists between red scalp and rosacea, where patients with the telangiectatic variant of rosacea reported stinging sensation to the topical application of 5 % lactic acid on the cheeks more frequently than patients with the papulopustular type of rosacea or normal controls.

On the one hand, these findings suggest a connection between sensory or subjective irritation and cutaneous vascular reactivity. On the other hand, dilated and tortuous vessels are typically found in photodamaged skin.

3.13.2.1 Treatment

We recently described patients with red scalp disease with clinical and histopathologic findings consistent with rosacea and response to oral tetracycline therapy. On the basis of the observation of clinical and histopathologic features of rosacea in our patients, and response to oral tetracycline therapy (Fig. 3.28a–f), we suggested that patients complaining of red scalp accompanied with scalp discomfort may represent a rosacea-like dermatosis of the scalp.

Fig. 3.28

(a–f) Red scalp or rosacea-like dermatosis of scalp. Clinical and dermoscopic findings (a–c) before and (d–f) following successful therapy with oral tetracycline

Careful examination of the affected scalp, including dermoscopy, invariably reveals erythema, telangiectasia, follicular papules, and pustules.

Histology demonstrates ectatic venules and a usually sparse perivascular infiltrate, in the case of papules a more pleomorphic perifollicular infiltration with granuloma formation, including neutrophils. Intrafollicular collections of neutrophils are found when pustules are observed.

Rosacea is a chronic inflammatory disorder usually affecting the central parts of the face with flushing, persistent erythema, and telangiectasia, in combination with episodes of swelling, papules, and pustules. It typically presents either as erythemato-telangiectatic rosacea or as the papulopustular type. Eye involvement (ocular rosacea) is common; other extrafacial locations may be involved more frequently than appreciated because of failure to search; in particular, rosacea affecting the upper forehead and bald scalp has previously been reported.

3.14 Concept of Multitargeted Treatment

Besides an understanding of the pathologic dynamics of hair loss as they relate to the hair growth cycle and integrity of the hair follicle, insight into a multitude of cause relationships is prerequisite for delivering appropriate patient care. It must be borne in mind that hair loss often does not result from a single cause effect but from a combination of internal and external factors that all need to be addressed simultaneously in an individualized manner for success, such as:

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· Nutrition: proteins, energy, vitamins, and trace metals

· Hormones

· Aging

· Seasonality of hair growth and shedding

· Cigarette smoking

· UV radiation

· Inflammatory phenomena

· Hair care

3.14.1 Multimorbidity

Ultimately, the problem of multimorbidity has to be taken into account, especially in the elderly population. The term multimorbidity means several concurrent medical conditions within one person. With technologic advances and improvements in medical care, an increasing number of patients survive medical conditions that used to be fatal. This fact combined with the aging of the population means that a growing proportion of patients have multiple concurrent medical conditions. According to a survey done in Canada in 1998, 30 % of the population reported suffering from more than one chronic health problem, and the percentage increased with age. In the United States, the prevalence of multimorbidity among those 65 and older has been estimated at 65 %.

The quantity and quality of hair are closely related to the nutritional, general and mental health state of the individual, while older patients increasingly suffer from a variety of conditions that affect the hair, that is, nutritional deficiency, endocrine disorders, psychologic problems, and drug-related adverse effects. Sometimes symptoms of overt pathologic conditions are misinterpreted as signs of normal aging, ignored and left untreated.

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In taking care of older patients with hair problems, it is important to be suspicious of the possibility of a more general problem underlying the patient’s complaint.

Finally, the increasing number of chronic conditions per patient and the increasing amount of multimorbidity in the elderly population also lead to a more complex approach to successful treatment of hair problems in the elderly.

3.14.2 Value of Nutritional Supplementation Therapy

The quantity and quality of hair are closely related the nutritional state of an individual. Normal supply, uptake, and transport of proteins, calories, trace elements, and vitamins are of fundamental importance in tissues with a high biosynthetic activity such as the hair follicle. Because hair shaft is composed almost entirely of protein, protein component of diet is critical for production of normal healthy hair. The rate of mitosis is sensitive to the calorific value of diet, provided mainly by carbohydrates stored as glycogen in the outer hair root sheath of the follicle. Finally, a sufficient supply of vitamins and trace metals is essential for the biosynthetic and energetic metabolism of the follicle.

In instances of protein and calorie malnutrition, deficiency of essential amino acids, of trace elements, and of vitamins, hair growth, and pigmentation may be impaired. In general, malnutrition is due to one or more of following factors: inadequate food intake, food choices that lead to dietary deficiencies, and illness that causes increased nutrient requirements, increased nutrient loss, poor nutrient absorption, or a combination of these factors.

It appears that on a typical Western diet, the hair follicle should have no problem in producing an appropriate hair shaft.

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Nevertheless, vitamin and nutritional deficiencies are not uncommonly observed in adolescent females and young women with eating disorders (anorexia and bulimia nervosa), and especially common in the elderly population.

There is evidence that with age, the needs for types and quantities of nutrients may change, and it has been found that as many as 50 % of older adults have a vitamin and mineral intake less than the recommended dietary allowance, and as many as 30 % of the elderly population have subnormal levels of vitamins and minerals.

Since an important commercial interest lies in the nutritional value of various vitamin and amino acid supplements, finally, an important question that arises is whether increasing the content of an already adequate diet with specific amino acids, vitamins, and/or trace elements may further promote hair growth, especially in the older population.

3.15 Dystrophic Anagen Effluvium

Dystrophic anagen effluvium is hair loss that results from the shedding of large numbers of hairs from the anagen phase of growth. It is a major characteristic of anagen that the epithelial hair follicle compartment undergoes proliferation, with the hair matrix keratinocytes showing the highest proliferative activity in building up the hair shaft.

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The common pathogenesis which unites the different etiologies of dystrophic anagen effluvium is a direct insult to the rapidly dividing bulb matrix cells.

The abrupt cessation of mitotic activity leads to the weakening of the partially keratinized, proximal portion of the hair shaft, its narrowing and subsequent breakage within the hair canal, and shedding. The morphological consequence is the dystrophic anagen hair with a tapered proximal end and lack of root sheath.

Hair loss is usually dramatic, involving 90 % of affected scalp hair that are shed within days to few weeks of the inciting event. Causes for dystrophic anagen effluvium are listed in Table 3.5.

The hair loss may be diffuse (in chemotherapy and toxic alopecia) or focal (in radiation-induced alopecia and alopecia areata).

3.16 Chemotherapy-Induced Hair Loss

Chemotherapy-induced hair loss is considered one of the most traumatic factors in cancer patient care, since hair loss negatively affects a patient’s perception of appearance, body image, sexuality, and self-esteem and patients feel deprived of their privacy because the hair loss is readily interpreted by the lay public as associated with having cancer.

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Forty-seven percent of female cancer patients consider hair loss the most traumatic aspect of chemotherapy, and 8 % would even decline chemotherapy because of this fear of hair loss.

Chemotherapy-induced hair loss occurs with an estimated overall incidence of 65 %. The incidence and severity of the hair loss are variable and related to the particular chemotherapeutic agent and protocol: Multiple classes of anticancer drugs induce alopecia (Table 3.6), with frequencies of chemotherapy-induced hair loss differing for the four major drug classes – more than 80 % for antimicrotubule agents (e.g., paclitaxel), 60–100 % for topoisomerase inhibitors (e.g., doxorubicin), more than 60 % for alkylators (e.g., cyclophosphamide), and 10–50 % for antimetabolites (e.g., 5-fluorouracil plus leucovorin). Combination therapy consisting of two or more agents usually produces greater incidences of more severe hair loss compared with single-agent therapy.

Table 3.6

Cytotoxic agents and hair loss

Cytostatic agents which usually do cause hair loss
Adriamycin	Docetaxel
Daunorubicin	Paclitaxel
Etoposide	Ifosfamide
Irinotecan	Vindesine
Cyclophosphamide	Vinorelbine
Epirubicin	Topotecan
Cytotoxic agents which sometimes cause hair loss
Amsacrine	Vincristine
Cytarabine	Vinblastine
Bleomycin	Lomustine
Busulfan	Thiotepa
5-Fluorouracil	Gemcitabine
Melphalan
Cytotoxic agents which unusually cause hair loss:
Methotrexate	Procarbazine
Carmustine	6-Marcaptopurine
Mitoxantrone	Streptozotocin
Mitomycin C	Fludarabine
Carboplatin	Raltritrexate
Cisplatin	Capecitabine

Chemotherapy-induced hair loss is a consequence of direct toxic insult to the rapidly dividing cells of the hair follicle. While chemotherapy-induced hair loss has traditionally been categorized as acute diffuse hair loss caused by dystrophic anagen effluvium, more recently it has been pointed out that, in fact, chemotherapy-induced hair loss may present with different pathomechanisms and clinical patterns. Evidence exists that the hair follicle may respond to the same insult capable of stopping mitosis with both shedding patterns, dystrophic anagen effluvium, and telogen effluvium. Accordingly, the hair may fall out very quickly in clumps or gradually. When mitotic activity is arrested, numerous and interacting factors may influence the shedding pattern. One of these factors is the mitotic activity of the hair follicle at the moment of the insult.

It is a major characteristic of the anagen hair follicle that the epithelial compartment undergoes proliferation, with the bulb matrix cells showing the greatest proliferative activity in building up the hair shaft. The abrupt cessation of mitotic activity leads to the weakening of the partially keratinized, proximal portion of the hair shaft, a narrowing, and a subsequent breakage within the hair canal. The consequence is hair shedding that usually begins at 1–3 weeks after initiation of chemotherapy. Due to its long anagen phase, the scalp is the most common location for hair loss, while other terminal hairs are variably affected depending on the percentage of hairs in anagen. Since normally up to 90 % of scalp hair is in the anagen phase, hair loss is usually copious and the resulting alopecia is quite obvious (Fig. 3.29). Nevertheless, chemotherapy given at high doses for a sufficiently long time and with multiple exposures may also affect the beard, eyebrows, eyelashes, and axillary and pubic hairs.

Fig. 3.29

Chemotherapy-induced hair loss

When the hair is in its late anagen phase, in which the mitotic rate is slowing down spontaneously, it simply accelerates its normal path to telogen, while mitotically inactive phases (catagen and telogen) are not affected. Since anagen duration is diminished in androgenetic alopecia, the probability is increased that the antimitotic insult strikes the hair close to the resting phase resulting in telogen effluvium. While synchronization of hair cycles also plays a role, and again in androgenetic alopecia the hair cycles tend to synchronize due to the diminished duration of anagen, even a minor antimitotic insult may produce marked hair loss.

The hair loss generally is usually reversible, with hair regrowth typically occurring after a delay of 3–6 months. In some patients, the regrown hair shows changes in color and/or texture. It might be curlier than it was before, or it could be gray until the follicular melanocytes begin functioning again. But the difference is usually temporary.

Ultimately, permanent alopecia has been reported after chemotherapy with busulfan and cyclophosphamide after bone marrow transplantation and has been associated with certain risk factors, including chronic graft-versus-host reaction, previous exposure to x-ray, and patient age.

3.16.1 Possibilities for Prevention or Reversal of Chemotherapy-Induced Hair Loss

A number of preventive measures have been proposed and tried to reduce chemotherapy-induced hair loss. Nevertheless, no treatment exists that can guarantee to prevent chemotherapy-induced hair loss.

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Of the treatments so far investigated, scalp cooling (hypothermia) has been the most widely used and studied, though most published data on scalp cooling are of poor quality.

Of 53 multiple patient studies published between 1973 and 2003 on the results of scalp cooling for the prevention of chemotherapy-induced hair loss, 7 trials were randomized. In 6 of the 11 randomized studies, a significant advantage was observed with scalp cooling. The positive results were most evident when anthracyclines or taxanes were the chemotherapeutic agents. In several publications, authors have expressed their concerns about the risk of scalp skin metastases after cooling.

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Scalp cooling is contraindicated for those with hematological malignancies, and its use is controversial in patients with non-hematological malignancies who undergo curative chemotherapy.

Patients undergoing scalp hypothermia commonly report feeling uncomfortably cold and suffering of headaches.

So far, no approved pharmacologic treatment exists for chemotherapy-induced hair loss. Among the agents that so far have been evaluated in cancer patients, the topical hair growth-promoting agent minoxidil was able to shorten the duration, albeit did not prevent chemotherapy-induced hair loss. Minoxidil also failed to induce significant regrowth of hair in busulfan- and cyclophosphamide-induced permanent alopecia.

Advances have been made in the understanding of the pathobiology of chemotherapy-induced hair loss, and several experimental approaches to the development of pharmacologic agents are under evaluation. Because the rapid cell proliferation of hair follicle keratinocytes during anagen renders the hair follicle susceptible to the toxicity of chemotherapy, a strategy to protect against chemotherapy-induced hair loss is arresting the cell cycle to reduce the sensitivity of the follicular epithelium to cell cycle-active antitumor agents. Inhibition of cyclin-dependent kinase 2 (CDK2), a positive regulator of the eukaryotic cell cycle, is believed to represent an approach for prevention of chemotherapy-induced hair loss by arresting the cell cycle. Potent small-molecule inhibitors of CDK2 are currently being developed using structure-based methods. Ultimately, the protection should be selective to the hair follicle, such that the anticancer efficacy of chemotherapy is not hampered. In view of the fact that cancer usually is treated with combinations of chemotherapeutics, an effective treatment of chemotherapy-induced hair loss would likely require agents that are effective for different chemotherapeutics with different action mechanisms. Moreover, variations in patient characteristics must be taken into account, since the pattern of chemotherapy-induced hair loss varies in individual patients.

Since chemotherapy-induced hair loss cannot be reliably prevented, the best way to deal with it is to plan ahead with a focus on making the patient as comfortable as possible with her/his appearance before, during, and after cancer treatment.

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The major approach to prevent or minimize chemotherapy-induced hair loss remains scalp cooling, while topical minoxidil may speed up hair regrowth.

Even if chemotherapy-induced hair loss cannot be prevented, it can be managed. Anticipating hair loss, coming to terms with the inevitability of hair loss, and taking control are the key steps in coping with chemotherapy-induced hair loss. Recommendations for hair care are summarized in Table 3.7.

Table 3.7

Chemotherapy-induced hair loss. Recommendations for hair care

Avoidance of physical or chemical trauma, such as bleaching, coloring, or perming of hair, curling irons, and hot rollers

Gentle hair strategies should be continued throughout chemotherapy, using a satin pillowcase, which is less likely to attract and catch fragile hair, using a soft brush, washing hair only as often as necessary and using a gentle shampoo

Cutting hair short or shaving hair. Short hair tends to look fuller than long hair, and when the hair is shed, it won’t be as noticeable when it is short. Moreover, cut hair might help to make a better transition to total alopecia. Also, a shaved head may be easier for securing a wig or hairpiece

Appropriate head covering should be planned ahead. Head covering as the hair falls out is a very personal decision. For women in particular, chemotherapy-induced hair loss involves a confrontation with the nature of their disease, while for men it is a normal and inevitable consequence of treatment. Depending on individual preference, temporarily wearing a wig or another head covering until the hair regrows may be the most effective way of dealing with this condition, while protecting the scalp from sun and cold exposure at the same time

Ultimately, women with concomitant female androgenetic alopecia who have undergone chemotherapy for breast cancer and are under anti-estrogen treatment may recover a remarkable amount of hair with topical minoxidil therapy (Fig. 3.30a–c).

Fig. 3.30

(a–c) Successful treatment of a 50-year-old woman who had undergone chemotherapy for breast cancer and was currently taking the aromatase inhibitor letrozole with 5 % topical minoxidil twice daily, a CYP-complex-based oral supplementation, and witch hazel shampoo, (a) before, (b) after 3 months, and (c) 6 months of therapy

3.17 Radiation-Induced Alopecia

The anagen hair follicle is highly susceptible to x-ray exposure. Loss of dystrophic hairs (anagen effluvium) results from acute damage to the actively dividing matrix cells of anagen follicles. This is followed by a telogen shedding due to premature catagen entry of follicles in late anagen at the time of the insult. Hair loss occurs within the exposure area (Fig. 3.31a), and most patients notice hair loss 2–3 weeks following radiation exposure.

Fig. 3.31

Radiation-induced alopecia: (a) Permanent alopecia within exposure is of therapeutic irradiation for brain tumor. (b) Temporary radiation-induced epilation following neuroradiologically guided embolization procedure

Radiation-induced alopecia may either be temporary or permanent, depending on the amount of radiation and other treatments received, such as concomitant chemotherapy.

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Hair loss occurs on hair-bearing skin, with doses above 300–400 cGy, and is permanent with a single dose above 1,200 cGy. If the dose is fractionated, permanent hair loss may not occur until the dose exceeds 4,500 cGy.

If the hair loss is temporary, complete hair regrowth occurs 2–4 months after x-ray exposure.

We first reported temporary radiation-induced epilation following a neuroradiologically guided embolization procedure in the dermatologic literature (Fig. 3.31b). Endovascular procedures have become a widely used treatment of cerebral vascular malformation. Transient alopecia following therapeutic embolization is probably underreported, since it seems not to be an uncommon even. It has been misinterpreted to be due to arterial occlusion; moreover, excluding the differential diagnosis of alopecia areata may be difficult, since the bald patch is devoid of inflammatory signs and hair loss is characterized by dystrophic hair. The patient history, chronology of events, and the localization and the geometry of the bald patch usually allow correct diagnosis.

3.17.1 Treatment

The scalp skin is sensitive to radiation and more so after hair loss. The skin may become erythematous, tender, or inflamed, much like a sunburn. After 2–3 weeks of radiation exposure, the scalp may become dry and itchy. If necessary, treatment can be prescribed to relieve discomfort and itching. Protection from UV radiation is mandatory. Recommendations for hair and scalp care are summarized in Table 3.8.

Table 3.8

Suggestions for patients to minimize scalp reaction to radiation treatment

Avoid frequent shampooing. Use a mild shampoo without any perfumes

Wash scalp with warm water only. Avoid rubbing or scratching. Pat dry with a soft towel

Avoid excessively combing or brushing hair

Avoid using hair spray, oils, or creams

Avoid using heat sources, including hair dryers, rollers, or curling irons

Do not perm or color hair until about 4 weeks after radiation treatment is complete

Protect head from sun, cold, and wind by wearing a head covering

3.18 Toxic Alopecia

Toxic alopecia from occupational exposure to hazardous chemicals has decreased over the years due to more stringent government regulations. More recently, interest has focused on mild aggressions from toxic metals of the environment.

Many heavy metals are capable of disrupting the formation of the hair shaft through covalent binding with the sulfhydryl groups in keratin: thallium, mercury, arsenic, copper, cadmium, and bismuth.

A study conducted 1979 by Pierard in Belgium reported diffuse alopecia related to ingestion of toxic metals in 36 of 78 patients with diffuse alopecia.

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Toxic metals in abnormal amount in blood and urine were observed only when >10 % of hair bulbs were dystrophic.

Copper was involved in 17 alopecias, arsenic in 12, mercury in 5, and cadmium in 2. Copper intoxication was found to be related to ingestion of tap water containing a high concentration of copper salts, presumably from low pH, presence of chelating agents, or connection of electrical ground wires to copper water pipes, which caused sufficient flow of electrical current to ionize the metal.

3.18.1 Amalgam Illness

Adverse effects related to dental amalgam, including hair loss, have also been the subject of recent attention. In one study, mercury levels in blood and urine correlated with the number of amalgam surfaces, indicating the release of mercury from dental amalgam restorations. Since the mercury levels were far below those where negative health effects would be expected and were similar in patients with complaints self-related to dental amalgam restorations and healthy control individuals, mercury was not found to be a likely cause of the impaired health reported by the patients. In another study, assays of mercury in urine samples of patients with amalgam illnessindicated that the exposure was far below the levels at which symptoms could be indicated by psychometric tests. Psychologic investigation indicated that the symptoms were psychosomatic. All patients had experienced important psychic traumata in close correlation with the first appearance of symptoms.

3.18.2 Misuse of Hair Analysis as a Diagnostic Tool

Hair analysis refers to the chemical analysis of a hair sample. Its most widely accepted use is in the fields of forensic toxicology and, increasingly, environmental toxicology. Hair analysis is also used for the detection of recreational drugs, including cocaine, heroin, benzodiazepines, and amphetamines, and the presence of illegal drugs. Chemical hair analysis may prove particularly useful for retrospective purposes when blood and urine are no longer expected to contain a particular contaminant, typically a year or less.

On the other hand, an increasing number of commercial laboratories are committed to providing multielemental hair analyses in which a single test is used to determine values for many minerals simultaneously. This type of analysis is used by several alternative medicine fields with the claim that hair analyses can help diagnose a wide variety of health problems and can be used as the basis for prescribing natural chelation therapy, mineral, trace elements, and/or vitamin supplements. However, these uses remain controversial for a number of reasons:

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Most commercial hair analysis laboratories have not validated their analytical techniques by checking them against standard reference materials

Hair mineral content can be affected by exposure to various substances such as shampoos, bleaches, and hair dyes. No analytic technique enables reliable determination of the source of specific levels of elements in hair as bodily or environmental

The level of certain minerals can be affected by the color, diameter, and rate of growth of an individual’s hair, the season of the year, the geographic location, and the age and gender of the individual

Normal ranges of hair minerals have not been defined

For most elements, no correlation has been established between hair level and other known indicators of nutrition status. It is possible for hair concentration of an element to be high even though deficiency exists in the body, and vice versa

3.19 Alopecia Areata

Alopecia areata represents the most frequent cause of anagen dystrophic effluvium, either localized or diffuse, occurring in the otherwise healthy child or adult. It is a common hair loss condition characterized by an acute onset of non-scarring hair loss in sharply defined areas. Any hair-bearing area can be affected, but the most noticeable surface is the scalp. The characteristic patch of alopecia areata is usually round or oval and is completely bald and smooth.

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The progress of alopecia areata is unpredictable.

Some patients lose hair in only a small patch, while others may have more extensive involvement. Alopecia totalis is the loss of all scalp hair; alopecia universalis is the loss of all scalp and body hair.

Alopecia areata is considered to be of autoimmune origin with an organ-specific, T-cell-mediated assault on the hair follicle at the level of the bulb. The hair bulb is an immune protected site with deficient MHC expression. There is circumstantial evidence suggesting that alopecia areata results from loss of immune privilege with presentation of autoantigens. A peribulbar lymphocytic infiltrate induces hair follicle keratinocytes to undergo apoptosis resulting in inhibition of cell division in the hair matrix. New drug treatment opportunities based on the results of a genome-wide association study, which implicate T cell and natural killer cell activation pathways, are leading to new approaches in future clinical trials of alopecia areata: Currently there are ongoing studies with the CTLA4-Ig fusion protein abatacept (blocks co-stimulation of T cells), anti-IL15Rβ monoclonal antibodies (blocks activation of CD8+ T cells), and the Janus Kinase (JAK) 3 inhibitor tofacitinib and JAK 1/3 inhibitor ruxolitinib (block signal transduction at the IL-15 receptor).

3.19.1 Acute Diffuse and Total Alopecia of the Female Scalp

In 2002 Sato-Kuwamora et al. suggested naming a peculiar type of inflammatory noncicatricial alopecia that is characterized by marked female predominance and a uniquely short clinical course “acute diffuse and total alopecia of the female scalp.” It is basically identical with a subtype of alopecia areata presenting with diffuse hair loss as originally proposed in the German literature by Braun-Falco and Zaun 40 years earlier in 1962.

Diffuse alopecia areata or alopecia areata incognita (yet another synonymous designation proposed by Rebora in 1987) represents an uncommon variety of alopecia areata characterized by diffuse hair shedding in the absence of typical patches. The condition usually affects women over 40 years of age, who complain of diffuse alopecia and are often misdiagnosed as having telogen effluvium. Presence of yellow dots and short regrowing miniaturized hairs seen in the terminal hair-bearing scalp are an important clue to the diagnosis. The diagnosis is usually confirmed by histopathology or response with hair regrowth to a trial course of oral prednisolone in doses > 0.5 mg/kg for 3–4 weeks with subsequent tapering.

3.19.2 Marie Antoinette Syndrome

Marie Antoinette syndrome designates the condition in which scalp hair suddenly turns white. The name alludes to the wretched French Queen Marie Antoinette (1755–1793), whose hair allegedly turned white the night before her last walk to the guillotine during the French Revolution. The term canities subita has also been used for this disorder.

Although the actual incidence is rare, this stigmatizing phenomenon has captured storytellers’ imagination like few other afflictions as a sign of grave sorrow. History also records that the hair of the English martyr Sir Thomas More (1478–1535) turned white overnight in the Tower of London before his execution. More modern accounts refer to the turning white of hair in survivors of bomb attacks during World War II. We reported a 54-year-old woman who initially presented with a single circular hairless patch of alopecia areata (Fig. 3.32, A, X) that had developed shortly before the photograph shown in Figure A was taken. Although she was successfully treated with topical steroids (betamethasone with dimethyl sulfoxide), her entire scalp hair suddenly turned white within a few weeks (Fig. 3.32, B). She was completely healthy, allegedly did not notice any loss of hair during the change of color, and underwent no frightful experience.

Fig. 3.32

(a, b) Marie Antoinette syndrome

Today, the syndrome is interpreted as an acute episode of diffuse alopecia areata in which the very sudden overnight graying is caused by the preferential loss of pigmented hair in this supposedly immune-mediated disorder. This observation has led some experts to hypothesize that the autoimmune target in alopecia areata may be related to the melanin pigment system.

3.19.3 Treatment

A recent metanalysis of published trials on treatment of alopecia areata states that only few treatments have been well evaluated in randomized trials. The authors found no randomized controlled trials on the use of diphenylcyclopropenone (DCP), intralesional corticosteroids, or dithranol, although commonly used in clinical practice. Although topical steroids and minoxidil are widely prescribed and appear to be safe, there is no convincing evidence that they are beneficial in the long term. Most trials have been reported poorly and are so small that any important clinical benefits are inconclusive. Of 17 trials including 6–85 participants with a total of 540 participants assessing a range of interventions that included topical and oral corticosteroids, topical ciclosporin, photodynamic therapy, and topical minoxidil, none showed significant treatment benefit in terms of hair growth when compared with placebo. The authors came to the conclusion that considering the possibility of spontaneous remission, especially for those in the early stages of the disease, the options of not being treated therapeutically or, depending on individual preference, of wearing a wig may be alternative ways of dealing with this condition.

Nonetheless, depending on patient age, surface area, and disease duration, a treatment algorithm can be designed (Fig. 3.33).

Fig. 3.33

Algorithm for treatment of alopecia areata

Any treatment of alopecia areata should fulfill the following criteria:

· Remission rates superior to the spontaneous remission rates of alopecia areata

· Proof of efficacy in half-side treatment of alopecia totalis or universalis

· Good safety profile with minimal toxicity

The spontaneous remission rates for patchy alopecia areata are one-third within 6 months, half within 1 year, and two-thirds within 5 years; thereafter, complete remissions are rare. Recurrence rates within 5 years are 80 % and within 20 years 100 %. Total remission rates for alopecia totalis or universalis with a disease duration of 5 years or more are 1 % in children and less than 10 % in adults.

Single patches of alopecia areata are best treated with intralesional triamcinolone acetonide 10 mg/mL by jet injector on a monthly basis, for an average of 3 to a maximum of 6 consecutive treatments (in children 5 mg/mL and for eyebrows 2.5–5 mg/mL by insulin needle) (Fig. 3.34a–f).

Fig. 3.34

(a–t) Successful treatments in alopecia areata: (a–f) Successful treatment of multiple patches of alopecia areata in a 16-year-old girl with intralesional triamcinolone acetonide 10 mg/mL in combination with a compound of topical 5 % minoxidil and 0.2 % triamcinolone acetonide, (a, b) before, (c, d) after 3 months, and (e, f) after 6 months of treatment Fig 3.34 (continued) (g, h) Successful i.v. methylprednisolone pulse therapy in a 64-year-old woman with acute diffuse and total alopecia of the scalp, (a) before and (b) 6 months after treatment. (i–k) Successful topical immunotherapy with DCP in a 12-year-old girl with subtotal alopecia, (a) before, (b) after 4, and (c) 8 months of treatment. (l–p) Successful treatment of total alopecia in a 43-year-old woman with 30 mg MTX weekly in combination with 20 mg prednisone, (l) before, (m) after 3 months, (n) after 6 months, Fig 3.34 (continued) (o) after 9 months, and (p) 12 months of treatment. (q, r) Successful treatment of total alopecia in a 47-year-old woman with symptom-oriented autosuggestion therapy, (a) before and (b) after 12 months therapy

With pulse corticosteroid therapy (500 mg i.v. methylprednisolone on 3 consecutive days, in 3 cycles 4 weeks apart) within 6 months of disease onset, remission rates are 88 % for multilocular alopecia areata with a surface area < 50 %, 59.4 % with a surface area > 50 %, and 21.4 % in alopecia totalis (Fig. 3.34g, h). After 6 months of disease onset, the remission rate is 15.8 %.

With 0.05 % topical clobetasol ointment under occlusion (Saran wrap) on 6 consecutive nights per week over 6 months, regrowth of hair is achieved in alopecia totalis or universalis in 17.8 %.

In a retrospective study of 68 patients with severe alopecia areata (>40 % scalp hair loss) treated for at least 5 months with topical diphenylcyclopropenone (DCP), we found an overall response rate of 70.6 % with 30.9 % complete remission and 39.7 % partial remission. Among the investigated prognostic factors for the outcome of DCP therapy, only the extent of AA at the time of initiation of treatment was found to be of significance. Total remission rates for multilocular alopecia areata was 43.8 %, for subtotal alopecia areata and ophiasis 33.3 %, and for alopecia totalis and universalis 21.4 %, irrespective of disease duration (Fig. 3.34i–k).

Joly proposed the use of methotrexate (MTX) alone or in combination with low doses of oral corticosteroids in the treatment of alopecia areata totalis or universalis with an overall success rate of 64 %. Best results are achieved with s.c. MTX in the maximal dosage of 30 mg weekly in combination with 20 mg prednisone daily with regrowth of hair beginning within 2–4 months of therapy (Fig. 3.34l–p). Drug toxicities are to be carefully weighed out against treatment benefit.

∎

Potentially disease-modifying comorbidi-ties are to be sought out and simultane-ously treated such as deficiencies of iron, zinc, vitamin B12, and vitamin D3, thyroid dysfunction, androgenetic alopecia, and emotional distress.

Some authors advocate combination treatment with antidepressant agents in alopecia areata with comorbid depression. Others suggest that hypnotherapy may enhance the mental well-being of patients with alopecia areata and may improve clinical outcome (Fig. 3.34q, r). Ultimately, the options available for adapting to the disease rather than treating in an effort to cure are to be taken into consideration in selected long-standing widespread cases or recurrent small spot disease.

3.20 Loose Anagen Hair and Short Anagen Hair of Childhood

Loose anagen hair and short anagen hair are conditions seen in children, often girls, with the chief complaint that the hair fails to grow long. While the hallmark of loose anagen hair is easily pluckable hairs in anagen, short anagen hair is characterized by a mild form of persistent telogen effluvium.

3.20.1 Loose Anagen Hair

Loose anagen hair, characterized by easily pluckable anagen hairs, is a disorder predominantly observed in children. The condition often recedes with age but can be seen in adulthood, either as a continuation of the disorder that has lingered since childhood or as late-onset loose anagen hair.

Patients with late-onset loose anagen hair state that their hair has increased shedding and does not grow as long as it used to.

The diagnosis of loose anagen hair is based on the following criteria: on pull test, painless extraction of >10 anagen hairs (devoid of hair root sheaths); in the trichogram, >80 % of plucked hairs are anagen hairs devoid of sheaths (see Fig. 2.14r). Clinically the hair may show uneven ends. Additionally, there may be variations in hair texture, and the hair is often dry and lusterless (Fig. 3.35).

Fig. 3.35

Loose anagen hair of childhood

Histological studies of scalp biopsies have demonstrated abnormal clefting between the internal root sheath and the hair shaft, premature keratinization, and degeneration of the inner sheath. Also, poor cohesion of the cells of the outer sheath has been described.

Ultrastructural studies show longitudinal grooves of the hair shaft. The presence of these alterations supports the hypothesis of some abnormality of the root sheath adversely affecting anchoring of the anagen hair in the follicle.

There is no specific treatment for loose anagen hair, except for careful grooming of the hair to avoid extracting the loose anagen hairs. Oral biotin may be beneficial for the strength and texture of the hair.

3.20.2 Short Anagen Hair

In his classification proposal of telogen effluvium into five functional types on the basis of changes in the different phases of the follicular cycle, Headington suggested the existence of a mild form of persistent telogen effluvium in association with decreased hair length due to a short anagen phase.

We originally reported two children with a peculiar type of isolated congenital hypotrichosis. Both presented with persistent short, fine hair since birth (Fig. 3.36a, b). We provided evidence that the short hair observed in these patients was due to a short anagen phase of the hair cycle, with a normal rate of hair growth. Shortening of the anagen phase of the scalp hair cycle leads to a decrease in the maximal hair length and an increase in the number of hairs in telogen, resulting in an increase in hair shedding. Scanning electron microscopy showed a widely spaced cuticular pattern, a finding typically seen in hair of thin caliber. One patient had affected family members with an apparently autosomal dominant mode of inheritance. The disorder appears to resolve spontaneously during puberty and adulthood.

Fig. 3.36

(a, b) Short anagen hair

The syndrome of short anagen hair was subsequently confirmed by Olsen who proposed methods for diagnosing this entity by clinical examination, trichogram, light microscopic examination of the hair shaft, scalp biopsy, and measurement of scalp hair growth rate. Short anagen hair appears to be an uncommon, though probably underreported condition, whose incidence is poorly documented in the medical literature.

The most important differential diagnosis includes short anagen hair in the trichodental syndrome, loose anagen hair, hereditary hypotrichosis simplex, and premature androgenetic alopecia.

Far more frequently, a short anagen phase is progressively acquired in the course of androgenetic alopecia. While in androgenetic alopecia shortening of the anagen phase occurs without synchronization of hair cycling, Sinclair provided evidence of short anagen hair with a persistent synchronized pattern of scalp hair growth in a 4-year-old boy.

Treatment is usually not necessary, though one would expect efficacy from reported successful treatment of a short anagen hair nevus with topical minoxidil.

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Imaginary Hair Loss (Psychogenic Pseudoeffluvium)

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Trichodynia and Red Scalp

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Trichodynia and Red Scalp: Treatment

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Concept of Multitargeted Treatment: Value of Nutritional Supplementation Therapy

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Chemotherapy-Induced Hair Loss

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Radiation-Induced Alopecia

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Toxic Alopecia

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Alopecia Areata

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Loose Anagen Hair and Short Anagen Hair of Childhood: Loose Anagen Hair

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Trüeb RM, Burg G (1992) Loose anagen hair. Hautarzt 43:505–508PubMed

Loose Anagen Hair and Short Anagen Hair of Childhood: Short Anagen Hair

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Barraud-Klenovsek MM, Trüeb RM (2000) Congenital hypotrichosis due to short anagen. Br J Dermatol 143:612–617PubMed

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Kersey PJW (1987) Tricho-dental syndrome: a disorder with a short hair cycle. Br J Dermatol 116:259–263PubMed

Thai KE, Sinclair RD (2003) Short anagen hair with persistent synchronized pattern of scalp hair growth. J Am Acad Dermatol 49:949–951PubMed

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