Hair Loss

Hair Loss: Principles of Diagnosis andManagement of Alopecia

Hair Loss: Principles ofDiagnosis and

Management of Alopecia

Jerry Shapiro, FRCPCClinical Professor and Director of the UBC Hair Research and

Treatment CentreDivision of Dermatology

University of British ColumbiaVancouver

Canada

Martin Dunitz

© 2002 Martin Dunitz Ltd, a member of the Taylor & Francis group

First published in the United Kingdom in 2002 byMartin Dunitz Ltd,The Livery House,7–9 Pratt Street,

London NW1 0AE

Tel: +44 (0) 20 7482 2202Fax: +44 (0) 20 7267 0159E-mail: [email protected]

Website: http://www.dunitz.co.uk

This edition published in the Taylor & Francis e-Library, 2004.

All rights reserved. No part of this publication may be reproduced,stored in a retrieval system, or transmitted, in any form or by any

means, electronic, mechanical, photocopying, recording, or otherwise,without the prior permission of the publisher or in accordance with theprovisions of the Copyright, Designs and Patents Act 1988 or under theterms of any licence permitting limited copying issued by the Copyright

Licensing Agency, 90 Tottenham Court Road, London, W1P 0LP.

A CIP record for this book is available from the British Library.

ISBN 0-203-42852-8 Master e-book ISBN

ISBN 0-203-44903-7 (Adobe eReader Format)ISBN 1-85317-876-4 (Print Edition)

Although every effort has been made to ensure that all owners ofcopyright material have been acknowledged in this publication, we

would be glad to acknowledge in subsequent reprints or editions anyomissions brought to our attention.

Distributed in the USA byFulfilment CenterTaylor & Francis

7625 Empire DriveFlorence, KY 41042, USA

Toll Free Tel.: +1 800 634 7064E-mail: cserve@routledge_ny.com

Distributed in Canada by

Taylor & Francis74 Rolark Drive

Scarborough, Ontario M1R 4G2, CanadaToll Free Tel.: +1 877 226 2237

E-mail: [email protected]

Distributed in the rest of the world byITPS Limited

Cheriton HouseNorth Way

Andover, Hampshire SP10 5BE, UKTel.: +44 (0)1264 332424

E-mail: [email protected]

Composition by Scribe Design, Gillingham, Kent

Foreword vii

Acknowledgements ix

1 Assessment of the patientwith alopecia 1

2 Alopecia areata: Pathogenesis,clinical features, diagnosisand practical management 19

3 Androgenetic alopecia:Pathogenesis, clinical featuresand practical medicaltreatment 83

4 Surgical management ofandrogenetic alopecia 121

5 Drug-induced alopecia 135

6 Telogen effluvium: acuteand chronic 147

7 Cicatricial (scarring)alopecia 155

Index 175

Contents

Jerry Shapiro is a dedicated clinician/scientistwho has devoted himself to all aspects pertain-ing to the hair follicle. He has written a uniquetext that will be invaluable for clinicians, re-searchers, and students of the hair follicle.This is an organized and rational guide for as-sessing and managing hair loss, which is setapart from others by the blending of rich clini-cal detail with the latest investigative researchand theories of pathogenesis, all extensivelyreferenced. It is a practical and personal ap-proach that reflects Dr Shapiro’s long experi-ence with hair problems both in the clinic andin the laboratory. His explicit recommenda-tions about management are given, and whereappropriate, he also includes the treatment

preferences of other hair experts. Complex is-sues are presented, such as immunological fac-tors in alopecia areata, in clear terms for allreaders. The illustrations are extensive, a col-lection of unique photographs andphotomicrographs from his own collection.The text is exceptionally readable and comple-ments the book’s systematic and inviting or-ganization. Jerry Shapiro has accomplished anamazing single-authored, comprehensive textabout hair that enriches the reader from benchto bedside.

Vera H Price MD, FRCPCProfessor of Clinical Dermatology School of

MedicineUniversity of California, San Francisco

Foreword

There are certainly many individuals to thankin the making of this book. First and foremost,I am most indebted to my hair loss patientswho have trusted me and given me the privi-lege of taking care of their hair. It continues tobe an honor for me and I thank them for this.

Next, I would like to thank certain individu-als who have played an important part in mycareer. Dr Harvey Lui, who has, and continuesto guide and nurture me in the field of derma-tology. Dr William Stewart, who was the firstindividual to encourage me to take on the fieldof hair. Dr David McLean, whose advice, sup-port and encouragement helped the Universityof British Columbia Hair Research and Treat-ment Centre flourish. Dr Vera Price, who hasbeen my ‘’hair’’ mentor for over 15 years andhas been an inspiration and role model. DrWilma Bergfeld, who allowed me to learn fromher in Cleveland and from whom I continue tolearn. My Hair Fellows: Dr Chantal Bolduc, DrShabnam Madani and Dr Olga Bernardo, whotook time out of their busy lives to commit ayear to studying hair with me. Each fellow hasquestioned, challenged and inspired me tolearn so much more; they truly are very spe-cial people. My research associate, Dr LirenTang, who continues to teach me the molecu-

lar biology and basic science of hair. DrsMagda Martinka and David Shum, who con-tinue to enlighten me regarding the histopa-thology of the hair follicle. Nina MacDonald,my first Hair Clinic nurse, who was dedicatedand helped shape the University of British Co-lumbia Hair Clinic during its early years.Lucianna Zanet, my Hair Transplant nurse,who has guided me for the last 10 years withall her great surgical skills and great commonsense approach to patients.

I thank my editors, Charlotte Mossop andRobert Peden, whose time and efforts wereabsolutely essential in making this book pos-sible.

I would like to thank the University of Brit-ish Columbia’s Division of Dermatology andthe Vancouver General Hospital Skin CareCentre for providing the environment for meto work in the field of hair.

I also would like to especially thank myfamily and friends who stood back and al-lowed me to take the weekends and eveningsto finally accomplish this endeavor.

Jerry ShapiroUniversity of British Columbia Hair Research

and Treatment Centre

Acknowledgements

1 Assessment of the patient withalopecia

Figure 1.1Diagrammatic representation of hairanatomy: The hair follicle is divided into 4parts: bulb, suprabulbar area, isthmus, andinfundibulum.

Hair loss (alopecia) is a very common patientproblem and often a significant source of pa-tient distress. An accurate diagnosis can fre-quently be difficult. A rational, organizedapproach is crucial, as therapy is dictated bythe appropriate diagnosis.1

The first task of the physician is to addressthe patients’ concerns fully, exploring the im-pact of alopecia on psychosocial well-being.Next, an organized diagnostic approach canassist the physician in the recognition of thecharacteristic differential features of each dis-order and help to identify the cause of alopeciaand guide therapeutic direction. Ancillarylaboratory evaluation may sometimes be nec-essary to help confirm a diagnosis. Patients aremost appreciative of a supportive diagnosticapproach.

Basic trichologicanatomy and physiologyIn order to appreciate an organized diagnosticprotocol for alopecia, it is important to reviewthe basics of hair anatomy and physiology ofthe scalp. Knowledge of the hair cycle is es-sential in understanding the patho-physiologyof hair diseases and the mechanism of actionof the present therapeutic agents used tomodulate hair growth.

The hair follicle is divided into 4 parts: (Fig-ures 1.1 and 1.2) 1. Bulb: consisting of dermal papilla and

matrix intermixed with melanocytes (Fig-ure 1.3)

2. Suprabulbar area from matrix to insertionof arrector pili muscle

3. Isthmus extending from insertion of arrec-tor pili muscle to sebaceous gland

4. Infundibulum extending from sebaceousgland to the follicular orifice.

2 Hair Loss: principles of diagnosis and management of alopecia

Figure 1.2(a) Histology of the hair follicle on longitudinal section showing dermal papilla (DP), matrix(M), inner root sheath (IRS), outer root sheath (ORS) and fibrous root sheath (FRS). (b) Twoanagen follicles side by side at the level of fat. Note the melanocytes within the matrixproviding pigment to the hair. (Courtesy of Dr Magdalena Martinka and Dr David Shum.)

The base of the follicle is invaginated by thedermal papilla, which contains highly vascu-larized connective tissue (Figure 1.4). Dermalpapilla fibroblasts are inherently differentfrom non-follicular dermal fibroblasts. Thereis a large amount of acid-mucopolysaccharideswithin the dermal papilla, staining positivelyfor Alcian blue and metachromatically for

The lower portion of the hair follicle consistsof five major portions (1) dermal papilla; (2)matrix; (3) the hair shaft, consisting from in-ward to outward of medulla, cortex, and cuti-cle; (4) inner root sheath, consisting of innerroot sheath cuticle, Huxley’s layer on the in-side and Henle’s layer on the outside; and (5)the outer root sheath.

Assessment of the patient with alopecia 3

Figure 1.3(a) Close-up of longitudinal section of dermal papilla (DP), which is an invagination of thedermis into the matrix (M). The DP allows capillaries to gain entrance to the cells of thematrix. It is the signal transduction and communication between the DP and the matrix thatdetermines how long a hair will grow and how thick a shaft will be produced. Melanocytesfill the matrix and produce the pigment of the hair. (b) Cross-section of the follicle at the levelof the dermal papilla. (Courtesy of Dr Magdalena Martinka.)

Figure 1.4The different layers of the hair follicle

toluidine blue. The ground substance consistsof not only non-sulfated polysaccharides suchas hyaluronic acid, but also sulfatedmucopolysaccharides such as chondroitinsulfate. Alkaline phosphatase activity is alsoincreased in the anagen phase. In persons withdark hair large amounts of melanin can be seenin the dermal hair papilla.

The hair matrix has large vesicular nucleiand deeply basophilic cytoplasm. Dopa-posi-tive melanocytes are interspersed between thebasal cells of the matrix lying on top of the der-mal papilla (Figures 1.2 and 1.3). Melanin,varying in quantity in accordance with thecolor of the hair, is produced in thesemelanocytes and incorporated into the futurecells of the hair through phagocytosis of thedistal portion of the dendritic melanocyte.Cells of the hair matrix differentiate into sixdifferent types of cells, each of which


keratinizes at a different level. The outer layerof the inner root sheath (IRS), Henle’s layer,keratinizes first, establishing a firm coataround the soft central portions of the follicle.The two apposed cuticles covering the insideportion of the IRS and the outside of the hairkeratinize next, followed by Huxley’s layer.The hair cortex then follows, and the medullais last (Figure 1.4).

The hair medulla appears amorphous be-cause of its only partial keratinization. It maynot always be present.

The hair cortex cells during upward growthfrom the matrix cells keratinize gradually bylosing their nuclei and become filled withkeratin fibrils. No keratohyaline granules (asin keratinizing epidermis) or trichohyalinegranules (as in inner root sheath) are formed

during keratinization. Keratin of the cortex ishard keratin, in contrast to the inner rootsheath or epidermis, which is soft keratin.

The hair cuticle located peripheral to thehair cortex consists of overlapping cells ar-ranged like shingles and pointing upwardwith their peripheral portions. The cells ofthe hair cuticle are tightly interlocked withthe cells of the inner root sheath cuticle, re-sulting in the firm attachment of the hair to itsinner root sheath. The hair and the inner rootsheath move in unison upward.

The inner root sheath is composed of threelayers (Figures 1.4 and 1.5). None of these lay-ers contain melanin, and all keratinize withtrichohyalin granule formation. These gran-ules stain eosinophilic, in contrast to the ba-sophilic keratohyalin granules of theepidermis. The cuticle of the IRS consists ofone layer of flattened overlapping cells that

Figure 1.5(a) Cross-section and (b) longtitudinal sec-tions of the follicle at the suprabulbar level.In the central portion of the follicle thematrix (M) is forming cortex, which issurrounded by the cuticle. This is subse-quently invested by the cuticle of the innerroot sheath (IRS), Huxley’s layer withtrichohyaline granules, and the alreadykeratinized Henle’s layer.The outer rootsheath (ORS), hyaline membrance andfibrous root sheath (FRS) surround the wholestructure. (courtesy of Dr David Shum.)


Figure 1.6Cross-section of the follicle just beneath theisthmus showing the eosinophilic completelykeratinized inner root sheath (IRS) enclosingthe hair shaft (HS). All of this is surroundedby outer root sheath, hyaline membrane andfibrous root sheath. Only anagen hairs haveinner root sheaths. (Courtesy of Dr DavidShum.)

point downward in the direction of the hairbulb. Since the cells of the hair cuticle pointupward, these two types of cells interlocktightly. Trichohyalin granules are few in theIRS cuticle. Huxley’s layer is two cell layersthick and develops numerous trichohyalingranules (Figure 1.5). Henle’s layer, only onecell layer thick, already shows numeroustrichohyalin granules as it emerges from thematrix. Just before the isthmus the IRS be-comes fully keratinized (Figure 1.6). However,at the level of the isthmus the IRS disinte-grates. The cells of the IRS do not contribute tothe emerging hair, but serve as a hard moldingscaffold up to the arrector pili muscle.

The outer root sheath (ORS) extends fromthe matrix cells to the entrance of the seba-ceous duct, where it changes into surface epi-dermis. The ORS is thinnest at the level of thehair bulb, gradually increases in thickness, andis thickest in the middle portion of the hair fol-licle, the isthmus. In its lower portion, belowthe isthmus, it is covered by IRS and does notundergo keratinization. The ORS has plentifulvacuolated cytoplasm owing to its plentifulglycogen.

The point of insertion of the arrector pilimuscle is referred to as the bulge area, and isthe likely location of the first primordial cells(stem cells) of the hair follicle.2–7 Stem cellsfrom the bulge area likely migrate to other por-tions of the hair follicle and differentiate intoits differing layers.

The isthmus is the segment that extendsfrom the arrector pili muscle to the sebaceousgland duct entrance. There is no inner rootsheath here. The ORS undergoes trichilemmalkeratinization, producing large homogeneouskeratinized cells without the formation ofkeratohyaline granules.

The upper portion of the follicle above theentrance of the sebaceous duct is the in-fundibulum. It is lined by surface epidermis

undergoing keratinization with the formationof keratohyaline granules.

The glassy or vitreous layer, which formsa homogeneous eosinophilic zone peripheralto the outer root sheath, is periodic acidSchiff-positive and diastase-resistant. It dif-fers from usual basement membrane zone bybeing thicker. It is thickest around the lowerthird of the hair follicle. Peripheral to thisvitreous layer lies the fibrous root sheath,which is composed of thick collagen bun-dles. This connective tissue sheath may con-tain considerable reproductive potential, aswas recently shown by Reynolds et al.8

Melanosomes of the hair cortex are largerthan those of the epidermis. They lie singly orwithin groups not within lysosomes. They arelocated usually in the interfibrillary matrix,


Figure 1.7Melanosomes, either eumelanin orpheomelanin, during anagen are transferredfrom melanocytes to matrical cortex cells viadendritic ends.

within the cells, and only rarely in the inter-cellular space (Figure 1.7). Two types of mela-nin are present in mammalian hair, the blackbrown pigment eumelanin and the yellow redpheomelanin. Both are synthesized from tyro-sine, which is converted to dopaquinonewhich can then undergo oxidative reactionsto form either eumelanin or pheomelanin. Inthe eumelanin containing follicle,melanocytes contain ellipsoidalmelanosomes with a lamellar internal struc-ture (eumelanosomes) Pheomelanogenesis isassociated with melanocyte-containingspherical melanosomes which have a lesswell defined internal structure containinggranules or vesicles. In fire-red hair there arehigh levels of pheomelanosomes. In otherhair colors, melanocytes have higher amountsof eumelanosomes. Dark hair contains moreeumelanin and blond hair morepheomelanin.

In white hair, melanocytes at the basallayer of the hair matrix are usually reduced innumber or are absent. Melanocytes show de-generative changes, especially ofmelanosomes. The hair shafts only containthe detritus of melanin or no melanin at all.

Unlike animals, where hair cycling is syn-chronous, on the human scalp there is anasynchronous mixture of hairs actively grow-ing and resting. During the hair cycle, themiddle and upper portions of the hair follicleare the permanent segment of the hair folli-cle, while the lower portion is non-perma-nent. (Figure 1.8). The growing or anagenhairs are anchored deeply within the subcuta-neous fat (Figure 1.8) and cannot be pulledout easily. Hair fiber is produced duringanagen at a rate of approximately 1 cm/monthor 0.35 mm/day. The telogen hairs are locatedhigher up in the dermis (Figures 1.8 and 1.10)and can be pulled out relatively easily. Thenormal scalp contains 100,000 hairs. Blonds

tend to have more, at 120,000, and redheadsless, at 80,000. The average number of hairsfor a normal scalp is 250 per square cm or1100 per square inch. There is ethnic varia-tion, with fewer hairs per square cm in Blacksand Orientals. The scalp consists of almost90% of hairs in anagen, 1% in catagen and10% in telogen. Anagen may last up to 2–6years, telogen 3 months, and catagen 3 weeks.This ratio is usually uniformly distributedover the entire scalp. In certain individuals,there is periodicity in the number of telogenhairs, with a maximal number in late summer.Increased hair shedding is usually noted inautumn. Decreased telogen hairs occur in De-cember, January or February. Physiologic hairshedding of 100 hairs per day is usual on theaverage, with fluctuations over the year.

The sizes of the hair shafts are important indetermining a diagnosis. Vellus hairs or mini-aturized vellus-like hairs of androgenetic alo-pecia (AGA) have a shaft diameter of less than


Figure 1.8During the hair cycle, the middle and upper portions of the hair follicle are the permanentsegments of the hair follicle, while the lower portion is non-permanent. (a) The growing oranagen hairs are anchored deeply within the subcutaneous fat and cannot be pulled outeasily. The telogen hairs are located higher up in the dermis and can be pulled out relativelyeasily. The scalp consists of almost 90% hairs in anagen, 1% in catagen and 10% in telogen.Anagen may last up to 2–6 years, telogen 3 months, and catagen 3 weeks. This ratio is usuallyuniformly distributed over the entire scalp. The dermal papilla (DP) is pulled upward witheach cycle, and during telogen is closely associated with the stem cells of the bulge area.Communication signals between dp and stem cells of the bulge probably determine the lengthof anagen and the matrix girth of the next hair cycle. (b) The newly formed anagen hairpushes out the previous telogen hair.

Figure 1.9Vellus-like hairs are less than 0.03mm in diameter and rarely growmore than 1–2 mm. Terminal hairsare coarse over 0.06 mm in diameterand can grow up to 3 feet. A truevellus hair does not have an at-tached arrector pili muscle. Onlyminiaturized vellus-like hairs ofandrogenetic alopecia have arrectorpili muscle.


Figure 1.10Cross-section of telogen hair. A central star-shaped area of trichilemmal keratin can benoted, surrounded by outer root sheath,hyaline membrane and fibrous root sheath.The lower portion of terminal telogen hairs isfound higher up in the dermis, unlike termi-nal anagen hairs, whose bulbs are found inthe area of subcutaneous fat. (Courtesy of DrDavid Shum.)

Figure 1.11Small vellus-like hairs (V) in androgenetic alopecia, (a) Hair shafts are small (<.03 mm). (b)The small size of the hairs make the sebaceous glands look more hyperplastic. (Courtesy of DrDavid Shum and Dr Magdalena Martinka.)

0.03 mm (Figures 1.9 and 1.11). Terminal hairshave a shaft diameter greater than 0.06 mm.

One can induce hair growth promotion byincreasing the number of anagen hairs per unitarea and by increasing the duration of theanagen phase.

Patient approachThere are many etiologic factors that causeclinical hair loss, or alopecia, including endo-crine abnormalities, genetic predisposition,systemic illness, drugs, psychological abnor-malities, diet, trauma, infections,autoimmunity, and structural hair defects. Be-cause of the multiplicity of disorders that canresult in hair loss, a thorough history andphysical examination are important, and an-cillary laboratory work-up may be necessary.


Table 1.1Hair loss history questionnaire

Table 1.2Differential diagnosis

History

The history is of critical importance in devel-oping the initial differential diagnosis (Table1.1). The age of the patient is very important.Certain conditions are more common in child-hood compared to the adult. The two mostcommon forms of hair loss in children are tineacapitis and alopecia areata. The duration andpattern (i.e. diffuse versus focal) of hair loss isvery important to determine. A full list of cur-rent and past medication should be obtained(see Chapter 5), since many medications caninduce hair loss. Patients should be askedquestions regarding hair shedding (alopecia ar-eata or telogen effluvium) versus simple hairthinning without shedding (androgenetic alo-pecia). Key questions implicating a telogen ef-fluvium are: Any pregnancy, high fever,operations/general anesthesia, crash diets, orweight loss in the preceding 6 months? A posi-tive family history of alopecia areata orandrogenetic alopecia may point to a geneticpredisposition for hair loss. In addition, thepresence or absence of coincidental acne and

abnormal menstrual cycles may indicate anandrogen excess causing androgenetic alo-pecia. Thyroid screening questions may pointto hyper- or hypothyroidism, and a strict veg-etarian diet can implicate iron deficiencyanemia. Some hair care practices (e.g. bleach-ing, back brushing, permanent waving) mayresult in hair breakage. It is important to estab-lish whether the hair falls out from the roots orbreaks off along the shafts, since there are com-pletely different causes for each of these situa-tions (Table 1.2). It is also important toquestion about the loss of axillary and pubichair, eyelashes, eyebrows, and body hairs,since any hair-bearing area may be affected byalopecia areata or trichotillomania.

The patient’s concerns and expectationsshould be acknowledged and fully explored.Many patients with hair disorders becomefrustrated when their worries about hair lossare either ignored or dismissed as insignifi-cant. Explanation and discussion may resolvethe problem without specific intervention. Oc-casionally an underlying depression or dys-morphophobia (pathologically focused


Figure 1.12Presence or absence of follicular ostia is crucial in the differential diagnosis. Note: (a)Follicular ostia in a non-scarring alopecia, such as alopecia areata. (b) Absence of follicularostia in a scarring alopecia.

Table 1.3Causes of alopecia

contrast paper and place the hairs against it toexamine the sizes of hairs (Figure 1.13).

Pull test: To determine the ongoing activityof hair loss, a useful ancillary test, the ‘pulltest’, should be conducted. Approximately 60hairs are grasped between the thumb, indexand middle fingers from the base of the hairsnear the scalp, and firmly, but not forcefully,tugged away from the scalp (Figure 1.14). If

fixation on body image) may be present. It isimportant that these psychiatric conditions berecognized and managed before any furthertreatment is initiated.

Clinical examination

Clinical examination should be performed inthree stages. On the scalp, first inspect for in-flammation, scale, and erythema. It is impor-tant to determine if the hair loss is associatedwith scalp scarring (Table 1.3), as this intro-duces an entirely different differential diagno-sis. Non-cicatricial alopecias demonstratevisible follicular units, while cicatricialalopecias are devoid of follicular units (Figure1.12). Second, examine the pattern of densityand distribution of hair. Certain characteristicpatterns of hair loss are more common for cer-tain diseases. Random patterns are more com-mon for alopecia areata. Finally, study thequality of the hair shaft in terms of caliber, fra-gility, length and shape. It is useful to take a


Figure 1.13A contrast paper positioned at an involvedarea of the scalp will help determine thelength, size and overall caliber of the hairshafts. This alopecia areata patient showedone month of spontaneous regrowth in a baldpatch without any treatment.

Figure 1.14Pull test: (a) Approximately sixty hairs aregrasped from the proximal portion of thehairs shafts at the level of the scalp. (b) Thehairs are then tugged from proximal to distalend. (c) The number of hairs extracted iscounted. It is normal to pull up to 6/60 (<10%) hairs. More than 6/60 hairs is a positivepull test and implies pathology. This is a 57-year-old female with diffuse alopecia areatadisplaying a very positive pull test.


Figure 1.15Trichogram/Pluck test: The trichogram/pluck test is another method of assessing hair loss. Onthe fifth day after the last shampoo, hairs are taken from specified sites. (a) The surroundinghair is fixed with clips and 60–80 hairs are grasped with a hemostat covered with rubber andare plucked, twisting and lifting the hair shafts rapidly in the direction of emergence from thescalp. (b) Anagen hairs are distinguished from telogen hairs and anagen to telogen ratios arecalculated.

more than 10% or 6 hairs are pulled awayfrom the scalp, this constitutes a positive pulltest and implies active hair shedding. If lessthan 6 hairs can be easily pulled away fromthe scalp, this is considered normalphysiologic shedding. The patient must notshampoo for at least one day prior to the pulltest. The pull test helps to assess the severityand location of hair loss.

Trichogram/pluck test: The trichogram/pluck test is another method of assessinghair loss. On the fifth day after the last sham-poo, hairs are taken from specified sites9.The surrounding hair is fixed with clips and60–80 hairs are grasped with a hemostat cov-ered with rubber and are plucked, twistingand lifting the hair shafts rapidly in the di-rection of emergence from the scalp (Figure1.15). Hair shafts are then cut off 1 cm abovethe root sheaths and roots are arranged side

by side on a slide. Anagen hairs are distin-guished from telogen hairs and anagen totelogen ratios are calculated. Counts of dys-trophic hairs are unreliable, since much ofthe observed hair dystrophy is artefactual,owing to hair damage caused by the pluckingprocedure. For noncicatrizing alopecias thisanagen/telogen ratio has diagnostic signifi-cance. Because a scalp biopsy can give thephysician the same information plus moreregarding inflammation and the size of hairs,the trichogram has not become routine. Theunit area trichogram, popularized byRushton,10 is more accurate than the regulartrichogram, as it takes into account not onlyanagen/telogen ratios but also hair densityand size. With this technique, a fixed area ismarked on the scalp through a template andall the hairs in that area are individuallyepilated with tweezers and mounted on a


slide for counting. This meticulous tech-nique can be quite laborious and requiresvery special skill.

Hair counts: Daily scalp counts can be use-ful to the physician to help quantify how muchthe patient is losing and make sure this is notmore than physiologic hair loss. It is normal tolose 100–150 hairs per day. Patients are askedto collect all the hairs shed in one day, countthem and place them in plastic sandwich bags.All hairs shed in the shower, or sink or on thebrush, counter or pillow are collected. Sham-poo days are labeled separately, as it is ex-pected that there will be more shedding onthose days. Patients are instructed to do this

daily for 7 days. If the patient is losing less than100 hairs per day, then there is currently noactive shedding, but only physiologic hair loss.Performing a hair count is tedious andtimeconsuming for the patient. But it is some-thing that patients can do on their own to fol-low their progress.11

Light-microscopic examination

Hairs extracted by slow pull can be exam-ined under the light microscope (Figure1.16). Hair shafts are mounted in parallel

Figure 1.16Light microscopic examination of hairs: (a)telogen hair with characteristic club; (b)anagen hair with inner root sheath; (c) hairshaft abnormality: trichorrhexis nodosasecondary to trauma. (Courtesy of Dr DavidShum.)


Figure 1.17How to do a scalp biopsy:(a) In order to obtain sufficient histopathologic information, the scalp biopsy should be takenfrom an active inflammatory area containing hair follicles or active hair destruction. In non-inflammatory conditions a biopsy in a representative area is sufficient. If possible the biopsyshould be taken from a cosmetically less apparent area of the scalp. Staying away from hairparts or the frontal portion of the scalp is recommended. The area to be biopsied is markedwith a red china marker. For local anesthesia, lidocaine 1 % with epinephrine in a concentra-tion of 1:100,000 is injected with a 30 gauge needle into the scalp. Epinephrine causes vaso-constriction, which has a hemostatic effect in a highly vascular site such as the scalp. Inaddition, a mandatory waiting period of at least 10 minutes is suggested following theanesthetic injection. This allows the vasoconstrictive effect of epinephrine to take effect andhence maximize the hemostasis. (b) A 4.0 mm punch biopsy is placed parallel to follow thedirection of the hair. In patients who have curly hair as above, insert the punch perpendicularto the scalp. (c) Direct vertical pressure is applied along with the rotation of the punch.Penetration of the punch to a depth of approximately 3.5–4.0 mm is sufficient to obtain a fullscalp thickness. The typical punch should be pushed right through to the hub.


between two glass slides taped together. Adrop of cyanoacrylic glue placed on the slidewill give greater contrast under the micro-scope compared to a dry mount. Rootsshould be examined to determine the stageof the hair cycle and for the presence of dys-trophy. Hair shaft abnormalities (which canincrease hair fragility and cause hair loss)can be diagnosed with this method. The hairshafts need to be examined to detect frac-tures, irregularities, coiling and twisting and

extraneous matter. The free ends of the hairshould be checked to see whether they aretapered, cut, fractured or weathered. For themost part, most hair shaft abnormalities arequite rare, and the hair mount is not usedroutinely at the University of British Colum-bia (UBC) Hair Clinic unless indicated. Iffungal diseases are suspected, hairs shouldbe placed on a glass slide with 20% potas-sium hydroxide added in order to demon-strate fungal spores and hyphae.

(d) The same needle for the anesthesia can beused to hook the tissue beneath the hairbulbs.(e) Aluminum chloride 20% solution on aQtip can be used for hemostasis after thebiopsy has been removed.(f) The biopsy defect is closed with abluecolored monofilament suture, whichhelps to identify the suture on the hairyscalp, particularly with pigmented hairs. Thesuture needle is passed through the upperdermis, preventing damage to the hair bulbslocated in the deep dermis. Wound dressingsare not necessary for scalp biopsies.


The scalp biopsy: Scalp biopsies are indi-cated in all cases of cicatrizing alopecias andin all cases of unexplained non-cicatrizingalopecias12. At the UBC Hair Clinic all biop-sies for non-cicatrizing alopecias are performedwith transverse/horizontal sectioning ratherthan longitudinal/vertical sectioning. This al-lows a greater number of follicles to be exam-ined. The biopsy must be deep and include theentire follicular unit, including some subcuta-neous fat (Figure 1.17). Usually this involves adepth of 4 mm. The technique of vertical sec-tioning was popularized by Headington13 andsubsequently by Whiting14 and Sperling.15 Atthe UBC Hair Clinic a 4 mm punch biopsy istrisected at two levels and subsequently hori-zontal sections are read from the base of thefollicle to the papillary dermis. Normally ascalp biopsy has 35–40 hairs at the upper lev-els in papillary dermis. At the level of reticulardermis near the base of the infundibulum, thenumber is reduced to 35; at the deeper levelsnear the subcutaneous fat, the numbers are evenless, at around 30. The upper levels containtelogen and anagen hairs, as well as terminaland vellus and vellus-like miniaturized hairs.The mid-levels consist of anagen and telogenhairs with terminal hairs only. The deeper lev-els contain anagen terminal hairs. The differ-ence between the upper levels and mid levelsis usually the number of vellus or vellus-likehairs. The difference between the mid levelsand the lower levels is the number of terminaltelogen hairs. Anagen/telogen ratios as well asterminal/vellus ratios can easily be calculatedon the basis of the above and the morphologyof the follicles. Peri-, intra- and interfollicularinflammation, if present, will be very promi-nent at all levels of the biopsy.

For cicatrizing alopecias, two biopsies aretaken. The first 4 mm punch biopsy is takenfor transverse sectioning. Another 4 mm bi-

opsy is bisected longitudinally. One half issent for direct immuno-fluorescence and theother half for longitudinal sectioning. Not onlyare the various scarring alopecias difficult todifferentiate from each other clinically, butoccasionally they may also be difficult to dis-tinguish clinically from non-scarringalopecias. For those difficult cases, it is obliga-tory to perform a 4 mm scalp biopsy.

The characteristic histologic features of themost common non-cicatrizing and cicatrizingalopecias are discussed in subsequent chapters.

Laboratory tests: Lab tests may be helpful inestablishing a diagnosis. Evaluation of serumferritin may be necessary to exclude iron defi-ciency anemia, particularly in women withdiffuse alopecia. If thyroid dysfunction is sus-pected, a thyroid-stimulating hormone levelshould be investigated. In women withandrogenetic alopecia and virilizing signssuch as hirsutism, acne, or irregular menses,an endocrinologic work-up consisting of freetestosterone, and dehydroepiandrosteronesulfate (DHEAS) is advised to rule out hyper-androgenemic states. In cases of confirmedscarring alopecia due to discoid lupus ery-thematosus, an antinuclear antibodies (ANA)examination should be performed.

Non-cicatricial alopeciasIn the non-cicatricial alopecias, there is pres-ervation of follicles on clinical and histologicexamination, although they can sometimes bedifficult to appreciate when miniaturized. Thethree most common forms of non-cicatricialalopecias are androgenetic alopecia, telogeneffluvium, and alopecia areata. Table 1.4 com-pares the key clinical features that distinguishthese three conditions from each other. Theseconditions are discussed at length in otherchapters of the book.


Table 1.4Common non-scarring alopecias

Cicatricial (scarring)alopeciaLocalized areas of cicatricial alopecia of thescalp may result from trauma, burns, acutefungal infections such as tinea capitis, viralinfections such as herpes zoster, and bacterialinfections. Discoid lupus erythematosus (DLE)is the most common primary cause of scarringalopecia, and lichen planus is another com-mon etiology. Lesions of DLE demonstratemarked erythema, atrophy, telangiectasia, andfollicular hyperkeratosis. A biopsy is neces-sary to establish an accurate diagnosis. Evi-dence of cutaneous disease elsewhere on theskin, oral or genital mucous membranes, andnails should be looked for carefully. Scarring

alopecias are considered true trichologic emer-gencies, as there is irreversible hair loss oncehair follicles have become scarred. The impor-tance of prompt appropriate therapy is crucial.The most common causes for scarring alopeciaare discussed at length in Chapter 7.

ConclusionThe majority of common hair disorders can bereadily diagnosed in the physician’s officethrough the recognition of the characteristicdifferential features of each disorder. The firsttask of the physician is to acknowledge the pa-tient’s concerns and have an empathetic ap-proach to the problem of hair loss. Thediagnosis depends upon a combination of find-


ings obtained from meticulous history, physi-cal examination and any necessary investiga-tions. An organized diagnostic andmanagement strategy will help both to iden-tify the cause of alopecia and to direct therapy.

References1. Shapiro J., Wiseman M. and Lui H. Practical

management of hair loss. Can Fam Physi-cian, 2000; 46:1469–77.

2. Cotsarelis G., Sun T.T. and Lavker R.M.Label-retaining cells reside in the bulge areaof pilosebaceous unit: implications forfollicular stem cells, hair cycle, and skincarcinogenesis. Cell, 1990; 61(7):1329–37.

3. Sun T.T., Cotsarelis G. and Lavker R.M. Hairfollicular stem cells: the bulge-activationhypothesis. J Invest Dermatol, 1991; 96(5):77S–78S.

4. Lavker R.M., Cotsarelis G, Wei Z.G. and SunT.T. Stem cells of pelage, vibrissae, andeyelash follicles: the hair cycle and tumorformation. Ann N Y Acad Sci, 1991; 642:214–24; discussion, 224–5.

5. Lavker R.M., Miller S., Wilson C. et al. Hairfollicle stem cells: their location, role in haircycle, and involvement in skin tumorformation. J Invest Dermatol, 1993; 101(1Suppl):16S–26S.

6. Cotsarelis G., Kaur P., Dhuailly P., et al.Epithelial stem cells in the skin: definition,markers, localization and functions. ExpDermatol, 1999; 8(1):80–8.

7. Lyle S., Christofidou-Solomidou M., Liu Y.,

et al. Human hair follicle bulge cells arebiochemically distinct and possess anepithelial stem cell phenotype. J InvestDermatol Symp Proc, 1999; 4(3):296–301.

8. Reynolds A.J., Lawrence C.,CserhalmiFriedman P.B., et al. Trans-genderinduction of hair follicles. Nature, 1999;402(6757): 33–4.

9. Orfanos C. Androgenetic alopecia: clinicalaspects and treatment. In Hair and HairDiseases, ed. C.Orfanos, pp. 485–527. 1990;Berlin: Springer-Verlag.

10. Rushton H., James K.C. and Mortimer C.H.The unit area trichogram in the assessmentof androgen-dependent alopecia. Br JDermatol, 1983; 109(4):429–37.

11. Olsen E. Clinical tools for assessing hair loss.In: Disorders of Hair Growth Diagnosis andTreatment, ed. E.Olsen, pp. 59–69, 1994;New York: McGraw-Hill, Inc.

12. Madani S. and Shapiro J. The scalp biopsy:making it more efficient. Dermatol Surg,1999; 25(7):537–8.

13. Headington J.T. Transverse microscopicanatomy of the human scalp. A basis for amorphometric approach to disorders of thehair follicle. Arch Dermatol, 1984; 120(4):449–56.

14. Whiting D.A. Diagnostic and predictivevalue of horizontal sections of scalp biopsyspecimens in male pattern androgeneticalopecia [published erratum appears in J AmAcad Dermatol 1993 29(4):554]. J Am AcadDermatol, 1993; 28(5 Pt 1): 755–63.

15. Frishberg, D.P., Sperling L.C. and GuthrieV.M. Transverse scalp sections: a proposedmethod for laboratory processing. J AmAcad Dermatol, 1996; 35(2 Pt 1):220–2.

2 Alopecia areata: Pathogenesis,clinical features, diagnosis andpractical management

Alopecia areata (AA) is an unpredictable, usu-ally patchy, non-scarring hair loss conditionaffecting any hair-bearing surface. AA is gen-erally felt to be mediated by T lymphocytes di-rected at hair follicles. The exact cause isunknown, but is likely to be an interaction be-tween genetic and environmental factors.Within the past decade, there have been sig-nificant advances in our understanding of alo-pecia areata. Most recent research and futuredirections in alopecia areata originate fromthree major research workshops co-sponsoredby the National Alopecia Areata Foundation(NAAF) and the National Institute of Arthritisand Musculoskeletal and Skin Diseases(NIAMS) in 1990, 1994 and 1998. At thesemeetings, numerous subspecialties, includingimmunologists, molecular biologists, bio-chemists, dermatologists, pathologists, and ge-neticists, discussed alopecia areata in an openforum. The proceedings of these meetings havebeen published in the Journal of InvestigativeDermatology.1–3 This chapter will review thelatest information on etiology, clinical featuresand state of the art treatment for AA.

EtiologyThe etiology of A A is unknown. Genetic andimmunologic factors have been important ar-

eas of attention. Other proposed etiologies in-clude infectious agents, cytokines, emotionalstress, intrinsically abnormal melanocytes orkeratinocytes and neurological factors.

Genetic factorsGenetic factors play an important role in theetiology of AA. There is a high frequency of apositive family history of AA in affected indi-viduals, ranging from 10% up to 42 % ofcases.4,5 There is a significantly higher inci-dence of a positive family history in patientswith early onset of AA.6 Familial incidence ofAA has been reported to be 37% in patientswho had their first patch by 30 years of ageand 7.1% with the first patch after 30 years ofage.6–9 Also, there have been reports of AA inidentical twins,10–14 with up to 55% concord-ance rate in identical twins.13 Scerri14 pre-sented a case of 11-year-old identical twinboys, with ophiasis occurring simultaneously.

Several closely linked genes, such as the hu-man leukocyte antigens (HLA) are located onthe short arm of chromosome 6, forming theMajor Histocompatibility Complex (MHC).6,15

The HLA complex has been investigated in AApatients because of the association of otherautoimmune diseases with increased frequen-cies of HLA antigens.15,16 Associations with


Figure 2.1(a, b) Alopecia areata and Down’s syndrome. There is up to an 8.8% increased frequency ofAA in patients with Down’s Syndrome, suggesting involvement of a gene located on chromo-some 21 in determining susceptibility to AA.

both HLA class I (HLA-A, -B, -C) and class II(HLA-DR, -DQ, -DP) have been studied in AA.The earlier studies identified the associationof AA with several class I antigens, such asHLA-A9, B7, and B8,16 B12,17 B18,18 B13, andB27.19. There have also been studies showingno correlation with HLA Class I antigens.20,21

Recently, there has been an increased consist-

ency in evidence revealing associations be-tween AA and HLA class II antigens. The stud-ies reveal a significant association ofHLA-DR11 and DQ3 in patients with AA.7–9,22–

29 The HLA alleles DQB1*03 (DQ3) and HLA-DRB1*1104 (DR11) appear to be markers ofgeneral susceptibility for all forms of AA.7–9,28,29

The HLA alleles DRB1*0401 (DR4) and DQB1*

Alopecia areata 21

0301(DQ7) are markers for more severe long-standing alopecia totalis/universalis.7–9 with arelative risk for AA of 30.2 for DRB1*0401. Theinvestigators9 suggest that amino acidsequencing of the antigen binding grooves ofthese HLA antigens may indicate the structureand identity of the elusive AA target antigens.Other investigators26 also suggest thatDRB3*52a may confer resistance to AA. Byidentifying these HLA genetic correlations, weare a step closer to understanding the struc-ture of the epitopes recognized by T cells,which are key to the follicular inflammatoryimmune response responsible for AA. Identi-fication of the AA antigens will be a major stepin understanding the mechanisms of AA andin the design of therapies for prevention andtreatment. However, one must bear in mindthat the presence of predisposing HLA is butone component in a cascade of factors leadingto autoimmune disease. Alopecia areata is acomplex trait expressed by a number of genes.Polygenic influences are clearly involved.There is up to an 8.8% increased frequency ofAA in patients with Down’s Syndrome, sug-gesting involvement of a gene located on chro-mosome 21 in determining susceptibility toAA (Figure 2.1).30,31 Thirty per cent of patientswith autoimmunepolyglandular syndromehave AA. The defective gene in this syndromeis mapped to chromosome 21, again implicat-ing this chromosome.59 Tarlow et al. reportedan association between the severity of AA andinheritance of allele 2 of a five-allele polymor-phism in intron 2 of the interleukin-1 receptorantagonist gene.32 The IL-1 gene cluster onchromosome 2 includes genes for theproinflammatory IL-1 proteins, their cell mem-brane receptors and the anti-inflammatory IL-1 receptor antagonist. Polymorphism withinthe IL-1 cluster may modulate IL-1 responses.IL-1 has a direct effect on hair growth. In hair

follicle organ cultures, IL-1 inhibits growth ofthe hair fiber33 and induces morphologicalchanges that resemble those seen in AA.34

In conclusion, many studies indicate thatAA is a polygenic disease with certain genescorrelated with susceptibility and others withseverity. Most probably, there is an interactionbetween genetic and environmental factorsthat triggers the disease. At this point, the ex-act causative genes have not been discovered.With the discovery of animal models for AA,and with the final data on the Human GenomeProject just completed, it is expected that ourunderstanding of this complex trait will be fur-ther clarified. Genetic research may ultimatelyexplain why, how and who develops AA.

Immunological factors

Indirect clues for autoimmunity

There are indirect clues for autoimmunity thatinclude the association of the disease with aHLA haplotype, other autoimmune diseasesand a responsiveness to immunosuppressivetherapy. HLA associations have been dis-cussed above. There are reported associationsbetween AA and classic autoimmune disor-ders. The main associations are with thyroiddiseases and vitiligo. Several reports reveal an8.0–11.8% incidence of thyroid disease in pa-tients with AA, compared to only 2% in thegeneral population.4,5 This evidence has beenfurther confirmed by documentation of an in-creased prevalence of anti-thyroid antibodies35

and thyroid microsomal antibodies.35 How-ever, Puavilai et al. showed no increase in mi-crosomal antibodies compared to normalcontrols.36 AA has been shown to have a sig-nificant association with vitiligo, with a four-fold greater incidence of vitiligo in AA


patients.4,37,38 Other studies have revealed anincreased prevalence of gastric parietal cell an-tibodies and anti-smooth muscle antibodies insera of patients with AA.39,40 There are also re-ported associations of AA with perniciousanemia,40 diabetes mellitus,40 lupus erythema-tosus,41 myasthenia gravis,42–46 polymyalgiarheumatica,47 ulcerative colitis,46,48–50 lichenplanus,51–55 and autoimmune polyendoc-rinopathy-candidiasis ectodermal dystrophy,also known as autoimmune polyglandular syn-drome Type 1(APS-1).56–59 Thirty per cent ofpatients with APS-1 have AA.

Successful treatment of AA with immuno-suppressive agents such as oral cyclos-porine60,61 and systemic steroids62 alsosupports the idea of immune-mediatedpathogenesis in AA.

Direct clues for autoimmunity

Humoral immunity

Studies in the past with direct immunofluo-rescence have failed to show particular anti-bodies to epidermal cells or hair follicles inAA.63 Studies of passive transfer of serum fromAA patients to nude mice failed to inhibit hairgrowth in grafted transplants of human scalpskin.64 However, Tobin and coworkers reporteddetection of antibodies to pigmented hair fol-licles by Western blotting in the sera of 100%of the AA patients examined, as compared toonly 44% of normal controls.65 In anotherstudy by Tobin et al,66 much higher levels ofautoantibodies to multiple structures ofanagen hair follicles in AA patients have beenreported, as compared to controls using indi-rect immunofluorescence. The antibody re-sponse to hair follicles in patients with AA hasbeen found to be heterogeneous, because dif-ferent patients develop different patterns of an-

tibodies to different hair follicle structures.The most common target structures were theouter root sheath, followed by the matrix, in-ner root sheath, and hair shaft.66

Cell-mediated immunity

Studies of cell-mediated immunity in AA havegiven conflicting results. Circulating total num-bers of T-lymphocytes have been reported asreduced40,67 or normal.68 Friedmann40 suggestedthat the number of circulating T-cells is reducedin AA, and that the level of this reduction isrelated to disease severity. In addition, he sug-gested that the impairment of helper T-cellfunction and the change in suppressor T-cellnumbers may also reflect changes in diseaseactivity. A slight increase in helper T-cells(CD4) and decrease in number of suppressorT-cells (CD8), resulting in an increase in theratio of helper to suppressor cells, may be cor-related with the amount of hair loss.67

The dense peribulbar lymphocytic infiltrateaffecting anagen follicles is one of the mostconsistent and reproducible immunologic ab-normalities in AA. The cellular infiltrate firstbecomes evident around the bulbar blood ves-sels, particularly in the dermal papilla/capil-lary network, and consists mostly of Tlymphocytes and, to a lesser extent,macrophages and Langerhans cells. The infil-trate is most prominent in active disease. Theinfiltrate subsides in inactive disease and dis-appears in the regrowth phase. Most of the Tcells are activated, as can be seen by the ex-pression of DR antigens and IL-2 receptors.The T cell helper to suppressor ratio is 2:1–4:1. The implication of these observations isthat there may be an immune response to anti-gens in the lower half of hair follicles or in theperibulbar blood vessels in AA. The presenceof cellular infiltrates around unaffected hair

Alopecia areata 23

Figure 2.2The pathogenesis of alopecia areata. Antigen-presenting cells, such as Langerhans cells,are increased in the bulb of the affectedfollicles. They present the responsibleepitope to the peribulbar lymphocytes. Thisleads to a cascade of immunologic eventswith increased interleukin-2 (IL-2), gammainterferon (γIFN) and intercellular adhesionmolecules (ICAM). This series of eventshelps to induce hair loss. This is consideredto be a Type 1 T helper cell response (Th

1).

follicles suggests that the process precedesrather than results from injury to hair follicles.

Gilhar69 and Tsuboi70 have shown that graft-ing affected scalp AA skin from humans on toSCID mice results in regrowth of hair, with thedisappearance of the T cell infiltrate. Tsuboihas shown that the CD8+ cells had disap-peared completely from almost all portions ofthe hair follicle, while CD4+ cells still re-mained in the upper portions of the hair folli-cle. This may imply the greater importance ofCD8+ in the expression of alopecia areata. Fur-thermore, more recently, Gilhar et al.69 re-ported that AA can be induced in human scalpexplants from AA patients transplanted on toSCID mice by transfer of autologous T-lymphocytes isolated from involved scalp. Inthis study, T-lymphocytes that had been cul-tured with hair follicle homogenate along withantigen-presenting cells and melanocyt-ederived protein were capable of inducing thechanges of AA. These changes include hairloss, perifollicular T-cell infiltration, HLA-DRand intercellular adhesion molecule-1 (ICAM-1) expression of follicular epithelium. T-cellsthat had not been cultured with follicular ho-mogenate were not able to induce AA. Thenecessity of the follicular homogenate to in-ducing AA suggests that T cells recognize afollicular auto-antigen. Furthermore, AA in-duction followed upon injection with CD8+cells cultured with follicular homogenate, butnot on injection of the cultured CD4+ cells.This study also suggests that AA is mediatedby T-cells, particularly CD8+ cells.69

In order for a medical condition to fit as anautoimmune disease, the following criteriashould be met:

1. Unique antigens in the affected organ2. An autoimmune response to that antigen3. An autoimmune response specifically as-

sociated with the disease

4. The autoimmune response producing, notfollowing, the condition

5. The disease being transferred passively byautoantibodies or T cells.

For AA, many of the above criteria are indeedmet. Increased frequency of hair-specific anti-bodies, antibodies to pigmented hair follicles,high levels of autoantibodies to multiplestructures of anagen hair follicles, an increasein the ratio of helper to suppressor cells, andinduction of AA on SCID mice by transfer ofT-lymphocytes cultured with follicularhomogenates are evidence supporting theview that AA is an autoimmune disease tar-geting the hair follicle. Figure 2.2 illustrates


some of the immunologic cascade events thattake place in alopecia areata.

The hair follicle has a distinct immune sys-tem71 that differs from that of its surroundingskin. The cellular components of the hair folli-cle immune system are composed ofintrafollicular T lymphocytes and Langerhanscells, located exclusively in the distal outer rootsheath, and perifollicular mast cells andmacrophages.71 There is also a unique expres-sion of follicular MHC class Ia/Ib, and ICAM-1.71 Human hair follicles may even serve as aLangerhans cell reservoir. The epithelium of theproximal anagen hair follicle is immune-privi-leged, since the inner root sheath and hair ma-trix do not express MHC class I molecules. Thisimmune privilege may collapse in alopecia ar-eata. A recent theory for AA proposed by Pauset al.72 involves the upregulation of MHC anti-gens and/or downregulation of locally producedimmunosuppressants (melanocyte- stimulatinghormone, adrenocorticotropin and transforminggrowth factor), allowing the immune system torecognize the immune-privileged hair follicleantigens, leading to onset of AA.

Cytokines

It appears that cytokines have a significantpathogenic role in AA. Cytokines areimmunomodulators mediating inflammationand regulating cell proliferation. Cytokines de-rived from epidermal keratinocytes,interleukins IL-1α, IL-1β and tumor necrosisfactor-α (TNF-α) are potent inhibitors of hair fol-licle growth, and in vitro produce changes inhair follicle morphology similar to those inAA.34,73 T helper cells produce cytokines di-vided into two subgroups depending on the pat-tern of cytokine production. Type 1 T helper(Th1) cells produce interferon γ (IFN-γ) and IL-

2. Type 2 helper (Th2) cells produce IL-4 andIL-5.74 Aberrant expression of cytokines of theTh1 type (see Figure 2.2) and IL-1β have beendetected in affected areas of the scalp in pa-tients with AA.73 As hair regrows with topicalimmunotherapy, these cytokine profileschange.

Infection

There has been a report regarding the possibil-ity of cytomegalovirus (CMV) infection foundwithin the patches of scalp AA. This initial re-port showed a convincing positive associationwith CMV,75 but this has not been confirmed,as other investigators have reported negativefindings.76–78 The whole concept of molecularmimicry of the hair follicle with a virus is in-triguing, but the evidence for a viral etiologyof AA at this point in time is not conclusive.

Emotional stress

Several studies suggest that stress may be aprecipitating factor in some cases of AA. Acutepsychotrauma before the onset of AA,79–81 ahigher number of stressful events in the 6months of preceding hair loss,80 higher preva-lence of psychiatric disorders81 and psychoso-matic factors in patients with AA have beenreported.82 In contrast, there are reports reveal-ing that emotional stress does not play any rolein the pathogenesis of AA.83

Intrinsically abnormal

melanocytes or keratinocytes

Morphological analysis of follicles in activeAA lesions has revealed regressive changes in

Alopecia areata 25

Figure 2.3Alopecia areata animal models: the C3H/HeJmouse and the DEBR rat.

the hair bulbs of anagen hair follicles.84–86 Ab-normal melanogenesis and melanocytes arecommon findings. This evidence, togetherwith the presence of antibodies to pigmentedhairs of AA, may explain some of the associ-ated pigmentary anomalies seen clinically inacute AA and the preferential effect of AA onpigmented hairs (Figure 2.12). Also, degenera-tion of pre-cortical keratinocytes has beenshown in follicles of active AA lesions.85 Ab-normal melanosomes in clinically normal re-gions, together with degenerative changes,including vacuolation, in outer root sheath ofall hair follicles from non-balding lesions ofAA,85 correspond well with the hypothesis ofa sub-clinical condition of the disease in clini-cally normal areas of AA.

Neurological factors

It has been suggested that local changes in theperipheral nervous system at the level of thedermal papilla or bulge region may play a rolein the evolution of AA, since the peripheralnervous system can deliver neuropeptides thatmodulate a range of inflammatory and prolif-erative processes.87 This theory has been sup-ported by Hordinksy et al., who revealed adecrease in calcitonin gene-related peptide(CGRP) and substance P (SP) expression in thescalps of patients with AA.88 The neuropeptideCGRP has a potent anti-inflammatory ac-tion,88,89 and neuropeptide SP is capable of in-ducing hair growth in the mouse.88,90 Inaddition, application of capsaicin, whichcauses neurogenic inflammation and releasesSP, to the entire scalp of two AA patients re-vealed an enhanced presence of SP in AA peri-follicular nerves and induced vellus hairgrowth.91

Animal models

Alopecia areata animal models

In the past our understanding of thepathogenesis of AA was slow to progress ow-ing to the lack of animal models for this dis-ease. Recently, investigations of AA have beenfacilitated by using animal models with eitherspontaneous or induced AA. Animal modelswith spontaneous AA include the C3H/HeJmouse,92 the Dundee experimental bald rat(DEBR)93 (Figure 2.3) and the Smyth chicken.94

The Smyth chicken model also has vitiligo,and may suggest a link between vitiligo, mela-nogenesis and the development of AA.

AA can be induced in normal C3H/HeJ miceusing full-thickness skin grafts from affectedC3H/HeJ mice.95 AA developed 8–10 weeksafter grafting. These same investigators95 notedthat AA could be induced in 8–10 weeks bytaking skin-draining lymph node cells from


Figure 2.4Diphencyprone was applied to half the C3H/HeJ alopecia areata mouse, showing signifi-cant regrowth on the treated portion of themouse.

AA-affected mice and transferring them to nor-mal-haired recipients.95 The ability to induceAA in a model suggests that, whereas indi-viduals may be genetically predisposed to-ward AA, susceptibility genes are not enoughto develop the condition. AA induction canalso be used to produce large numbers of micefor testing pharmaceutical agents.

A preliminary study using C3H/HeJ miceexamined potential chromosome locationsthat may contain genes involved in AA.96

Three gene loci common to AA susceptibilitywere located. A region on mouse chromosome6 may contain genes involved in inflammatoryevents associated with AA.96 A separate inves-tigation on human AA by Tarlow et al.32 iden-tified the equivalent chromosome region2p12–13 as being a location for AA suscepti-bility. These human-animal correlations mayhave importance to understanding the map-ping of the putative genes.

Lymphocyte cells from C3H/HeJ AA micewere screened, and T cell clones expressing aVß8.2/Jß2.5 T cell receptor (TCR) arrange-ment predominated.97 The receptor arrange-ment of these cell clones may help identifytargeted antigens in AA. This may eventuallypermit selective immune therapy using anti-TCR antibodies or clonal vaccination treat-ments.

Animal models are now used in research fornew and improved treatments. Lui et al. haveshown that leflunomide, an IL-2 inhibitor, hassome efficacy in the DEBR rat.98 Shapiro et al.99

have shown efficacy of diphenylcyclopropenonein the C3H/HeJ mouse (Figure 2.4). Freyshmidt-Paul has shown the efficacy of squaric aciddibutyl ester in the C3H/HeJ AA mouse.100

Animal models with AA-like hair loss aresignificantly useful in investigations regardingpathogenesis, disease behavior, efficacy andside-effects of available or future treatments.

Non-alopecia areata

animal models

The hairless mouse has an autosomal recessiveallelic mutation that maps to chromosome14.101,102 These mice develop a normal pelageat about 14 days and then lose their hair over 1week. Recently investigations have correlatedthis hairless gene in mice with congenitalatrichia in humans. The human hairless genehas been cloned to chromosome 8p12.103 Thisgene does not cause AA. However, this genemay have importance in maintaining hair fol-licle integrity by balancing cell proliferation,differentiation and apoptosis within the hairfollicle.

Hox genes are involved in controlling theposition, density and development of hair invertebrate embryos. Transgenic Hoxc13 defi-

Alopecia areata 27

cient mice were unable to synthesize hairkeratins and have sparse brittle hair.104 Hoxc13may play a significant role in follicular prolif-eration and differentiation.104 More knowledgeof Hoxc13 expression in epidermal append-ages will in turn provide further insight intothe functioning of the normal ordered follicle,which in turn will allow us to understand thedisordered follicle more clearly.

Non-AA animal hair mutations may even-tually help us to unravel the delicate mecha-nisms of the hair cycle and subsequently bringus closer to understanding the disordered hairfollicle as it is found in AA.

PathologyIn early active AA, the hair cycle is abnormal,with hair follicles entering the telogen or latecatagen stage prematurely in the involved ar-eas.105 There are distinct stages in the histopa-thology of AA: (a) acute alopecia; (b) persistentalopecia; (c) recovery.106 A peribulbar lym-phocytic infiltrate (‘swarm of bees’) with noscarring is characteristic of the diagnosis of AA(Figure 2.5). The inflammatory cellular infil-trate is composed chiefly of activated T-lymphocytes together with macrophages andLangerhans cells.107,108 Also, miniaturization ofhairs, with numerous fibrous tracts along withpigment incontinence within these fibroustracts, is appreciable (Figure 2.5). During theacute phase of hair loss, matrix cell and matri-cal melanocyte failure with a formation of dys-plastic hair shafts is noted. Followingcomplete matrix failure, the involved follicleenters the end-stage telogen. A decreasedanagen to telogen ratio, resulting in marked in-crease in telogen and catagen hairs, can be ob-served in horizontal sections of scalp

biopsies109,110 (Figure 2.5e). The terminal tovellus ratio is decreased and even reversed bythe increased numbers of miniaturized hairs.Inflammatory changes in the mid and upperdermis are generally not prominent unlessmany vellus hairs are affected by the disease.In patients with long-standing persistent alo-pecia, the involved hair follicles arrest in theend-stage telogen phase. In these cases,peribulbar infiltration along with an increasein Langerhans cell numbers,111 a decrease infollicular density and follicular miniaturiza-tion may be present. In patients with completerecovery, normal hair follicles with little or noperibulbar lymphocytic infiltration and no de-crease in hair density are noted.

Eosinophils are also detectable in all stagesof AA, both within the peribulbar infiltrate andthe fibrous tracts. Although clinical correlationis necessary, this feature is helpful in diagno-sis of AA in some biopsy specimens withoutperibulbar lymphocytic infiltrate.112 Mast cellswere also noted in a small series of AAslides.113

Electron-microscopic examination ofmicrodissected hair follicles from AA scalpsdemonstrated ultrastructural abnormalities inthe dermal papillae of both lesional and clini-cally normal hair follicles.114 This shows that,with patchy involvement, AA is not a local-ized process. Immunohistochemical evalua-tion of clinically normal AA specimens revealsa prominent expression of ICAM-1 in the der-mal papilla and keratinocytes of the matrixand outer root sheath.115

Histopathologically, AA should be differen-tiated from androgenetic alopecia, telogen ef-fluvium, trichotillomania and syphiliticalopecia. In androgenetic alopecia, miniaturi-zation of hairs is present with lack of lymphoidinfiltration at the level of the bulb and a lack ofpigment incontinence within fibrous tracts. In


telogen effluvium, miniaturization of folliclesis not present. Trichotillomania is character-ized by empty anagen follicles, multiplecatagen hairs, trichomalacia and pigment castsin the follicular infundibulum. Syphilitic alo-pecia is very difficult to distinguish from AA.Presence of plasma cells along with noperibulbar eosinophils and abundantlymphocytes in the isthmus are features ofsyphilitic alopecia, while the presence ofperibulbar eosinophils and lymphocytesstrongly suggests AA.116

Clinical featuresAA occurs all over the world. It accounts forabout 2% of new dermatology outpatient at-tendances in the UK and the USA.117 Theprevalence of alopecia areata in the UnitedStates, as reported by the First National Healthand Nutrition Examination Survey conductedfrom 1971 through 1974, was 0.1 to 0.2 per centof the population.117 The lifetime risk has beenestimated at 1.7%.117 AA affects men andwomen equally.4 Patients are frequently quite

Alopecia areata 29

young. Sixty per cent of patients present withtheir first patch under the age of 20.118,119 (Fig-ure 2.6). Colombe et al.8 suggest a bimodal pat-tern for AA, with an early-onset formassociated with greater severity, long duration,and family history of the disease and a late-onset form characterized by milder severity,shorter duration, and low family incidence.

Alopecia areata can manifest with severaldifferent clinical features. Patients usuallycomplain of abrupt hair loss and marked hairshedding. Frequently, patients will present tothe physician with one or several bags of hair.

Figure 2.5Histopathology of alopecia areata. (a) ‘Swarm of bees’ noted in the deep subcutaneousperibulbar area of the follicle. (b) Close-up the lymphocytic infiltrate, with matrix destruc-tion. (c) Two follicles, with one showing marked lymphocytic infiltration, while the otherdoes not. This highlights the fact that AA is a very heterogeneous condition, not only on thesame scalp, but within the same follicular bundle. (d) Follicular stellae (ST) remnants inalopecia areata. (e) The large number of telogen hairs in alopecia areata. Almost all follicleswithin this field are telogen. (f) Reduction of follicular numbers in chronic alopecia areata.(Courtesy of Drs Magda Martinka, David Shum and Martin Trotter.)

The characteristic lesion of AA is commonly around or oval, totally bald, smooth patch in-volving the scalp or any hair bearing area onthe body (Figure 2.7). The patch may have amild peachy or pinkish-red color (Figure 2.7).Hair loss is seen both as intact and as fracturedhairs (Figure 2.7). The intact hairs are dys-trophic anagen or telogen hairs. The fracturedhairs develop owing to damage involving bothcortex and medulla, resulting in distal frac-tures.120 These hairs are described as ‘exclama-tion-mark’ hairs, because the distal segment isbroader than the proximal end (Figure 2.7).


The pull test may be positive at the margins ofthe patch, indicating very active disease. Al-though hair loss is usually asymptomatic inmost cases, some patients describeparesthesias, with mild to moderate pruritus,tenderness, burning sensation or pain, beforethe appearance of the patches.

The clinical presentation of alopecia areatais subcategorized according to pattern or ex-tent of the hair loss.

If categorized according to pattern, the fol-lowing forms are seen: patchy AA—round oroval patches of hair loss (most common);

reticular AA—reticulated pattern of patchyhair loss; ophiasis-bandlike AA—hair loss intemporo-occipital scalp; ophiasis inversus(sisapho)119—a rare bandlike pattern of hair lossin fronto-parieto scalp (the exact opposite ofophiasis);121 and diffuse AA—a diffuse de-crease in hair density over the entire scalp(Figure 2.8).

If categorized by extent of involvement, thefollowing forms may be seen: alopecia areata:partial loss of scalp hair; alopecia totalis: 100%loss of scalp hair; and alopecia universalis: 100%loss of hair on scalp and body (Figure 2.9).

Figure 2.6Alopecia universalis for 1 year in a 3-yearoldgirl. (a) Front view showing loss of hair onscalp, eyebrows, and eyelashes. (b) Sideview. (c) Back view. This early-onset form ofAA is associated with greater severity, longerduration, and greater probability of a positivefamily history of AA. HLA studies suggestthis early-onset group of severe AA patientsare a genetically distinct group. They areprognostically and therapeutically distin-guishable, too.

Alopecia areata 31

Figure 2.7Alopecia areata circumscripta. Patients frequently present with just a patch. (a) A single smallcircular patch. (b) A single large circular patch totally devoid of hair ‘bare as a baby’s bottom’.(c) The patch may be skin-colored with broken-off hairs. (d) The color of an AA patch may bepeach, (e) Another peach-colored patch of AA. (f) The AA patch may be red. This patientcomplained of burning on the patch before the hair fell out.


(g) Exclamation point hairs may be seenduring an active phase of the condition.(Courtesy of Dr Harvey Lui.) (h) Circumscriptpatches can be very constant and persistent.This is a patch on a 40-year-old male that hasbeen present in the same place and has beenthe same size for 10 years. He has not hadany other spots for over a decade.(i) Simultaneous circumscript alopecia inmother and son.

Alopecia areata 33

Figure 2.8Clinical forms of AA based on pattern:(a) Patchy alopecia areata in multifocal areas.(b) Reticulated patches in AA. (c) Ophiasis(d) Simultaneous ophiasis in mother anddaughter. (e) Sisapho—the diametric oppo-site of ophiasis, mimicking androgeneticalopecia. (f) Early diffuse A A with nodistinct patches. (g) Advanced diffuse AA.


Any hair-bearing surface can be affected.Where there is hair, there can be alopecia ar-eata! Beard AA is very common, as well asbody AA, affecting the limbs or the thorax area.(Figure 2.10 and 2.11).

Most patients present with the limitedpatchy type that is easily camouflaged. Theinitial regrowth in AA is frequently white, fol-lowed by repigmentation. Frequently AA pref-erentially affects pigmented hair, and only thewhite hairs remain (Figure 2.12).

Both regrowth in one site and extension ofthe alopecia on another site may be seen at thesame time in the same patient.

Nail dystrophy may be associated with AA.The reported incidence of onychodystrophyin AA ranges from 10 to 66%,122 dependingon how diligently it is looked for. Changesmay be seen in one, many or all the nails. Thedystrophy may precede, coincide or followresolution of the AA. Pitting with an irregularpattern or in organized transverse or longitu-dinal rows, trachyonychia (longitudinalstriations resulting in sandpaper appearance),Beau’s lines (grooves through the nail match-ing that of the lunula’s margin), onychorrhexis(superficial splitting of the nail extending tothe free edge), thinning or thickening

Figure 2.9Clinical forms of AA based on extent:(a) Alopecia areata with its characteristiccircular patches. (b) Alopecia totalis affecting100% of the scalp. (c) Alopecia universalis inan adult affecting all hairs on the body,including eyelashes and eyebrows.

Alopecia areata 35

Figure 2.10Extracranial AA: (a) AA affecting just theeyelash. (b) AA affecting one eyebrow. (c) AAaffecting the chest. (d) AA affecting the dorsaof the arms. (e) A A affecting just the lateralportion of the leg.


(pseudomycotic), onychomadesis (onycholy-sis with nail loss), koilonychia (concave dor-sal nail plate), punctate or transverseleukonychia and red spotted lunula may beassociated with AA.123-128 (Figure 2.13).

PrognosisThe only predictable thing about the progressof the AA is that it is unpredictable. Patientsusually present with several episodes of hairloss and hair regrowth during their lifetime.The recovery from hair loss may be complete,partial or non-existent. The majority of pa-tients will regrow their hair entirely withinone year without treatment. However, 7–10%

Figure 2.11Alopecia areata of the beard is very common.(a) Random patches on the beard area. (b)The characteristic peach color on an A A ofthe beard. (c) Extensive AA of the beard, butnot affecting the great head of dreadlocks.

Alopecia areata 37

can eventually end up with the severe chronicform of the condition. Poor prognostic indica-tors are atopy, the presence of other immune

diseases, a positive family history of AA, ayoung age of onset, nail dystrophy, extensivehair loss and ophiasis.82,129

Figure 2.12White hairs, vitiligo and alopecia areata. (a)Hair regrowth in a young child who had beendiagnosed as a case of trichotillomania. Thewhite hair regrowth proves the diagnosis hadalways been AA. (b) and (c) White regrowthon the side of the scalp. (d) White regrowthin an area of previous ophiasis.


that are shed are either telogen or dystrophicanagen in AA, and purely telogen in telogeneffluvium. Patients with AGA usually demon-strate the typical predictable pattern of bald-ing, and shedding is not prominent. The pulltest is usually negative in AGA. In trichotillo-mania and traction alopecia twisted and bro-ken hairs are frequently evident. In tineacapitis, usually, there is an inflammatory com-ponent. However, non-inflammatory tinea

(e) Circumscript AA, sparing white hairs. (f) AA and vitiligo in the same person. (g) Whitemoustache in a vitiliginous area in the patient illustrated in 12f.

Differential diagnosisClinically, the differential diagnosis is usuallybetween telogen effluvium, androgenetic alo-pecia (AGA), trichotillomania, traction alo-pecia, triangular temporal alopecia,pressure-induced alopecia, tinea capitis andpseudopelade (Figure 2.14). In telogen efflu-vium, hair loss is generalized over the wholescalp, whereas in AA it is usually patchy. Hairs

Alopecia areata 39

Figure 2.13Nail changes and alopecia areata.(a) Trachyonychia, and red-spotted lunula onthe fingernails. (b) Red-spotted lunula on thetoenails. (c) Koilonychia present in AA. (d)and (e) Severe nail dystrophy in AA.


Figure 2.14Differential diagnosis of AA. (a) This is an early case of biopsy-proven diffuse AA which canbe difficult to differentiate from telogen effluvium. (b) Temporal triangular alopecia canmimic AA. (c) AA may be linear and mimic morphea. (d) Morphea mimicking AA. It iscrucial to look for the presence of follicular ostia, which may be difficult to see on a shinysmooth scalp. (e) & (f) AA

Alopecia areata 41

mimicking AGA in a female patient. (g) Trichotillomania, which can easily mimic AA. (h)Simulaneous trichotillomania in a mother and daughter. (i) Broken hairs in trichotillomania.(j) & (k) Pseudopelade mimicking AA. Note the loss of follicular ostia. (l) Post surgicalpressureinduced alopecia can appear like AA, but usually has a significant scarred compo-nent to it.


capitis may be most difficult to distinguishfrom AA. Look for the characteristic scaling intinea capitis. A KOH preparation and fungalculture may be necessary to distinguish non-inflammatory tinea capitis from AA. Woodslight examination may help if the patient is inor has been in an area where the fluorescenttineas predominate. In British Columbia, themost common cause of tinea capitis is Micro-sporum canis, which does fluoresce. Tempo-ral triangular alopecia (TTA) may mimic AA.The lifetime incidence of TTA is 0.11%.130 Thisis ten times less frequent than AA. Lesionspresent as a triangular, oval or lancet-shapedpatch of non-scarring alopecia overlying thefronto-temporal suture. There is controversy asto whether the lesions are present at birth oracquired later in life. A biopsy may occasion-ally be necessary to distinguish TTA from AA.Histologically, peribulbar lymphocytic infil-trates are not present. Pressure-induced alo-pecia131–134 (PIA) may also mimic AA. Usuallythe history of coma or surgery is present. Clini-cally, there is usually some scarring with PIA.Occasionally in AA, the scalp may be so shinyand smooth that follicular ostia may be diffi-cult to see, and patchy AA may be difficult todifferentiate from pseudopelade. A 4 mmpunch biopsy may be necessary to make a de-finitive diagnosis in some cases.135 Diffuse AAcan be especially difficult to diagnose clini-cally from other non-cicatrizing alopecias. Seeabove for histologic differentiation of non-cicatrizing alopecias.

TreatmentModern therapy for AA is best appreciatedwithin a historical framework. Bateman,136 inthe 1800s, wrote about AA and concluded that

the application of a caustic substance with thesubsequent production of bullae was often suc-cessful in the treatment of AA. He advocatedthe use of ointments prepared with oil of mace,turpentine, mustard and black pepper. Al-though this may seem crude, some currenttreatment regimens have similar objectives.They cause blisters and erythema, and an im-munologic patient response to modify the peri-follicular immunologic milieu. Despite theadvance of medicine over the last 200 years,some of the fundamental principles in thetreatment of AA remain unchanged.

There is great difficulty in evaluating the lit-erature on treatment modalities for alopecia ar-eata, as there is so much variability as tobaseline patient populations and the terms‘successful regrowth’ or ‘responders’.

Most studies have grouped patients with alo-pecia totalis (AT) and alopecia universalis (AU)with those with just patchy alopecia areata(AA). There is no question that AT/AU is a dis-tinct prognostic and therapeutic group, andresults can be skewed by this more difficult andseverely affected population. There is a pau-city of studies that distinguish AT/AU frompatchy AA. This lack of stratification of patientpopulation can have a profound influence onevaluating therapeutic efficacy. Unfortunately,the treatment of AA is very difficult, and thereare no consistently reliable treatments. Whilethe FDA has never approved any drug for AA,this does not mean that there are no effectivetreatments. Evaluating efficacy is most difficult,especially for patchy AA, as it is so unpredict-able and frequently improves on its own. Inorder to prove efficacy with sufficient powerand statistical significance, large patientpopulations are necessary. Most publishedstudies for AA have been small. Half-head stud-ies are very powerful; but again, much of thispublished work has involved patient

Alopecia areata 43

populations with a preponderance of AT/AU.The new Alopecia Areata Investigational As-sessment Guidelines are helpful in establish-ing criteria for selecting and assessing patientsfor clinical studies of AA, facilitating collabo-ration, comparison of data, and measuring theextent of scalp involvement.137 These guide-lines highlight the fact that AT and AU are con-sidered a separate entity from AA, and mustbe separated out in order to determine the effi-cacy of any trichogenic agent. It is of paramountimportance that dermatologists should beknowledgeable and conscious of this importantsegregation when evaluating modalities in thetreatment of AA. Otherwise, all results areskewed and will probably show ineffectiveness.

The terms ‘responder’ and ‘successfulregrowth’ are not used in the same way fromone study to another. The Guidelines help usto evaluate what is ‘successful regrowth’. Mostdermatologists consider successful regrowth tobe cosmetically acceptable regrowth, meaningbeing able to abandon one’s wig or cap. Whencomparing studies, it is important to ascertainclearly what the authors have defined as a ‘re-sponder’.

At present, all treatments are palliative,only controlling the problem, and not curingthe condition. All local treatments may helpthe treated areas, but do not prevent furtherspread of the condition. In addition, any modeof treatment may require long periods of us-age, owing to the chronic nature of AA. At thepresent time, topical, intralesional and sys-temic steroids, topical immunotherapy, an-thralin, minoxidil and photo-chemotherapyare available for the treatment of AA. Treat-ment guidelines for AA have been publishedby the American Academy of Dermatology.138

All treatment plans for patients depend onthree major factors: the extent of scalp involve-ment, the age of the patient, and the motiva-tion level of the patient.

Corticosteroids

The main mechanism of action is immunosup-pression. However, some biochemical abnor-malities relating to steroid chemistry have beendiscovered in AA patients by Sawaya andHordinsky.139 They showed that patients withAA have abnormalities in glucocorticoidreceptors (GCR) for type 2 binding. Thisreceptor is found to influence long-term, slow-growth cellular processes. Scalp biopsies from15 untreated AA patients showed a twofold in-crease in unoccupied GCR. This suggests sup-pressed cellular transcription. It was found thatlow concentrations of calmodulin stimulate acytosol kinase, and thus hormone binding toGCR. This suggests that patients with AA haveabnormalities in type 2 GCR activation becauseof abnormal calcium-calmodulin metabolism.These abnormalities may explain why patientswith AA show a varied response in hair areagrowth when treated with glucocorticoids.139

Topical corticosteroids

Fluocinolone,140,141 halcinonide142 and dexam-ethasone in a penetration-enhancing vehiclehave been reported to have some success.143

Only one of these studies was performed in adouble-blind controlled manner. Price andKhoury144 have not had success with topicalsteroids. Fiedler145 believes that a combinationof 0.05% betamethasone dipropionate creamand minoxidil may be more beneficial than ei-ther alone. She reports that quality of responsein severe recalcitrant AA was fair to good after16 weeks of treatment with placebo in 13%,with 0.05% betamethasone dipropionate in22%, with 5% minoxidil in 27% and with 5%minoxidil and 0.05% betamethasonedipropionate in 56%. This suggests asynergistic benefit of using both modalities.


Figure 2.15Intralesional corticosteroid injections for AA.(a) Injecting triamcinolone acetonide 5 mg/ml with a 3 ml syringe and a 30 gauge nee-dle.(b) Patch of alopecia before injection.(c) Same patch after 2 months of injections.(d) Best position for injecting eyebrows:patient lying flat, physician positioned at oneend of the table and approaching with needlefrom the top of the patient.

Alopecia areata 45

Intralesional corticosteroids

Intralesional corticosteroid injection is first-linetherapy for adult patients with less than 50% ofscalp involvement.146 For circumscribed AA, in-tradermal corticosteroids remain the therapeu-tic standard.147 They are not indicated whenmore than 50% of the scalp is involved. Porterand Burton148 demonstrated response rates of64% using triamcinolone acetonide and 97%using the less soluble and more atrophogenictriamcinolone hexacetonide. Price,146

Shapiro,149 Mitchell and Krull,129 Whiting,150

Bergfeld,151 and Thiers152 prefer triamcinoloneacetonide. Concentrations of triamcinolone ac-

etonide vary from 2.5–10.0 mg/ml diluted ei-ther in xylocaine or sterile saline. Price146 pre-fers 10mg/ml, Whiting150 prefers 5–10 mg/ml.Shapiro149 prefers 5 mg/ml. Bergfeld prefers2.5–5.0 mg/ml151 and Thiers152 prefers 3.3 mg/ml. At the University of British Columbia HairClinic, for scalp A A, we inject a concentrationof 5 mg/ml with a maximum total of 3 ml oftriamcinolone acetonide. A weaker concentra-tion of 2.5 mg/ml is used for the beard area andthe eyebrows. Triamcinolone acetonide is ad-ministered with a 0.5 inch long 30-gauge nee-dle as multiple intradermal injections of 0.1 mlper site, approximately 1 cm apart. Initialregrowth is often seen in 4–8 weeks. Treatments

(e) Injection of eyebrows with triamcinolone2.5 mg/ml for a total of 0.5 ml per eyebrow.(f) Regrowth in eyebrow area after 4 weeks.Injections are performed every 4 weeks, withthe next set in between areas of regrowth.(g) Atrophy secondary to injection withtriamcinolone acetonide 40 mg/ml, which isat least 4–8 times what is recommended.


are repeated every 4 to 6 weeks. The main side-effect is minimal transient atrophy. This can beprevented by avoiding injections that are toogreat in volume per injected site, too frequent,or too superficial (intraepidermal). Topicalanesthesia cream (2.5% lidocaine and 2.5%prilocaine in a cream) in a thick layer with oc-clusion 1 hour prior to injection can be used.However, this cream can be difficult to use onthe hairy scalp. Children under 10 years of ageare not usually treated with intralesional ster-oids owing to the local pain at the injectionsites. After 6 months of treatment, if there is noresponse, discontinue, intralesionalcorticosteroids, because these patients may lackadequate corticosteroid receptors in the scalp.139

(Figure 2.15).Ferrando et al.153 recently published a paper

on the use of a multi-injection plate forintralesional corticosteroid injection of patchyAA. This disposable device has some advan-tages, in that it permits the simultaneous injec-

tion in 5–7 different points at a fixed distance,leading to uniformity in treatment applications.With this method there is only one painfulstimulus instead of five to seven, and an exten-sive alopecic area can be treated in a shorterperiod of time. One disadvantage is the needlecalibre. The 27 gauge needles are large, andtherefore likely to produce pain if the procedureis not performed gently, and atrophy can occurif the application is not followed by a local mas-sage that spreads the steroid solution uniformlythrough the treated area.

Systemic steroids

Systemic corticosteroids are frequently effec-tive in the treatment of AA, but their use iscontroversial. They are not routinely used, be-cause of side-effects, and they do not alter thelong-term prognosis (Figure 2.16).Abdulkareen et al.154 recently showed success

Figure 2.16The chronic use of systemic steroids for AA can have significant side-effects. (a) & (b) Striaein a patient with alopecia universalis who had been on systemic steroids for 1 year.

Alopecia areata 47

with systemic steroids in 38% of patients withextensive patchy AA and AT/AU. However, inall patients, once the steroid was discontinued,the hair fell out.

At the UBC Hair Clinic, we use systemic ster-oids only in exceptional cases. Winter et al.155

reported the occurrence of numerous side-ef-fects such as striae, acne, obesity, cataracts andhypertension while using alternate-day pred-nisone. The authors concluded that alternate-day prednisone does not appreciably alter thecourse of AA. Unger and Schemmer,156 how-ever, believe that the initial administration ofsomewhat lower doses of prednisone, 30–40mg/d, together with the use of topical andintralesional steroids, frequently yields goodresults while minimizing the risk of side-ef-fects. Price146 feels that systemic corticosteroidsmay be indicated in select patients with pro-gressive AA, either to slow progression or toinitiate growth. For patients weighing morethan 60 kg with active, extensive or rapidlyspreading AA, she recommends prednisone 40mg/day for 1 week, 35 mg/day for 1 week, 30mg/day for 1 week, 25 mg/day for 1 week, 20mg/day for 3 days, 15 mg/day for 3 days, 10 mgfor 3 days and 5 mg for 3 days. She will usethis regimen in combination with minoxidil 5%solution twice daily with or withoutintralesional corticosteroid injections every 4–6 weeks. For active, less extensive AA, she usesprednisone 20 mg daily or every second day,which can be tapered slowly by decrements of1 mg after the condition is stable. Whiting150

has found systemic steroids useful in revers-ing some cases of rapidly progressing alopeciathat appear to be evolving into alopecia totalis.In adults, prednisone, 20–40 mg/d for 1–2months may be necessary to control the hairloss. Reduction of the dosage after that dependson the patient’s progress. Whiting tries to main-tain hair regrowth with the lowest possible dose

of prednisone, even if it is necessary to con-tinue it for 6 months or until concomitant treat-ments such as minoxidil can take effect.

Sharma et al. have used pulsed oral pred-nisolone at 300 mg once per month for a mini-mum of 4 months for patients with extensivepatchy AA and AT/AU.157 They showed an ini-tial response at 2.4 months and a 58% successrate for cosmetically acceptable regrowth after4 months. They feel this treatment is safe onan outpatient basis. This study was uncon-trolled. The long-term safety of this regimenhas yet to be determined.

Intramuscular corticosteroid therapy has avery high rate of recurrence, and as a result hasvery little to offer patients.158

Pulse therapy with intravenous methyl-prednisolone 250 mg twice daily for three suc-cessive days for rapidly progressive extensivemulti-focal AA was found to be effective incontrolling the active phase of hair loss.Twelve out of 20 with extensive patchy diseaseshowed 50–100% regrowth after 12 months.This regimen was not effective for ophiasic AAor AT/AU.159 This study was not controlled,and a controlled-randomized study needs to beperformed to confirm efficacy.

The treatment of AA with systemic steroidsis not recommended for children.

Minoxidil

Minoxidil is a biologic response-modifier thatenhances hair growth. Minoxidil stimulatesfollicular DNA synthesis, has a direct effect onthe proliferation and differentiation offollicular keratinocytes in vitro, and regulateshair physiology independently of blood flowinfluences.144,160 Minoxidil does not have animmunomodulatory effect.161 Topicalminoxidil 5% solution is the most effectiveconcentration compared to other lower con-


centrations.162–166 There clearly is a dose-re-sponse effect.162–166 Cosmetically acceptablehair regrowth using topical 5% minoxidil so-lution has been shown in approximately 40%in patients, with 20–99% scalp involvementafter one year.163 More successful results areseen in less severe cases of the disease. Thistreatment should not be expected to be effec-tive in patients with alopecia totalis/universalis.163 At the University of British Co-lumbia Hair Clinic only the extrastrength topi-cal minoxidil 5% solution is used for patchyAA. It must be applied twice daily. Initial hairregrowth is usually seen after 12 weeks. Theresponse is usually maximized at 1 year. Itmust be continued until remission occurs. Itcan be used on the scalp and eyebrows. It canalso be used on the beard area in men.

There are negative studies with topicalminoxidil.167–169 However, all these studies didnot maximize on the 5% solution. More im-

portant, the vast majority of patients withinthese studies had AT/AU. One would not ex-pect efficacy with topical 5% minoxidil solu-tion in this difficult sub-population.

The efficacy of minoxidil solution can beenhanced with anthralin170 or betamethasonedipropionate.145 In combination with topicalminoxidil, anthralin is applied 2 hours afterthe second minoxidil application.Betamethasone dipropionate cream is appliedtwice daily, 30 minutes after each use ofminoxidil (Figure 2.17). Although combina-tion therapy has been found to be more effec-tive than monotherapy, this therapy is noteffective in patients with alopecia totalis/universalis.

Side-effects of minoxidil are rare. These in-clude local irritation, allergic contact dermati-tis and facial hair growth (Figure 2.18), whichtends to diminish with continued treatment.Systemic absorption is minimal.146

Figure 2.17The use of minoxidil and topical betamethasone dipropionate. (a) 4-year-old patient with a 2-year history of AA. (b) After 8 months of treatment there was cosmetically acceptableregrowth. It is difficult to know if this was truly the effect of therapy or spontaneousregrowth.

Alopecia areata 49

Anthralin

Anthralin may have a non-specificimmunomodulating effect (anti-Langerhanscell), as it does in psoriasis.171 Clinical irrita-tion is not necessary for efficacy, just as clini-cal irritation is not necessary in psoriasis.There are citations in the literature that sug-gest that skin irritants are not effective inAA.172,173

Cosmetically acceptable regrowth has beenreported to vary from 20% to 25% for patchyAA.174 Schmoekel et al.175 have shown withphotographs that anthralin has benefit in ahalf-head study and is effective for patchy AA.

Anthralin 0.5%–1.0% cream is appliedonce daily.146,147,149,174 Short-contact therapy ispreferred. It is left on 20–30 minutes daily for2 weeks, and then 45 minutes daily for 2weeks, up to a maximum of 1 hour daily. It is

not to be used on the eyebrows or the beardarea. Some patients may tolerate overnighttherapy.146 When therapy is effective, new hairgrowth is usually seen within 3 months. It maytake 24 or more weeks for a cosmetically ac-ceptable response. Because of its good safetyprofile, anthralin is a good choice for children.

Combination therapy with minoxidil mayhave a synergistic effect, as was mentionedabove.170

Nelson and Speilvogel report a negativestudy with anthralin.176 However, AT/AU pa-tients were grouped in with patchy AA in thissmall study of 10 people—it is not specifiedhow many AT/AU. It is unlikely that anthralinhas as much efficacy, if any, in AT/AU as itdoes in patchy AA.

Side-effects of anthralin are irritation, scal-ing, folliculitis, and regional lymphadenopa-thy. Patients are cautioned to avoid getting

Figure 2.18Hypertrichosis with topical minoxidil solution. (a), (b) 5-year-old boy who had used topical5% minoxidil solution for over 6 months. There is marked symmetrical hypertrichosis on theforehead and cheeks.


Alopecia areata 51

anthralin into the eyes, to protect treated skinagainst sun exposure, and to be aware of stain-ing of the treated skin, clothes and linens (Fig-ure 2.19).

Topical immunotherapy

Topical immunotherapy is the most effectivetherapeutic modality with the best safety pro-file in the treatment of chronic severe AA. Sys-temic steroids may be the most effectivemodality, but their safety profile is unaccept-able to most dermatologists. Three contactsensitizers have been used extensively in alo-pecia areata—dinitrochlorobenzene (DNCB),squaric acid dibutyl ester (SADBE) anddiphenylcyclopropenone (DPCP).

The mechanism of action of topical immu-notherapy is unclear. The immunomodulatingeffect of the topical sensitizers is supported by

a decrease in the peri-bulbar CD4+/CD8+lymphocyte ratio,177 and a shift in the positionof the T-lymphocytes away from perifollicularareas to the interfollicular area and dermis.99,100

It has been suggested that the immunogen mayattract a new population of T cells into thetreated area of the scalp that could eliminatethe antigenic stimulus present in AA.178

Happle has proposed the concept of antigeniccompetition.179 This theory presumes that thegeneration of T-suppressor cells into the areamay exert a non-specific inhibitory effect onthe autoimmune reaction to the hair-associ-ated antigen, and thus allow hair to regrow.Immunogens may interfere with the initial orcontinued production of proinflammatorycytokines by the follicular keratinocytes. Care-ful dissection of the mechanism by which con-tact dermatitis is able to suppress alopeciaareata is important, because it may be possiblein the future to mimic the effect on the derma-titis by providing specific cytokines or specificinhibitors of cytokines.

Dinitrochlorobenzene

Rosenberg and Drake178 first reported regrowthof hair in two patients following application ofDNCB. The overall efficacy of DNCB treatmentfor AA has been investigated and has variedfrom 25% to 89%.180,181 Concerns have beenraised about the safety of DNCB. DNCB is rap-idly absorbed after topical application, with53% recoverable in the urine. Excretion is pri-marily renal, and serum half life is 4 hours.Kratka et al.,182 Stobel and Rohrborn183 andSummer and Goggelman184 found DNCB to bemutagenic in Salmonella typhimurium in thebacterial plate incorporation assay (Ames as-say). Therefore, extreme caution must be usedwith DNCB. The issue of DNCB safety is con-troversial. Weisburger et al.185 found DNCB to

Figure 2.19Anthralin for alopecia areata. (a) 27-year-oldfemale with AA for 8 months. Baseline, leftside; treated with anthralin 1 % cream for 1hour daily. (b) Baseline, right side; untreatedside. (c) 4 months of treatment: left (treated)side showing regrowth. (d) 4 months oftreatment: right (untreated) side showingregrowth, but less than the treated side.There was clearly unilateral preference forthe treated side. (e) Unilateral preferentialregrowth of hair with anthralin on the C3H/HeJ mouse on the treated half. (f) Markedredness can occur from anthralin.


be non-carcinogenic when fed in large dosesto mice and rats up to 4 months. The purity ofDNCB samples is also an issue. Certain chloro-nitrobenzenes that are known mutagens arepossible contaminants in preparations ofDNCB.186

Side-effects of DNCB include a marked blis-tering reaction, auto-eczematization, adenopa-thy, urticaria and tolerance. Tolerance cansometimes be reversed with cimetidine 300 mgorally three times a day for 3–4 weeks.129

Squaric Acid Dibutyl Ester

Happle achieved good results in 70% of pa-tients treated with topical squaric acid dibutylester (SADBE).187 Flowers et al.188 foundSADBE to be effective in 4/8 cases. Case et al.189

showed excellent responses in 11/26 (52%) ofcases. Caserio190 showed a success rate of 28%(4/14 cases). Giannetti and Orecchia191 re-ported a good response in 5/26 cases. Micali etal.192 showed a 49% success rate in 73 caseswith over 50% scalp involvement. Chua etal.193 reported a 68% (13/19) success rate in ahalf-head study. Orecchia194 has used SADBEin children under 13 and showed a 32% (9/28)chance of cosmetically acceptable regrowth.Tosti et al.195 also treated children, with an ini-tial success rate of 30% (10/33). Two-thirds ofthe initial responders no longer responded tothe SADBE, with subsequent relapses over thelong term. Barth et al.196 showed only minimalsigns of terminal hair regrowth in 3/17 patientsand do not recommend the use of SADBE inAA. Orecchia et al.197 used SADBE in combi-nation with PUVA on three patients and didnot find increased efficacy with combinedtreatment. They concluded that the two asso-ciated therapies showed an impaired efficacybecause of the inhibition of the SADBE actionby PUVA. PUVA impairs Langerhans cells, and

thus inhibits induction and elicitation of aller-gic contact dermatitis. PUVA also results in asystemic immuno-suppression through director indirect (via interleukin-1) stimulation ofprostaglandins (PGE2), with the effect of an ef-ferent lymphatic blockade. This would clearlyaffect any benefits of a contact allergen.

SADBE has been shown to be Ames-assaynegative. No mutagenic contaminantswere detected on gas chromatography-massspectrometry.198 Furthermore, lifetime subcu-taneous injections of squaric acid into ICR/HaSwiss mice resulted in a low incidence oftumors at the injection site, equaling that ofcontrol animals.199 It is an ideal immunogen inthat it is a strong topical sensitizer, is used onlyrarely in industry, is not found in the naturalenvironment and does not react with otherchemicals. However, it loses its stability in thepresence of water.

Diphenylcyclopropenone

Diphenylcyclopropenone (DPCP) has beenused not only in the treatment of alopecia ar-eata, but also as an immunomodulator in thetreatment of melanoma200 and warts.201 Effi-cacy in alopecia has varied from study tostudy. Van der Steen et al.202 showed a re-sponse rate (on 139 patients) of 50.4%, withexcellent or satisfactory results. Of 107 whoshowed a unilateral response, 30 relapsedand were resistant to further therapy. In 8/107, a tolerance phenomenon was seen, de-fined as a required continuous increase inDPCP concentration until a concentration of2.0% was reached without producing an ad-equate dermatitis, resulting in loss of all re-grown hair. In 3/107, a paradoxical regrowthof hair on the untreated side of the scalp wasseen. This phenomenon is known ascastling.

Alopecia areata 53

MacDonald-Hull and Norris203 reported 29%(8/28) of patients had a cosmetically acceptableresult. MacDonald-Hull and Cunliffe204 studiedpost-therapy relapse rates within 6 months af-ter treatment. They found that 7 of 19 (37%)showed no hair loss after treatment had beenstopped for 6 months. In 68%, the appearanceof the scalp 6 months later was cosmetically ac-ceptable, although 53% developed patchy alo-pecia and 10% lost all hair that had re-grown.In 1991, MacDonald Hull et al.205 reported fur-ther results with DPCP on a larger series of pa-tients. Of 78 patients, 25 (32%) showed completeregrowth of hair. The authors felt that elicitingan allergic reaction was an integral part of suc-cessful treatment resulting in hair growth.

Wiseman et al.206 utilized Kaplan-Meier sur-vival analysis to determine cosmetically accept-able regrowth over time and a cox regressionmodel to determine factors predictive ofregrowth in the largest series to date of 148 AApatients. Using the survival analysis model, thecumulative patient response at 32 months was77.9%. A cosmetically acceptable endpoint wasobtained in 17.4% of subjects with 100% hairloss, 60.3% of subjects with 75–99% hair loss,88.1% of subjects with 50–74% hair loss, and100% of subjects with 25–49% hair loss. A lagperiod of 3 months was present between initia-tion of therapy and detection of the first clini-cal response. Factors affecting response wereclearly extent of condition and age of onset.Those patients with a younger age of onset areless likely to respond. It appears those with AT/AU and an early age of onset are prognosticallya separate group. This fits well with Colombe etal’s8 data that this group is a distinct sub-popu-lation of AA. Duration of condition, the pres-ence of atopy and nail changes were notcorrelated to response.

Gordon et al.207 showed that 38% of 48 pa-tients responded to DPCP with cosmeticallyacceptable regrowth. Pericin208 showed that in

68 patients, 70.6% showed a response, withcomplete regrowth in 30.9%. The only prog-nostic indicator correlated with response wasextent of the condition. Monk209 showed cos-metically acceptable results in 33% (6/18).Hatzis et al.210 showed satisfactory regrowth in24% (11/45). Ashworth et al. showed efficacyin only 1/26.211. Orecchia and Rabiossi212 alsohad a success rate of 1/26. Berth-Jones andHutchinson213 showed only an 18% responserate over 6 months, with no significant differ-ence in response with inosine pranobex(inosiplex). Shapiro et al.214 showed that topi-cal 5% minoxidil solution combined withDPCP showed no benefit over DPCP alone.

Regarding children, MacDonald-Hull etal.215 treated 12 children aged 5–15 years, with33% showing complete regrowth. Six monthsafter treatment was discontinued three of thefour children with complete regrowth main-tained their hair.

DPCP is not mutagenic in the Ames test, andteratogenicity and organ toxicity could not bedetected in the hen’s egg test or in the mouseteratogenicity test.216 Analysis on serum andurine samples following application of at least0.5 ml of a 1% solution of diphencyprone tothe scalp of 18 patients under treatment foralopecia areata revealed no detectableamounts of diphencyprone in any sample ofserum or urine from these subjects. These datasuggest that diphencyprone is not absorbedfollowing application to the skin.217 Commer-cial DPCP may contain a precursor,dibromoketone, that is positive in the Amestest.218,219 It is therefore recommended that allDPCP samples be purified as described by vander Steen et al.216 or that a pharmaceuticalchemist do high-pressure liquid chromatogra-phy on the DPCP sample to ensure that thereare no detectable amounts of thisdibromoketone compound. DPCP is degrada-ble upon exposure to light, and must be stored


Figure 2.20Topical immunotherapy for alopecia areata. (a) Standard diphencyprone (DPCP) tray concen-trations varying from 0.0001–2.0%. (b) Intermediate concentrations may be necessary. (c)DPCP is stored away from the clinic in the fridge in a plastic container. (d) The cotton iswound around the stick to make a reinforced swab approximately three times the thickness ofan average cotton-tipped applicator. (e) The physician or nurse must wear gloves when

Alopecia areata 55

handling the bottles. (f) After the application, gloves must be removed carefully from theinside out. (g) Cotton swab is dipped directly into the bottle. If the swab needs to beremoistened, an eyedropper is used to saturate the swab. (h) An area that has been sensitizedone week before with a 2% solution. (i) and (j) One coat is painted is the anteroposteriordirection. k. Another coat is painted in the lateral direction. Only unilateral application isperformed until hair regrowth is seen on one side.


in amber bottles. At the University of BritishColumbia, DPCP is dissolved in acetone andstored away from the staff in the fridge in aspecial container.

For adults with more than 50% scalp hair loss,topical immunotherapy with DPCP is our treat-ment of choice at the University of British Co-lumbia Hair Clinic. We use DPCP on patientswith less than 50% hair loss only if all othermodalities have failed, such as intralesionalcorticosteroids, topical minoxidil 5% solution incombination with topical corticosteroids, or topi-cal anthralin. As Peret and Happle220,221 suggest,patients should be thoroughly informed aboutthe experimental character of the treatment, thelack of sufficient toxicologic data, the chance forregrowth, the possible side-effects, and the pos-sible failure to respond. Patients must be warnedthat the induction of an allergic contact dermati-tis is a desired side-effect, and one that is neces-sary for a good result. A local ethics committeeshould be asked for consent.

DPCP is used at the University of British Co-lumbia Hair Clinic as follows:

Prior to commencing treatment, risks andbenefits are carefully reviewed with all pa-tients and an informed consent is signed. Thepatient is encouraged to meet with and observeother patients undergoing treatment.

Post-treatment guidelines for the patient in-clude: 1. Scalp/hair should not be washed in the 48

hours following treatment.2. The scalp must be protected from all

sources of light. The wearing of a hairpieceor scarf is sufficient.

3. A commitment is made to return forweekly treatments for at least 24 weeks.

4. A low-potency topical corticosteroid isgiven to the patient for mild inflammatoryreactions post-treatment. The physicianmust be notified of severe reactions.

DPCP is compounded in an acetone base andstored in opaque bottles to protect the solutionfrom photodegradation. All bottles are datedon first use, because we have found that theshelf life after opening is approximately 6months. We periodically check the DPCP forpurity with high-pressure liquid chromatogra-phy. All the screw-top lid bottles of DPCP arestored in a large plastic bin with a lid to pre-vent both accidental spillage and inadvertentstaff sensitization. The standard DPCP tray forAA includes the following concentrations:0.0001%, 0.001%, 0.01%, 0.1%, 0.5%, 1.0%and 2%. Intermediate concentrations may benecessary. The transition from 0.1% to 1.0% isbest bridged with a 0.5% solution of DPCP(Figure 2.20). Although not routinely used, ithas occasionally been necessary to use 0.05%and 0.25% strengths for sensitive patients.

Safety precautions must be implementedwhen handling DPCP, because of the risk ofsensitization of staff administering the treat-ment. Gloves must be worn and caution used toprevent the DPCP from coming in contact withthe skin of the staff member. If the person ad-ministering the DPCP develops eczema, the useof a barrier cream and double gloving is help-ful. A gown covering the arms should be wornand laundered after each treatment session.Spills should be wiped up immediately using adry towel, followed by a moist towel, to eradi-cate all traces of the DPCP. There is a report inthe literature where DPCP treatment had to beabandoned in a clinic owing to the largenumber of staff becoming sensitized to DPCP.222

The DPCP solution is applied to the scalpusing a thick cotton swab that has been dippedinto the bottle. If the swab needs to beremoistened, an eye-dropper is used to satu-rate the swab and prevent contamination.These swabs are constructed with longwooden applicator sticks and cotton balls. The

Alopecia areata 57

Figure 2.2140-year-old female with an 18-year history of alopecia involving 99% of the scalp. (a) base-line. (b) 12 weeks of unilateral DPCP treatment. (c) 24 weeks of unilateral treatment. (d) 30weeks of treatment of the left side and 6 weeks on the contralateral side. (e) 1 year of treat-ment. (f) 5 years of intermittent treatment.


cotton is wound around the stick to make afirm swab approximately three times the thick-ness of an average cotton-tipped applicator(Figure 2.20). Cotton-tipped applicators do notretain enough moisture to paint the scalp ad-equately.

Once the patient commits to DPCP treat-ment, an initial sensitizing dose of 2% DPCPis administered to a 4×4 cm circular area onthe occipital region of the scalp, Patients re-turn for weekly visits until hair growth is es-tablished. After 1 week, if no reaction or only amild to moderate reaction is observed, a0.0001% solution is applied to half the scalp.Two coats are applied, the first coat in an an-teroposterior direction and the second coat in

a lateral direction. We avoid application on tothe nape of the neck, as well as the area wherethe tape for the hairpiece is applied. If this areabecomes irritated, it is difficult for the patientto continue wearing a hairpiece. The nape ofthe neck is a very sensitive area that will reactwhen other parts of the scalp do not. This canbe confusing when attempting to titrate thepatient to the correct dosage. Titration must beconducted carefully, because severe reactionscan discourage the patient and preciptate dis-continuation of treatment. If there is a markedreaction, we do not apply any solution untilthe following week. DPCP is left on the scalpfor 48 hours and then washed off. The patientmust protect the scalp from light with a cap,

Figure 2.22Ophiasis in a 43-year-old female of 2 years’duration. (a) baseline. (b) 12 weeks of DPCPtreatment, showing some white regrowth. (c)24 weeks of DPCP treatment.

Alopecia areata 59

wig or scarf during this period of time, as DPCPis degraded when exposed to light. The follow-ing week, DPCP is reapplied to the same halfof the scalp. The aim is to maintain erythemaand pruritus, or a low tolerable eczema, on thetreated side for 36–48 hours after application.The concentration is adjusted individually onthe basis of the severity of the previous reac-tion. Concentrations vary (0.0001%, 0.001%,0.01%, 0.05%, 0.1%, 0.5%, 1.0%, 2.0%). Oncehair growth is established one one side, theother side is treated (see Figure 2.20). Eachweek when the patient returns, the severity ofreaction and the presence of any hair growthare assessed. The tolerance to the discomfortfrom the eczema varies with patients. It is im-portant to listen to your patients. It is better tobe cautious than to be very aggressive andcause a severe reaction.

Figure 2.24Delayed DPCP response. The patient had been treated unilaterally for 6 months without aresponse. (a) She returned to the clinic after treatment had been discontinued for 6 monthswith a unilateral response on the treated side. (b) Both sides were then subsequently treated,with full regrowth.

Figure 2.23Unilateral treatment with DPCP, showingcircular areas refractory to treatment. Theserefractory areas can be injected oncemonthly. DPCP is applied weekly for 3 weeksout of every month. Intralesional corticoster-oid is injected once monthly.


Figure 2.26Eczematous eruptions from DPCP. (a) Unilateral eczematous response one week after applica-tion. This reaction is too strong. No application for 1 full week with a lower concentrationapplied the following week. (b) Marked bulla formation is possible.

Figure 2.25Treatment of eyebrows with DPCP. (a) Posi-tion used to apply DPCP to eyebrows. Eyesare well shielded. (b) Baseline before treat-ment in a 40-year-old female with no eye-brows for 18 years. (c) Complete regrowthwith treatment.

Alopecia areata 61

(c),(d),(e) The neck area is a common area fora bad reaction. (f) Frontal unilateral edemaand eczema. (g) Contact dermatitis to remoteareas.


Figure 2.27Lymphadenopathy occurs in 100% of pa-tients.

Figure 2.28Pigmentary changes with DPCP: (a) Hypo- and hyperpigmentation (‘dychromia in confetti’)after 24 weeks of treatment in an East Indian patient. (b) The same patient, with most pigmen-tary changes resolved. (c) Hypo- and hyperpigmentation in an African-American patient. (d)Vitiligo on the back of the neck.

Alopecia areata 63

If patients have discontinued treatment be-cause of intolerable effects, it is difficult to getthem to resume therapy. The strength can al-ways be increased later when the patient be-comes familiarized with the treatments. Oncefull regrowth has occurred (Figures 2.21 and2.22), the frequency of treatment is graduallyreduced, using the rule of four: treatment isadminstered every other week for 4 weeks,

then every third week for 4 weeks, and so on.This reduction of visits continues until the pa-tient experiences some hair loss and estab-lishes the maintenance requirement.Maintenance requirements vary with indi-viduals and commonly range from biweekly tobimonthly treatments. One patient was able todiscontinue treatments for 4 years before sheexperienced any hair loss. The requirement for

(e) Vitilgo on half of the scalp in a patient who had been applying DPCP at home. (f), (g), (h).Vitiliginous patches on areas remote to the scalp.


maintenance therapy illustrates the palliativenature of the treatment.

Regrowth of hair will take at least 12 weeks.However, we have had patients that have taken41 weeks to see unilateral regrowth. If the pa-tient has not responded by 52 weeks, we con-sider the patient unlikely to respond, and wemay abandon topical immunotherapy and pro-ceed to another modality of therapy. In certainresponders, most of the scalp regrows hair ex-cept for a few small areas refractory to DPCP.These resistant areas are treated withintralesional triamcinolone acetonide 5 mg/mlonce monthly, and usually respond well (seeFigure 2.23).

We have had a few patients that we identifyas ‘slow growers’. They consistently grow newhair in more areas and do not seem to lose hair.The process of complete regrowth is lengthy,with gradual new growth in multiple areas.Another phenomenon we have seen is the ‘ini-tial non-responder’. These patients initially donot respond, and discontinue treatment.Within 2 years of stopping treatment, a smallnumber of individuals have returned with hairgrowth only on the orginally treated side.Upon recommencing treatment, growth wasobtained (Figure 2.24).

DPCP has been used with success to treat eye-brows. Extreme caution must be used. The pa-tient should be lying flat, the eyes shielded withgauze, and the swab should be minimally moist.This is best done at the end of the treatment, af-ter the scalp has been treated (see Figure 2.25).

Side-effects include eczema (Figure 2.26),autoeczematization,223 severe blistering and lym-phadenopathy (Figure 2.27) in the neck behindthe ears. Consort dermatitis to spouse/partnerhas also been reported.223 Shah et al.222 report therisk to medical and nursing staff. Pigmentchanges (Figure 2.28), such as hyperpigme-ntation, hypopigmentation,224 a combination of

both referred to as ‘dyschromia in confetti’225 andvitiligo226–229 have been reported. Vitiligo is morecommon in AA patients, and because vitiligo hasa tendency to koebnerize on to inflamed skin,one must be very cautious about rapid extensionof vitiligo in an AA patient who already has thecondition. Vitiligo is a relative contraindicationfor treatment with topical immunogens. Extremecaution should be exercised when treating pa-tients of dark pigmentation. Contact urti-caria,230,231 severe dermographism,232 anderythema multiforme233 have also been reported.Because of the possible side-effects, we do notever give DPCP to the patient for self-application.

DPCP is contraindicated in pregnancy, al-though teratogenicity has not been demon-strated. All female patients are counselled touse reliable birth control while on DPCP. Atour clinic, six women have become pregnantwhile on DPCP therapy, despite all the warn-ings on the informed consent form. DPCPtherapy was immediately halted once ourclinic was informed. All six pregnancies haveproduced normal children.

Photochemotherapy (PUVA)

The mechanism of action of PUVA on AA isbelieved to be a photoimmunologic action.234

It may effect T cell function and antigen pres-entation, and possibly inhibit local immuno-logic attack against the hair follicle bydepleting Langerhans cells.234 (see Figure2.29).

The psoralen is administered either topi-cally or orally, and is followed in 1 hour or 2hours with UVA irradiation. Treatments are ad-ministered two to three times a week, withgradual increase in UVA dosage. Burns aremore likely to occur with topical therapy, butocular toxicity is avoided.

Alopecia areata 65

Lassus et al.237 studied 41 patients with oral8-MOP and whole body irradiation, and local8-MOP plus local UVA irradiation. No signifi-cant differences were seen. There was a re-sponse rate of almost 50% in each group. Only10% relapsed after 6–12 months.

The major problem with PUVA therapy isthe high relapse rate that frequently sets in af-ter tapering the treatment.238,239 Today’s con-cern about PUVA and its promotion of all typesof skin cancer, including melanoma,240 to-gether with the need for long-term therapy inAA, make PUVA therapy less than satisfactory.

CyclosporinSystemic cyclosporin has been shown to havesome benefit in AA.60,61 (Figure 2.30). As withsystemic corticosteroids, owing to the side-ef-fect profile, the high recurrence rate following

Figure 2.29PUVA therapy in alopecia areata: a 22-year-old patient with extensive alopecia affecting 95%of his scalp for 2 years. He was unresponsive to 24 weeks of topical immunotherapy withDPCP. (a) Baseline before PUVA. (b) After 1 year of PUVA. He still has refractory patches thatare amenable to intralesional corticosteroid therapy.

Mitchell and Douglas234 used a combinationof topical 0.1% 8-methoxypsoralen (8-MOP)and UVA and showed excellent regrowth in 8/22 (36.3%) and good regrowth in 2/22 (9%).Mean total UVA exposure for responders was171.1 joules/cm2, with a mean total number oftreatments of 47. Almost all the patients avail-able for follow-up experienced relapse whenPUVA was tapered.

Claudy and Gagnaire235 used systemicPUVA with total body irradiation and showeda success of rate of 70%. Larko andSwanbeck236 studied 40 patients with systemicPUVA, comparing whole body irradiation andscalp irradiation only. Whole body treatmentdid not produce significantly better hairgrowth. Thirty-five percent experienced hairregrowth, but only 20% experienced a fullregrowth. Relapses were frequent, with me-dian time to relapse being 10 weeks.


discontinuation of the treatment, the longtreatment periods and the inability to changethe ultimate prognosis of the disease, this treat-ment is simply not practical in AA. Gilhar etal.241 and De Prost et al.242 could not prove anycosmetic benefit from topical cyclosporin withconcentrations of 10%.

Treatment planTherapeutic selection for AA depends on pa-tient age, extent of alopecia and motivation fortreatment. The dermatologist should first dis-cuss all therapeutic options and outcomes, al-

Figure 2.30Cyclosporin in alopecia areata. (a) Mechanism of action by inhibiting the Th

1 response to the

hair follicle. (b) A 28-year-old male with alopecia universalis for 2 years. (c) 3 months ofsystemic cyclosporin (4 mg/kg/day) and prednisone 5 mg/day. (d) 5 months of therapy. Thepatient had to discontinue therapy owing to serum transaminase changes and cholesterolelevation.

Alopecia areata 67

lowing the patient to become an active mem-ber of the therapeutic team. Topical therapieswith minoxidil, corticosteroids and anthralinare considered in children of less than 10 yearsof age, while in adults other options to be con-sidered include intralesional corticosteroids orimmunotherapy.

A practical treatment algorithm for the treat-ment of AA is the University of California, SanFrancisco—University of British ColumbiaAlopecia Areata Treatment Protocol (see Fig-ure 2.31).

Patients are divided into those less than 10years of age and those over 10 years of age. Pa-

tients over 10 are then subdivided into thosewith less than 50% scalp hair loss and thosewith more than 50% scalp hair loss.

For those with less than 50% scalp hair loss,the following options are offered. Firstly, wealways offer the patient the option of no treat-ment, as many AA patients will regrow theirhair without treatment. However, most of ourpatients are well-motivated and want treat-ment. First-line therapy for scalp AA isintralesional corticosteroid injections into thealopecic patches. If there is no response after3–4 months, we will add a minoxidil 5% solu-tion twice daily and a superpotent corticoster-

Figure 2.31University of California at San Francisco-University of British Columbia Treatment protocolfor alopecia areata (permission granted by Drs Jerry Shapiro, Vera H.Price, and Harvey Lui).


oid cream such as clobetasol propionate ap-plied 30 minutes after the minoxidil in addi-tion to the monthly injections. If there is nobenefit, another option is short-contact anthra-lin therapy with anthralin 1.0% cream appliedfor up to 1 hour daily combined with topicalminoxidil 5% solution applied twice daily.

For those patients with more than 50%scalp involvement, our first line is topical im-munotherapy with DPCP. If there is no re-sponse by 52 weeks, topical immunotherapyis discontinued. Other options that can be of-fered to the patient are systemic PUVA,

minoxidil 5% solution, short-contact anthra-lin and superpotent topical steroids. A scalpprosthesis should be available to all patientswith more than 50% scalp involvement, andcan give great satisfaction to a majority of pa-tients. Scalp prostheses come in an assortmentof net linings that are light, and cool and allowair to circulate (see Figure 2.32). It should beemphasized to the patient that a prosthesisdoes not imply permanent hair loss, but hav-ing one on hand is comforting for episodes ofextensive hair loss. Use of eyeliner or alopeciamasking lotion (Figure 2.33) can give the AA

Figure 2.32Scalp prostheses come with different liningsthat are light and allow air to circulate. (a) Alining that will allow one’s own natural hairto be pulled through. (b), (c) Net meshes thatare typical.

Alopecia areata 69

patient considerable camouflage. Dermatogra-phy of eyebrows is a technique that can be rec-ommended for AA patients with prolongedeyebrow loss243 (Figure 2.34).

Children: Therapeutic modality choices de-pend upon patient age. Those older than 10years are treated with the same protocols asadults. In those younger than 10 yearsintralesional corticosteroids are avoided andtopical immunotherapy is not implemented,although several European studies have dem-onstrated efficacy and safety in children asyoung as 5 years.194,195 For those under 10 yearsof age, therapeutic options include minoxidilalone or in combination with a mid-potencytopical corticosteroid or anthralin.

The ultimate therapeutic plan is developedthrough team interaction between the patient,the patient’s family and the physician. For somepatients, support groups play an important rolein the overall therapeutic strategy, and the der-matologist needs to become familiar with sup-

port groups and suppliers of hairpieces. Physi-cians need to take the time to address the psy-chological needs of their patients, exploring theimpact of alopecia on the patient’s emotional

Figure 2.33Camouflage with eyeliner. (a) The patient is a 23-year-old who likes his hair short. He has asmall patch of alopecia areata. (b) Camouflage with eyeliner, giving the illusion of hair in thearea.

Figure 2.34Dermatography: a semi-permanent tattoo forthe eyebrows.


well-being. It is the role of dermatologist to ex-plain the diagnosis and inform the patient of allthe therapeutic options, safety profiles and out-comes. It is imperative that the physician spendsufficient time with the patient, just as onewould with a patient who had recently beendiagnosis as diabetic. The National AlopeciaAreata Foundation (710 C Street, Suite 11, SanRafael, California 94901–3853; www.alopecia-areata.org) offers patients and physicians infor-mation, including brochures, bimonthlynewsletters, research updates, sources for scalpprostheses, penpals for children, videos forchildren to take to school and information aboutsupport groups, which are present in manylarge cities in the USA and Canada. The Na-tional Alopecia Areata Foundation (NAAF) hasan annual convention for patients and theirfamilies, and this is often the turning-point forthem in terms of coping with the condition.Physicians are welcome to attend.

Outlook for the future foralopecia areata treatmentsNew therapeutic directions for alopecia areatawill involve specifically targeted immun-omodulatory agents. Rodent models currentlyavailable have become an important part oftherapeutic research. The eventual discovery ofcytokines specific for hair growth promotion intopical immunotherapy will offer more focusedtreatments. Newer immunomodulators specificfor CD4 or CD8 and IL-2 receptors may furtherenhance treatments. Other biotechniques to in-terrupt the peptide-antigen or T-cell receptorare being evaluated.

Gene replacement therapy based on currentgenetic studies may eventually allow lastingcorrection of abnormal gene expression.

Phototherapy beyond PUVA, involving newphotosensitizers and novel non-UV lightsources (lasers, light-emitting diode arrays),has the potential to immunomodulate. Therole of this therapy in the treatment of AAholds great potential for the future.

References1. Alopecia areata. A workshop. Bethesda,

Maryland, October 25–26, 1990. J InvestDermatol, 1991; 96(5):67S–100S.

2. 2nd International Research Workshop onAlopecia Areata. Bethesda, Maryland,November 7–8, 1994. J Invest Dermatol,1995; 104(5 Suppl):1S–45S.

3. Third International Research Workshop onAlopecia Areata. J Invest Dermatol, 1999;4(3):197–254.

4. Muller R.W.S. Alopecia areata: an evaluationof 736 patients. Arch Dermatol, 1963;88:290–7.

5. Shellow W.V., Edwards J.E. and Koo J.Y.Profile of alopecia areata: a questionnaireanalysis of patient and family. Int JDermatol, 1992; 31(3):186–9.

6. Price V.H. and Colombe B.W. Heritablefactors distinguish two types of alopeciaareata. Dermatol Clin, 1996; 14(4):679–89.

7. Colombe B.W., Price V.H., Khoury E.L. andLou C.D. HLA class II alleles in long-standing alopecia totalis/alopecia universalisand long-standing patchy alopecia areatadifferentiate these two clinical groups. JInvest Dermatol, 1995; 104(5 Suppl):4S–5S.

8. Colombe B.W., Price V.H., Khoury E.L., et al.HLA class II antigen associations help todefine two types of alopecia areata. J AmAcad Dermatol, 1995; 33(5 Pt 1):757–64.

9. Colombe B.W., Lou C.D. and Price V.H. Thegenetic basis of alopecia areata: HLAassociations with patchy alopecia areataversus alopecia totalis and alopeciauniversalis. J Invest Dermatol Symp Proc,1999; 4(3):216–19.

Alopecia areata 71

10. Cole G.W. and Herzlinger D. Alopeciauniversalis in identical twins. Int JDermatol, 1984; 23(4):283.

11. Gol’dshtein L.M. and Chipizhenko V.A.[Familial alopecia areata]. Vestn DermatolVenerol, 1978(10):36–8.

12. Dmitrienko L.P. and Shakhnes I.E. [Familialalopecia in twins]. Vestn Dermatol Venerol,1977(9):59–61.

13. Jackow C., Puffer N., Hordinsky M., et al.Alopecia areata and cytomegalovirusinfection in twins: genes versus environ-ment? J Am Acad Dermatol, 1998;38(3):418–25.

14. Scerri L. and Pace J.L. Identical twins withidentical alopecia areata. J Am AcadDermatol, 1992; 27(5 Pt 1):766–7.

15. So A. Genetics, polymorphism and regula-tion of expression of HLA region genes. InHLA and disease, ed. R.Lechler, p. 1. 1994;San Diego: Academic Press.

16. Kuntz B.M., Selzle D., Braun-Falco O., et al.HLA antigens in alopecia areata. ArchDermatol, 1977; 113(12):1717.

17. Kianto U., Reunala T., Karvonen J., et al.HLA-B12 in alopecia areata. Arch Dermatol,1977; 113(12):1716.

18. Hacham-Zadeh S., Brautbar C., Cohen C.A.and Cohen T. HLA and alopecia areata inJerusalem. Tissue Antigens, 1981; 18(1):71–4.

19. Averbakh E.V. and Pospelov L.E. [HLAantigens of patients with alopecia areata].Vestn Dermatol Venerol, 1986; 1:24–6.

20. Lutz G., Kessler M. and Bauer R. [Class Ialloantigens in alopecia areata]. Z Hautkr,1986; 61(14):1014, 1019–22.

21. Zlotogorski A., Weinrauch L. and BrautbarC. Familial alopecia areata: no linkage withHLA. Tissue Antigens, 1990; 36(1):40–1.

22. Frentz G., Thomsen K., Jacobsen B.K. andSvejgaard A. HLA-DR4 in alopecia areata[letter]. J Am Acad Dermatol, 1986; 14(1):129–30.

23. Mikesell J.F., Bergfeld, W.F. and Braun W.E.HLA-DR antigens in alopecia areata.

Preliminary report. Cleve Clin Q, 1986;53(2):189–91.

24. Orecchia G., Belvedere M.C., Martinetti M.,et al. Human leukocyte antigen regioninvolvement in the genetic predisposition toalopecia areata. Dermatologica, 1987;175(1):10–14

25. Zhang L., Weetman A.P., Friedmann P.S. andOliveira D.B. HLA associations with alopeciaareata. Tissue Antigens, 1991; 38(2):89–91.

26. Duvic M., Hordinsky M.K., Fiedler V.C., etal. HLA-D locus associations in alopeciaareata. DRw52a may confer disease resist-ance. Arch Dermatol, 1991; 127(1):64–8.

27. Morling N., Frentz G., Fugger L., et al. DNApolymorphism of HLA class II genes inalopecia areata. Dis Markers, 1991; 9(1):35–42.

28. Welsh E.A., Clark H.H., Epstein S.Z., et al.Human leukocyte antigen-DQB1*03 allelesare associated with alopecia areata. J InvestDermatol, 1994; 103(6):758–63.

29. Duvic M., Welsh E.A., Jackow C., et al.Analysis of HLA-D locus alleles in alopeciaareata patients and families. J InvestDermatol, 1995; 104(5 Suppl):5S–6S.

30. Carter D.M. and Jegasothy B.V. Alopeciaareata and Down syndrome. Arch Dermatol,1976; 112(10):1397–9.

31. Du Vivier A. and Munro D.D. Alopeciaareata, autoimmunity, and Down’s syn-drome. Br Med J, 1975; 1(5951):191–2.

32. Tarlow J.K., Clay F.E., Cork M.J., et al.Severity of alopecia areata is associated witha polymorphism in the interleukin-1receptor antagonist gene. J Invest Dermatol,1994; 103(3):387–90.

33. Harmon C.S. and Nevins T.D. IL-1 alphainhibits human hair follicle growth andhair fiber production in whole-organcultures. Lymphokine Cytokine Res, 1993;12(4): 197–203.

34. Philpott M.P., Sanders D.A., Bowen J. andKealey T. Effects of interleukins,colonystimulating factor and tumournecrosis factor on human hair follicle


growth in vitro: a possible role forinterleukin-1 and tumour necrosis factor-alpha in alopecia areata. Br J Dermatol,1996; 135(6):942–8.

35. Bergfeld W. Alopecia areata and thyroiddisease. J Invest Dermatol, 1999;4(3):252.

36. Puavilai S., Puarilai G., CharuwichitratanaS., et al. Prevalence of thyroid diseases inpatients with alopecia areata. Int J Dermatol,1994; 33(9):632–3.

37. Shong Y.K. and Kim J.A.Vitiligo inautoimmune thyroid disease. Thyroidology,1991; 3(2):89–91.

38. Kenney Jr. J.A.Vitiligo. Dermatol Clin, 1988;6(3):425–34.

39. Kumar B., Sharma V.K. and Sehgal S.Antismooth muscle and antiparietal cellantibodies in Indians with alopecia areata.Int J Dermatol, 1995; 34(8):542–5.

40. Friedmann P.S. Decreased lymphocytereactivity and auto-immunity in alopeciaareata. Br J Dermatol, 1981; 105(2):145–51.

41. Werth V.P., et al. Incidence of alopecia areatain lupus erythematosus. Arch Dermatol,1992; 128(3):368–71.

42. Noguchi Y., Fuchigami T., Morimoto S. andHarada K. Myasthenia gravis with alopeciatotalis. Acta Paediatr Jap, 1998; 40(1): 99–101.

43. Kamada N., Hatamochi A. and Shinkai H.Alopecia areata associated with myastheniagravis and thymoma: a case of alopecia withmarked improvement following thymectomyand high level prednisolone administration.J Dermatol, 1997; 24(12):769–72.

44. Korn-Lubetzki I., Virozov Y. and Klar A.Myasthenia gravis and alopecia areata [letter;comment]. Neurology, 1998; 50(2): 578.

45. Kubota A., Komiyama A. and Hasegawa O.Myasthenia gravis and alopecia areata [seecomments]. Neurology, 1997; 48(3):774–5.

46. Tan R.S.Ulcerative colitis, myastheniagravis, atypical lichen planus, alopecia67(3):195–6. areata, vitiligo. Proc R Soc Med,1974;

47. Faergemann J.Lichen sclerosus et atrophicusgeneralisatus, alopecia areata, andpolymyalgia rheumatica found in the samepatient. Cutis, 1979; 23(6):757–8.

48. Treem W.R., Veligati L.N., Rotter J.L., et al.Ulcerative colitis and total alopecia in amother and her son. Gastroenterology, 1993;104(4):1187–91.

49. [Study of lichen planus conducted by theIGESD: results, implications for clinicalpractice, prospects. Italian Group of Epide-miological Studies in Dermatology (IGESD)].G Ital Dermatol Venereol, 1990;125(12):563–7.

50. Thompson D.M., Robinson T.W. andLennard-Jones J.Alopecia areata, vitiligo,scleroderma and ulcerative colitis. Proc RSoc Med, 1974; 67(10):1010–12.

51. Mann R.J., Wallington T.B. and Warin R.P.Lichen planus with late onsethypogammaglobulinaemia: a causal relation-ship? Br J Dermatol, 1982; 106(3): 357–60.

52. Brenner W., Diem E. and Gschnait F. Coinci-dence of vitiligo, alopecia areata,onychodystrophy, localized scleroderma andlichen planus. Dermatologica, 1979; 159(4):356–60.

53. Aloi P.G., Colonna S.M. and Manzoni R.[Association of lichen ruber planus, alopeciaareata and vitiligo]. G Ital DermatolVenereol, 1987; 122(4):197–200.

54. Conte A., Inverardi D., Loconsole F., et al. [Aretrospective study of 200 cases of lichen]. GItal Dermatol Venereol, 1990; 125(3):85–9.

55. Dhar S. Colocalization of alopecia areata andlichen planus [letter]. Pediatr Dermatol,1996; 13(3):258–9.

56. Boni R., Trueb R.M. and Wuthrich B.Alopecia areata in a patient with candidia-sis-endocrinopathy syndrome: unsuccessfultreatment trial withdiphenylcyclopropenone. Dermatology,1995; 191(1):68–71.

57. Bunnag P. and Rajatanavin R. Polyglandularautoimmune (PGA) syndromes: report of

Alopecia areata 73

three cases and review of the literature. JMed Assoc Thai, 1994; 77(6):327–33.

58. Delambre C., Teillac D., Brauner R. and deProst Y. [Autoimmune polyendocrinopathyand chronic mucocutaneous candidiasis].Ann Dermatol Venereal, 1989; 116(2):117–21.

59. Betterle C., Greggio N.A. and Volpato M.Clinical review 93: Autoimmune polyglan-dular syndrome type 1. J Clin EndocrinolMetab, 1998; 83(4):1049–55.

60. Shapiro J., Lui H., Tron V. and Ho V. Sys-temic cyclosporine and low-dose prednisonein the treatment of chronic severe alopeciaareata: a clinical and immunopathologicevaluation. J Am Acad Dermatol, 1997;36(1):114–17.

61. Gupta A.K., Ellis C.N., Cooper K.D., et al.Oral cyclosporine for the treatment ofalopecia areata. A clinical and immunohisto-chemical analysis. J Am Acad Dermatol,1990; 22(2 Pt 1):242–50.

62. Olsen E.A., Carson S.C. and Turney E.A.Systemic steroids with or without 2%topical minoxidil in the treatment ofalopecia areata. Arch Dermatol, 1992;128(11):1467–73.

63. Muller H.K., Rook A.J. and Kubba R.Immunohistology and autoantibody studiesin alopecia areata. Br J Dermatol, 1980;102(5):609–10.

64. Gilhar A., Pillar T., Assay B. and David M.Failure of passive transfer of serum frompatients with alopecia areata and alopeciauniversalis to inhibit hair growth intransplants of human scalp skin grafted onto nude mice. Br J Dermatol, 1992;126(2):166–71.

65. Tobin D.J., Orentreich N., Fenton D.A,Bystryn J.C. Antibodies to hair follicles inalopecia areata. J Invest Dermatol, 1994;102(5):721–4.

66. Tobin D.J., Hann S.K., Song M.S., BystrynJ.C. Hair follicle structures targeted byantibodies in patients with alopecia areata.Arch Dermatol, 1997; 133(1):57–61.

67. Majewski B.B., Koh M.S., Taylor D.R., et al.Increased ratio of helper to suppressor Tcells in alopecia areata. Br J Dermatol, 1984;110(2):171–5.

68. Hordinsky M.K., Hallgren H., Nelson D. andFilipovich A.H. Suppressor cell number andfunction in alopecia areata. Arch Dermatol,1984; 120(2):188–94.

69. Gilhar A., Ullmann Y., Berkutzki T., et al.Autoimmune hair loss (alopecia areata)transferred by T lymphocytes to humanscalp explants on SCID mice. J Clin Invest,1998; 101(1):62–7.

70. Tsuboi H., Tanei R., Fujimura T., et al.Characterization of infiltrating T cells inhuman scalp explants from alopecia areatato SCID nude mice: possible role of thedisappearance of CD8+ T lymphocytes in theprocess of hair regrowth. J Dermatol, 1999;26(12):797–802.

71. Christoph T., Muller-Rover S., Audring H., etal. The human hair follicle immune system:cellular composition and immune privilege.Br J Dermatol, 2000; 142(5): 862–73.

72. Paus R., Christoph T. and Muller-Rover S.Immunology of the hair follicle: a shortjourney into terra incognita. J InvestDermatol Symp Proc, 1999; 4(3):226–34.

73. Hoffmann R., Eicheler W., Huth A., et al.Cytokines and growth factors influence hairgrowth in vitro. Possible implications for thepathogenesis and treatment of alopeciaareata. Arch Dermatol Res, 1996; 288(3):153–6.

74. Mosmann T.R. and Coffman R.L. TH1 andTH2 cells: different patterns of lymphokinesecretion lead to different functionalproperties. Annu Rev Immunol, 1989; 7:145–73.

75. Skinner Jr. R.B., Light W.H., Bale G.F., et al.Alopecia areata and presence of cytomegalo-virus DNA [letter]. JAMA, 1995;273(18):1419–20.

76. Tosti A., La Placa M., Placucci F., et al. Nocorrelation between cytomegalovirus and


alopecia areata [letter]. J Invest Dermatol,1996; 107(3):443.

77. Garcia-Hernandez M.J., Torres M.J.,Palomares J.C., et al. No evidence of cytome-galovirus DNA in alopecia areata [letter]. JInvest Dermatol, 1998; 110(2):185.

78. McElwee K.J., Boggess D., Burgett B., et al.Murine cytomegalovirus is not associatedwith alopecia areata in C3H/HeJ mice[letter]. J Invest Dermatol, 1998;110(6):986–7.

79. Baker G.H. Psychological factors and immu-nity. J Psychosom Res, 1987; 31(1): 1–10.

80. Perini G.I., Veller Fornasa C., Cipriani R., etal. Life events and alopecia areata.Psychother Psychosom, 1984; 41(1):48–52.

81. Colon E.A., Popkin M.A., Callies A.L., et al.Lifetime prevalence of psychiatric disordersin patients with alopecia areata. ComprPsychiatry, 1991; 32(3):245–51.

82. De Waard-van der Spek F.B., Oranje A.P.,De Raeymaecker D.M. andPeereboomWynia J.D. Juvenile versusmaturity-onset alopecia areata—a compara-tive retrospective clinical study. Clin ExpDermatol, 1989; 14(6):429–33.

83. van der Steen P., Baezman J., Duller P. andHapple R. Can alopecia areata be triggeredby emotional stress? An uncontrolledevaluation of 178 patients with extensivehair loss. Acta Derm Venereol, 1992; 72(4):279–80.

84. Tobin D.J., Fenton D.A. and Kendall M.D.Ultrastructural observations on the hair bulbmelanocytes and melanosomes in acutealopecia areata. J Invest Dermatol, 1990;94(6):803–7.

85. Nutbrown M., Hull S.P., Cunliffe W.J. andRandall V.A. Abnormalities in the ultrastruc-ture of melanocytes and the outer rootsheath of clinically normal hair folliclesfrom alopecia areata scalps. J InvestDermatol, 1995; 104(5 Suppl):12S–13S.

86. Tobin, S.J., Morphological analysis of hairfollicles in alopecia areata. Microsc Res Tech, 1997; 38(4):443–51.

87. Hosoi J., Murphy G.F., Egan C.L., et al.Regulation of Langerhans cell function bynerves containing calcitonin gene-relatedpeptide. Nature, 1993; 363(6425):159–63.

88. Hordinsky M.K., Kennedy W.,Wendelschafer-Crable G. and Lewis S.Structure and function of cutaneous nervesin alopecia areata. J Invest Dermatol, 1995;104(5 Suppl):28S–29S.

89. Raud J., Lundeberg T., Brodda-Jansen G.,et al. Potent anti-inflammatory action ofcalcitonin gene-related peptide. BiochemBiophys Res Commun, 1991; 180(3):1429–35.

90. Paus R., Heinzelmann T., Schultz K.D., et al.Hair growth induction by substance P. LabInvest, 1994; 71(1):134–40.

91. Ericson M. Differential expression of sub-stance P in perifollicular scalp blood vesselsand nerves after topical therapy withcapsaicin 0.075% (Zostrix) in controls andpatients with alopecia areata. J InvestDermatol, 1999; 112:653.

92. Sundberg J.P., Cordy W.R. and King Jr. L.E.Alopecia areata in aging C3H/HeJ mice. JInvest Dermatol, 1994; 102(6):847–56.

93. Michie H.J., Jahoda C.A., Oliver R.F. andJohnson B.E. The DEBR rat: an animal modelof human alopecia areata. Br J Dermatol,1991; 125(2):94–100.

94. Smyth Jr. J.R. and McNeil M. Alopeciaareata and universalis in the Smyth chickenmodel for spontaneous autoimmunevitiligo. J Invest Dermatol Symp Proc, 1999;4(3): 211–15.

95. McElwee K.J., Boggess D., King L.E.,Sundberg J.P. Experimental induction ofalopecia areata-like hair loss in C3H/HeJmice using full-thickness skin grafts. J InvestDermatol, 1998; 111(5):797–803.

96. McElwee K.J. Third International ResearchWorkshop on Alopecia Areata. J InvestDermatol, 1999; 112(5):822–4.

97. Benichou G. and Price V.H. T cell repertoirein mice with alopecia areata. J InvestDermatol Symp Proc, 1999; 4(3):224–5.

Alopecia areata 75

98. Liu H., Tang L., McLean D., et al.Leflunomide in the alopecia areata DEBR rat.J Invest Dermatol, 1999; 4(3):249.

99. Shapiro J., Sundberg J.P., Bissonette R., et al.Alopecia areata-like hair loss in C3H/HeJmice and DEBR rats can be reversed usingtopical diphencyprone. J Invest DermatolSymp Proc, 1999; 4(3):239.

100. Freyschmidt-Paul P., Sundberg J.P., HappleR., et al. Successful treatment of alopeciaareata-like hair loss with the contactsensitizer squaric acid dibutylester (SADBE)in C3H/HeJ mice. J Invest Dermatol, 1999;113(1):61–8.

101. Green M. Catalog of mutant genes andpolymorphic loci. In Genetic variants andstrains of the laboratory mouse, ed. M. Lyon.1989; Oxford: Oxford University Press.

102. Sundberg J. The hairless and rhino muta-tions, chromosome 14. In Handbook ofmouse mutations with skin and hairabnormalities, ed. J.Sundberg, pp. 291–312.1994; Boca Raton, FL: CRC Press.

103. Ahmad W., Panteleyev A.A. and ChristianoA.M. The molecular basis of congenitalatrichia in humans and mice: mutations inthe hairless gene. J Invest Dermatol SympProc, 1999; 4(3):240–3.

104. Godwin A.R. and Capecchi M.R. Hair defectsin Hoxc13 mutant mice. J Invest DermatolSymp Proc, 1999; 4(3):244–7.

105. Messenger A.G., Slater D.N. and BleehenS.S. Alopecia areata: alterations in the hairgrowth cycle and correlation with thefollicular pathology. Br J Dermatol, 1986;114(3):337–47.

106. Headington J. The histology of alopeciaareata. J Invest Dermatol, 1991; 96:69S.

107. Perret C., Wiesner-Menzel L. and Happle R.Immunohistochemical analysis of T-cellsubsets in the peribulbar and intrabulbarinfiltrates of alopecia areata. Acta DermVenereol, 1984; 64(1):26–30.

108. Wiesner-Menzel L. and Happle R.Intrabulbar and peribulbar accumulation ofdendritic OKT 6-positive cells in alopecia

areata. Arch Dermatol Res, 1984; 276(5):333–4.

109. Whiting D. Alopecia areata. In Color atlas ofdifferential diagnosis of hair loss, ed. D.Whiting, pp. 32–7. 1996; Cedar Grove:Canfield Publishing.

110. Whiting D.A. Histopathology of alopeciaareata in horizontal sections of scalpbiopsies. J Invest Dermatol, 1995; 104(5Suppl):26S–27S.

111. Kohchiyama A., Hatamochi A. and Ueki H.Increased number of OKT6-positive den-dritic cells in the hair follicles of patientswith alopecia areata. Dermatologica, 1985;171(5):327–31.

112. Elston D.M., McCollough M.L., BergfeldW.F., et al. Eosinophils in fibrous tracts andnear hair bulbs: a helpful diagnostic featureof alopecia areata [see comments]. J AmAcad Dermatol, 1997; 37(1):101–6.

113. El Darouti M., Marzouk S.A. and Sharawi E.Eosinophils in fibrous tracts and near hairbulbs: A helpful diagnostic feature ofalopecia areata [letter; comment]. J Am AcadDermatol, 2000; 42(2 Pt 1):305–7.

114. Nutbrown M., MacDonald Hull S.P., BakerT.G., et al. Ultrastructural abnormalities inthe dermal papillae of both lesional andclinically normal follicles from alopeciaareata scalps. Br J Dermatol, 1996; 135(2):204–10.

115. McDonagh A.J., Snowden J.A., Stierle C.,et al. HLA and ICAM-1 expression inalopecia areata in vivo and in vitro: therole of cytokines. Br J Dermatol, 1993;129(3):250–6.

116. Lee J.Y. and Hsu M.L. Alopecia syphilitica, asimulator of alopecia areata: histopathologyand differential diagnosis. J Cutan Pathol,1991; 18(2):87–92.

117. Safavi K. Prevalence of alopecia areata in theFirst National Health and Nutrition Exami-nation Survey [letter]. Arch Dermatol, 1992;128(5):702.

118. Price V.H. Alopecia areata: clinical aspects. JInvest Dermatol, 1991; 96(5):68S.


119. Camacho F. Alopecia areata: clinical fea-tures. In Trichology: Diseases of the pilose-baceous follicle, ed. F.Camacho, pp. 417–50.1997, Madrid, Spain: Aula Medica Group.

120. Peereboom-Wynia J.D., Koerten H.K., VanJoost T., Stolz E. Scanning electronmicroscopy comparing exclamation markhairs in alopecia areata with normal hairfibres, mechanically broken by traction. ClinExp Dermatol, 1989; 14(1):47–50.

121. Muralidhar S., Sharma V.K. and Kaur S.Ophiasis inversus: a rare pattern of alopeciaareata [letter] [see comments]. PediatrDermatol, 1998; 15(4):326–7.

122. DeBerker D. Handbook of the diseases of thenails and their management, ed. R.B.D.DeBerker and R.Dawber, pp. 76–7. 1995;Blackwell Science, Oxford.

123. Tosti A., Barclazzi F., Piraccini B.M., et al. Istrachyonychia, a variety of alopecia areata,limited to the nails? J Invest Dermatol, 1995;104(5 Suppl):27S–28S.

124. Tosti A. Idiopathic trachyonychia(twenty-nail dystrophy): a pathologicalstudy of 23 patients. Br J Dermatol, 1994;131(6): 866–72.

125. Tosti A., et al. Prevalence of nail abnormali-ties in children with alopecia areata. PediatrDermatol, 1994; 11(2):112–15.

126. Tosti A., et al. Trachyonychia associatedwith alopecia areata: a clinical andpathologic study. J Am Acad Dermatol,1991; 25(2 Pt 1):266–70.

127. Tosti A., et al. [Nail changes and alopeciaareata]. G Ital Dermatol Venereol, 1985;120(3):169–71.

128. Tosti A., Palmerio B. and Veronesi S. [20 naildystrophy, alopecia areata, lichen planus], GItal Dermatol Venereol, 1985; 120(2):131–2.

129. Mitchell A.J. and Krull E.A. Alopecia areata:pathogenesis and treatment. J Am AcadDermatol, 1984; 11(5 Pt 1):763–75.

130. Garcia-Hernandez M.J., Rodriguez-PichardoA. and Camacho F. Congenital triangular

alopecia (Brauer nevus). Pediatr Dermatol,1995; 12(4):301–3.

131. Dominguez E., Eslinger M.R. and McCordS.V. Postoperative (pressure) alopecia: reportof a case after elective cosmetic surgery.Anesth Analg, 1999; 89(4):1062–3.

132. Wiles J.C. and Hansen R.C. Postoperative(pressure) alopecia. J Am Acad Dermatol,1985; 12(1 Pt 2):195–8.

133. Kosanin R.M., Riefkohl R. and Barwick W.J.Postoperative alopecia in a woman after alengthy plastic surgical procedure. PlastReconstr Surg, 1984; 73(2):308–9.

134. Poma P.A. Pressure-induced alopecia. Reportof a case after gynecologic surgery. J ReprodMed, 1979; 22(4):219–21.

135. Madani S. and Shapiro J. The scalp biopsy:making it more efficient [In Process Cita-tion]. Dermatol Surg, 1999; 25(7):537–8.

136. Bateman T. Practical Synopsis of CutaneousDisease, 4th edn. 1817.

137. Olsen E., Hordinsky M., McDonald-Hull S.,et al. Alopecia areata investigational assess-ment guidelines. National Alopecia AreataFoundation. J Am Acad Dermatol, 1999;40(2 Pt 1):242–6.

138. Drake L.A., Dinehart S.M., Farmer E.R., et al.Guidelines of care for alopecia areata. J AmAcad Dermatol , 1992; 26(2 Pt 1):247–50.

139. Sawaya M.E. and Hordinsky M.K. Glucocor-ticoid regulation of hair growth in alopeciaareata. J Invest Dermatol, 1995; 104(5Suppl):30S.

140. Perret C.M., Steijlen P.M. and Happle R.Alopecia areata. Pathogenesis and topicalimmunotherapy. Int J Dermatol, 1990;29(2):83–8.

141. Gill K. Alopecia totalis—treatment withfluocinolone acetonide. Arch Dermatol,1963; 87:384.

142. Montes L.F. Topical halcinonide in alopeciaareata and in alopecia totalis. J Cutan Pathol,1977; 4(2):47–50.

143. Leyden J.L. and Kligman A.M. Treatment ofalopecia areata with steroid solution. ArchDermatol, 1972; 106(6):924.

Alopecia areata 77

144. Price V. Progress in Dermatology. BullDermatol Foundation, 1991; 25:1.

145. Fiedler V.C. Alopecia areata: current therapy.J Invest Dermatol, 1991; 96(5):69S–70S.

146. Price V.H. Treatment of hair loss. New Engl JMed, 1999; 341(13):964–73.

147. Shapiro J. and Price V.H. Hair regrowth.Therapeutic agents. Dermatol Clin, 1998;16(2):341–56.

148. Porter D. and Burton J.L. A comparison ofintra-lesional triamcinolone hexacetonideand triamcinolone acetonide in alopeciaareata. Br J Dermatol, 1971; 85(3):272–3.

149. Shapiro J. Alopecia areata. Update ontherapy. Dermatol Clin, 1993; 11(1):35–46.

150. Whiting D.A. The treatment of alopeciaareata. Cutis, 1987; 40(3):247–50.

151. Bergfeld W. Alopecia areata symposium.Pediat Dermatol, 1987; 4:144.

152. Thiers B. Alopecia areata symposium. PediatDermatol, 1987; 4:136.

153. Ferrando J. and Moreno-Arias G.A.Multiinjection plate for intralesionalcorticosteroid treatment of patchy alopeciaareata. Dermatol Surg, 2000; 26(7):690–1.

154. Alabdulkareem A.S., Abahussein A.A. andOkoro A. Severe alopecia areata treated withsystemic corticosteroids. Int J Dermatol,1998; 37(8):622–4.

155. Winter R.J., Kern F. and Blizzard R.M.Prednisone therapy for alopecia areata. Afollow-up report. Arch Dermatol, 1976;112(11):1549–52.

156. Unger W.P. and Schemmer R.J.Corticosteroids in the treatment of alopeciatotalis. Systemic effects. Arch Dermatol,1978; 114(10):1486–90.

157. Sharma V.K. Pulsed administration ofcorticosteroids in the treatment of alopeciaareata. Int J Dermatol, 1996; 35(2):133–6.

158. Michalowski R. Alopecia areata totalis/universalis and systemic corticosteroids[letter; comment]. Int J Dermatol, 1999;38(12):947.

159. Friedli A., et al. Pulse methylprednisolonetherapy for severe alopecia areata: an open

prospective study of 45 patients. J Am AcadDermatol, 1998; 39(4 Pt 1):597–602.

160. Buhl A.E. Minoxidil’s action in hair folli-cles. J Invest Dermatol, 1991; 96(5):73S–74S.

161. Khoury E.L., Price V.H., Abdel-Salam M.M.,et al. Topical minoxidil in alopecia areata:no effect on the perifollicular lymphoidinfiltration. J Invest Dermatol, 1992;99(1):40–7.

162. Fiedler V.C. Alopecia areata. A review oftherapy, efficacy, safety, and mechanism[editorial] [see comments]. Arch Dermatol,1992; 128(11):1519–29.

163. Price V.H. Topical minoxidil in extensivealopecia areata, including 3-year follow-up.Dermatologica, 1987; 175(Suppl 2):36–41.

164. Fiedler-Weiss V.C. Topical minoxidilsolution (1% and 5%) in the treatment ofalopecia areata. J Am Acad Dermatol, 1987;16(3 Pt 2):745–8.

165. Fiedler-Weiss V.C., West D.P., Buys C.M. andRumsfield J.A. Topical minoxidildoseresponse effect in alopecia areata. ArchDermatol, 1986; 122(2):180–2.

166. Price V.H. Topical minoxidil (3%) inextensive alopecia areata, including long-term efficacy. J Am Acad Dermatol, 1987;16(3 Pt 2):737–44.

167. Ranchoff R.E., Bagfeld W.F., Stack W.D. andSubichin S.J. Extensive alopecia areata.Results of treatment with 3% topicalminoxidil. Cleve Clin J Med, 1989; 56(2):149–54.

168. Fransway A.F. and Muller S.A. 3 percenttopical minoxidil compared with placebo forthe treatment of chronic severe alopeciaareata. Cutis, 1988; 41(6):431–5.

169. Vestey J.P. and Savin J.A. A trial of 1%minoxidil used topically for severe alopeciaareata. Acta Derm Venereol, 1986; 66(2):179–80.

170. Fiedler V.C., Wendraw A., Szpunar G.J., et al.Treatment-resistant alopecia areata. Re-sponse to combination therapy withminoxidil plus anthralin. Arch Dermatol,1990; 126(6):756–9.


171. Morhenn V.B., Orenberg E.K., Kaplan J., etal. Inhibition of a Langerhans cell-mediatedimmune response by treatment modalitiesuseful in psoriasis. J Invest Dermatol, 1983;81(1):23–7.

172. Swanson N.A., Mitchell A.J., Leahy M.S., etal. Topical treatment of alopecia areata. ArchDermatol, 1981; 117(7):384–7.

173. Buchner U. Irritant versus allergic contactdermatitis for the treatment of alopeciaareata. Arch Dermatol Res, 1979; 264:123.

174. Fiedler-Weiss V.C. and Buys C.M. Evalua-tion of anthralin in the treatment of alo-pecia areata. Arch Dermatol, 1987;123(11):1491–3.

175. Schmoeckel C., Weissman I., Plewig G. andBraun-Falco O. Treatment of alopecia areataby anthralin-induced dermatitis. ArchDermatol, 1979; 115(10):1254–5.

176. Nelson D.A. and Spielvogel R.L. Anthralintherapy for alopecia areata. Int J Dermatol,1985; 24(9):606–7.

177. Happle R., Klein H.M. and Macher E.Topical immunotherapy changes thecomposition of the peribulbar infiltrate inalopecia areata. Arch Dermatol Res, 1986;278(3):214–8.

178. Daman L.A., Rosenberg E.W. and Drake L.Treatment of alopecia areata withdinitrochlorobenzene. Arch Dermatol, 1978;114(7):1036–8.

179. Happle R. Antigenic competition as atherapeutic concept for alopecia areata. ArchDermatol Res, 1980; 267(1):109–14.

180. Happle R., Cebulla K. andEchternachtHapple K. Dinitrochlorobenzenetherapy for alopecia areata. Arch Dermatol,1978; 114(11):1629–31.

181. Hehir M.E. and du Vivier A. Alopecia areatatreated with DNCB. Clin Exp Dermatol,1979; 4(3):385–7.

182. Kratka J., Goerz G., Vizethum W. and StrobelR. Dinitrochlorobenzene: influence on thecytochrome P-450 system and mutageniceffects. Arch Dermatol Res, 1979;266(3):315–18.

183. Strobel R. and Rohrborn G. Mutagenic andcell transforming activities of 1-chlor-2,4-dinitrobenzene (DNCB) and squaricacid-dibutylester (SADBE). Arch Toxicol, 1980;45(4):307–14.

184. Summer K.H. and Goggelmann W. l-chloro-2,4-dinitrobenzene depletes glutathione inrat skin and is mutagenic in Salmonellatyphimurium. Mutat Res, 1980; 77(1):91–3.

185. Weisburger E.K., Russfield A.B., HomburgerF., et al. Testing of twenty-one environmen-tal aromatic amines or derivatives for long-term toxicity or carcinogenicity. J EnvironPathol Toxicol, 1978; 2(2):325–56.

186. Wilkerson M.G., Wilkin J.K. and Smith R.G.Contaminants of dinitrochlorobenzene. J AmAcad Dermatol, 1983; 9(4):554–7.

187. Happle R., Kalveram K.J., Buchner U., et al.Contact allergy as a therapeutic tool foralopecia areata: application of squaric aciddibutylester. Dermatologica, 1980; 161(5):289–97.

188. Flowers F.P., Slazinski L., Fenske N.A. andPullara T.J. Topical squaric acid dibutylestertherapy for alopecia areata. Cutis, 1982;30(6):733–6.

189. Case P.C., Mitchell A.J., Swanson N.A., et al.Topical therapy of alopecia areata withsquaric acid dibutylester. J Am AcadDermatol, 1984; 10(3):447–50.

190. Caserio R.J. Treatment of alopecia areatawith squaric acid dibutylester. ArchDermatol, 1987; 123(8):1036–41.

191. Giannetti A. and Orecchia G. Clinicalexperience on the treatment of alopeciaareata with squaric acid dibutyl ester.Dermatologica, 1983; 167(5):280–2.

192. Micali G., Cicero R.L., Nasca M.R. andSapuppo A. Treatment of alopecia areatawith squaric acid dibutylester. Int JDermatol, 1996; 35(1):52–6.

193. Chua S.H., Goh C.L. and Ang C.B. Topicalsquaric acid dibutylester therapy for alo-pecia areata: a double-sided

Alopecia areata 79

patientcontrolled study. Ann Acad MedSingapore, 1996; 25(6):842–7.

194. Orecchia G., Malagoli P. and Santagostino L.Treatment of severe alopecia areata withsquaric acid dibutylester in pediatricpatients. Pediatr Dermatol, 1994; 11(1):65–8.

195. Tosti A., Guidetti M.S., Bardazzi F. andMiscali C. Long-term results of topicalimmunotherapy in children with alopeciatotalis or alopecia universalis. J Am AcadDermatol, 1996; 35(2 Pt 1):199–201.

196. Barth J.H., Darley C.R. and Gibson J.R.Squaric acid dibutyl ester in the treatment ofalopecia areata. Dermatologica, 1985;170(1):40–2.

197. Orecchia G., Perfetti L., Borroni G. andRabbiosi G. Photochemotherapy plus squaricacid dibutylester in alopecia areata treatment[letter]. Dermatologica, 1990; 181(2):167–9.

198. Wilkerson M.G., Henkin J., Wilkin J.K. andSmith R.G. Squaric acid and esters:analysis for contaminants and stability insolvents. J Am Acad Dermatol, 1985; 13(2Pt 1): 229–34.

199. Van Duuren B.L., Melchionne S., Blair R., etal. Carcinogenicity of isosters of epoxidesand lactones: aziridine ethanol, propanesultone, and related compounds. J NatlCancer Inst, 1971; 46(1):143–9.

200. Harland C.C. and Saihan E.M. Regression ofcutaneous metastatic malignant melanomawith topical diphencyprone and oralcimetidine [letter]. Lancet, 1989;2(8660):445.

201. Lane P.R. and Hogan D.J. Diphencyprone[letter]. J Am Acad Dermatol, 1988; 19(2 Pt1):364–5.

202. Van der Steen P.H., Boezeman J.B. andHapple R. Topical immunotherapy foralopecia areata: re-evaluation of 139 casesafter an additional follow-up period of 19months. Dermatology, 1992; 184(3): 198–201.

203. Hull S.M. and Norris J.F. Diphencyprone inthe treatment of long-standing alopeciaareata. Br J Dermatol, 1988; 119(3): 367–74.

204. MacDonald-Hull S. Post therapy relapserate in alopecia areata after successfultreatment with diphencyprone. J DermatolTreat, 1989; 1:71.

205. Hull S.M. and Cunliffe W.J. Successfultreatment of alopecia areata using thecontact allergen diphencyprone [letter]. Br JDermatol, 1991; 124(2):212–13.

206. Wiseman M., Shapiro J., MacDonald N., LuiH. Predictive model for immunotherapy ofalopecia areata with diphencyprone. ArchDerm, 2001; 137: in press.

207. Gordon P.M., Aldridge R.D., McVitie E. andHunter J.A. Topical diphencyprone foralopecia areata: evaluation of 48 cases after30 months’ follow-up. Br J Dermatol, 1996;134(5):869–71.

208. Pericin M. and Trueb R.M. Topical immuno-therapy of severe alopecia areata withdiphenylcyclopropenone: evaluation of 68cases. Dermatology, 1998; 196(4):418–21.

209. Monk B. Induction of hair growth inalopecia totalis with diphencypronesensitization. Clin Exp Dermatol, 1989;14(2):154–7.

210. Hatzis J., Georgiotono K., Kostakis P., et al.Treatment of alopecia areata withdiphencyprone. Australas J Dermatol, 1988;29(1):33–6.

211. Ashworth J., Tuyp E. and Mackie R.M.Allergic and irritant contact dermatitiscompared in the treatment of alopecia totalisand universalis. A comparison of the valueof topical diphencyprone and tretinoin gel.Br J Dermatol, 1989; 120(3):397–401.

212. Orecchia G. and Rabbiosi G. Treatment ofalopecia areata with diphencyprone.Dermatologica, 1985; 171(3):193–6.

213. Berth-Jones J. and Hutchinson P.E. Treatmentof alopecia totalis with a combination ofinosine pranobex and diphencypronecompared to each treatment alone. Clin ExpDermatol, 1991; 16(3): 172–5.


214. Shapiro J., Tan J., Ho V. and Tron V. Treat-ment of chronic severe alopecia areata withtopical diphenylcyclopropenone and 5%minoxidil: a clinical and immunopathologicevaluation. J Am Acad Dermatol, 1993; 29(5Pt 1):729–35.

215. Hull S.M., Pepall L. and Cunliffe W.J.Alopecia areata in children: response totreatment with diphencyprone. Br JDermatol, 1991; 125(2):164–8.

216. Van der Steen P.H., van Baar H.M., PerretC.M. and Happle R. Treatment of alopeciaareata with diphenylcyclopropenone [seecomments]. J Am Acad Dermatol, 1991; 24(2Pt 1):253–7.

217. Berth-Jones J., Mc Burney A. andHutchinson P.E. Diphencyprone is notdetectable in serum or urine followingtopical application. Acta Derm Venereal,1994; 74(4):312–3.

218. Wilkerson M.G., Connor T.H., Henkin J., etal. Assessment of diphenylcyclopropenonefor photochemically induced mutagenicityin the Ames assay. J Am Acad Dermatol,1987; 17(4):606–11.

219. Wilkerson M.G., Henkin J. and Wilkin J.K.Diphenylcyclopropenone: examination forpotential contaminants, mechanisms ofsensitization, and photochemical stability. JAm Acad Dermatol, 1984; 11(5 Pt 1): 802–7.

220. Perret C.M., Steijlen P.M. and Happle R.[Alopecia areata; pathogenesis and topicalimmunotherapy]. Ned Tijdschr Geneeskd,1989; 133(25):1256–60.

221. Perret C. Treatment of alopecia areata. InHair and Hair Diseases, ed. C.O.R.Happle, p.529. 1990; New York: Springer Verlag.

222. Shah M., Lewis P.M. and Messenger A.G.Hazards in the use of diphencyprone [letter][see comments]. Br J Dermatol, 1996;134(6):1153.

223. Fernandez-Redondo V., Gomez-Centeno P.,Florez A. and Toribio J. Hazards in the use ofdiphencyprone. Allergy, 2000; 55(2): 202–3.

224. Orecchia G. and Stock J.Diphenylcyclopropenone: an importantagent known to cause depigmentation [letter;comment]. Dermatology, 1999; 199(2):198.

225. Van der Steen P. and Happle R. ‘Dyschromiain confetti’ as a side effect of topical immu-notherapy with diphenylcyclopropenone.Arch Dermatol, 1992; 128(4):518–20.

226. Orecchia G. and Perfetti L.Vitiligo andtopical allergens [letter; comment].Dermatologica, 1989; 179(3):137–8.

227. Hatzis J., Gourgiotou K., Tosca A., et al.Vitiligo as a reaction to topical treatmentwith diphencyprone [see comments].Dermatologica, 1988; 177(3):146–8.

228. Henderson C.A. and Ilchyshyn A.Vitiligocomplicating diphencyprone sensitizationtherapy for alopecia universalis [letter]. Br JDermatol, 1995; 133(3):496–7.

229. Duhra P. and Foulds I.S. Persistent vitiligoinduced by diphencyprone [letter]. Br JDermatol, 1990; 123(3):415–16.

230. Alam M., Gross E.A. and Savin R.C. Severeurticarial reaction todiphenylcyclopropenone therapy foralopecia areata. J Am Acad Dermatol, 1999;40(1):110–12.

231. Tosti A., Guerra L. and Bardazzi F. Contacturticaria during topical immunotherapy.Contact Dermatitis, 1989; 21(3):196–7.

232. Skrebova N., Nameda Y., Takiwaki H. andArase S. Severe dermographism after topicaltherapy with diphenylcyclopropenone foralopecia universalis. Contact Dermatitis,2000; 42(4):212–15.

233. Perret C.M., Steijlen P.M., Zaun H. andHapple R.Erythema multiforme-like erup-tions: a rare side effect of topical immuno-therapy with diphenylcyclopropenone.Dermatologica, 1990; 180(1):5–7.

234. Mitchell A.J. and Douglass M.C. Topicalphotochemotherapy for alopecia areata. JAm Acad Dermatol, 1985; 12(4):644–9.

Alopecia areata 81

235. Claudy A.L. and Gagnaire D.Photochemotherapy for alopecia areata. ActaDerm Venereal, 1980; 60(2):171–2.

236. Larko O. and Swanbeck G. PUVA treatmentof alopecia totalis. Acta Derm Venereal,1983; 63(6):546–9.

237. Lassus A., Kianto U., Johansson E. andJuvakoski T., et al. PUVA treatment foralopecia areata. Dermatologica, 1980;161(5):298–304.

238. Healy E. and Rogers S. PUVA treatment foralopecia areata—does it work? A retrospec-tive review of 102 cases. Br J Dermatol,1993; 129(1):42–4.

239. Taylor C.R. and Hawk J.L. PUVA treatmentof alopecia areata partialis, totalis anduniversalis: audit of 10 years’ experience atSt John’s Institute of Dermatology. Br JDermatol, 1995; 133(6):914–18.

240. Stern R.S., Nichols K.T. and Vakeva L.H.Malignant melanoma in patients treated forpsoriasis with methoxsalen (psoralen) andultraviolet A radiation (PUVA). The PUVAFollow-Up Study [see comments]. New EnglJ Med; 1997; 336(15):1041–5.

241. Gilhar A., Pillar T. and Etzioni A. Topicalcyclosporin A in alopecia areata. Acta DermVenereal, 1989; 69(3):252–3.

242. de Prost Y., Teillac D., Paquez F., et al.Placebo-controlled trial of topicalcyclosporin in severe alopecia areata [letter].Lancet, 1986; 2(8510):803–4.

243. Van der Velden E.M., Drost B.H.,Ijsselmuiclen O.E., et al. Dermatography asa new treatment for alopecia areata of theeyebrows. Int J Dermatol, 1998; 37(8):617–21.

IntroductionAndrogenetic alopecia (AGA) is by far the mostcommon cause of hair loss. It affects approxi-mately 50% of men by the age of 50 and 20%to 53% of women by the age of 50.1–3 Althoughit is a medically benign condition, it can havea significant psycho-social impact for pa-tients.4–6 This chapter will highlight thepathogenesis, clinical features and state of theart medical management of AGA.

PathogenesisKnowledge of the patho-physiology of AGA isessential in understanding the mechanism ofaction of current therapeutic agents. We areonly beginning to understand the different fac-tors underlying AGA. The following is a sum-mary of the current knowledge on AGApathogenesis. As its name implies, AGA in-volves both genetic and hormonal factors.1 Ge-netics determine both the density and thelocation of androgen-sensitive hair follicles onsite-specific areas of the scalp. After puberty,androgens trigger a series of events withinthese genetically-programmed hair follicles,predominantly of the fronto-parietal scalp, thattransform terminal to miniaturized follicles.7–

16 The hair cycle is altered, with progressiveshortening of the anagen phase occurring overmany cycles. This shortening of anagen andsubsequent miniaturization of hairs leads todecreased scalp coverage.1,17,18 These finersmall vellus-like hairs of varying lengths anddiameters are the hallmark of AGA (Figure3.1). However, in AGA the number of folliclesper unit of area remains the same. It is still con-troversial what becomes of these miniaturizedfollicles. Complete permanent regression isunlikely, since cases of severely advancedbalding male to female transsexuals have ex-perienced considerable regrowth usingfinasteride, minoxidil, spironolactone andestrogen (personal observation).

Genetic factors

The exact inheritance pattern of AGA is stilldebated. It is believed to be most likely auto-somal dominant,3 polygenic,19 and inheritedfrom either parent.19 The gene frequency ap-pears to be most common in Caucasians, lessso in Africans, and least frequent in Amerindi-ans, Asians and Inuits.20 The McKusick Men-delian Inheritance in Man (MIM) number forAGA is 109200. A MIM entry that begins withthe number one indicates an autosomal domi-nant inheritance.21

3 Androgenetic alopecia: Pathogenesis,clinical features and practical medicaltreatment


Some previous work on the genetics of AGAdates back to 1919. Osborn22 stated that AGAwas a sex-limited autosomal dominant traitsimilar to the inheritance of horns in sheep.She believed that men could be eitherhomozygotes (BB) or heterozygotes (Bb), andwomen who presented with AGA werehomozygotes only. Smith and Wells23 have hy-pothesized that the expressivity of the genemight be partly determined by the androgenlevel: the genotype BB may lead to the clinicalpicture of AGA even at low androgen levels inwomen, whereas the genotype Bb requireshigher amounts of androgen. The genotype bbmay remain sub-clinical in both sexes. Harris24

found that of 117 men with AGA, 66% of thebrothers were bald if the father of the probandwas also bald, and 46% of the brothers werebald if the father was not bald. Fifty-six percent of bald men had bald fathers. The authorsconcluded that this was consistent with anautosomal dominant gene. Salomon25 felt thatAGA is inherited through multifactorial orconditioned dominance via an autosomaldominant gene of variable expressivity. Hestudied 119 males with AGA. Sixteen had nofamily history, 65 had two generations, 24three generations and 3 four generations in-volved. Eleven had two generations of familieswith both parents affected. There was an asso-ciation of increasing amounts of chest hair, butnot back hair, in affected individuals. This ob-servation is quite interesting, in that Shapirohas noted the same trend in increased bodyhair distribution in a disproportionately largenumber of his balding male patients, althoughno formal study has been performed. A familyhas been described in which common bald-ness with early onset occurred in femalesonly.26

Kuster and Happle.19 favor a polygenic in-heritance rather than a simple Mendelianmodel. They present very credible arguments

Figure 3.1In androgenetic alopecia, there is miniaturi-zation of coarse terminal hairs into smallvellus-like hairs with each subsequent cycle.

Androgenetic alopecia 85

supporting multi-allelic inheritance. The highprevalence rate, the distribution of the baldingpatterns in the general population along aGaussian curve of variation, and the fact thatthe risk increases with the number of relativesalready affected, and that there is an increasedrisk to relatives of severely affected women ascompared to the relatives of mildly affectedwomen all support a more complex polygenicinheritance. Carey et al. described severalfamilies in which premature balding in malemembers appeared to denote carrier status foran autosomal dominant gene responsible forpolycystic ovarian disease.27,28 There was anassociation with one allele of the steroid me-tabolism gene CYP17, although this geneticchange was not the primary cause of eithercondition.27,28 The search for the gene contin-ues. The X-linked mutation for adrenoleuk-odystrophy, which is correlated to prematureAGA in men, may be a part of the polygenicspectrum of genes responsible for AGA.29 Thehuman hairless gene responsible for papularatrichia was shown not to be correlated to AGAwhen studying 31 heterozygous male carriersof this mutation with respect to onset or extentof AGA.30 Sreekumar et al.31 did not find anyevidence of linkage of early-onset AGA to anymarkers of chromosomes 2 and 5 that areknown to code for 5 a-reductase Type I and II.It is expected over the next decade that the in-formation from the Human Genome Projectwill have great relevance in mapping out thegenes that express the complex trait of AGA.

Hormonal factors

A major determinant of AGA is intracellularandrogen metabolism, which involves twosteroid-metabolizing enzymes (5a-reductaseand aromatase) and androgen receptor pro-

teins. Other important factors may still remainto be discovered. Variances in levels of theseandrogen-metabolizing enzymes and androgenreceptor proteins help explain the differencesbetween balding and non-balding scalp at vari-ous ages and the different clinical patterns andseverities between men and women.1,32,33

5a-reductase isoenzymes, type I and II, areboth part of normal androgen metabolism andreduce testosterone (T) to dihydrotestosterone(DHT). The 5a-reductase type I isoenzyme islocated mainly in sebaceous glands, epidermaland follicular keratinocytes, dermal papillacells, and sweat glands.34 The 5a-reductasetype II isoenzyme is located mainly in the rootsheaths of the scalp hair follicle33,34 as well asin the epididymis, vas deferens, seminal vesi-cles, prostate, and fetal genital skin.34 Bothtype I and type II isoenzymes play an impor-tant role in AGA.33,35–37 Both isoenzymes areincreased in frontal balding follicles comparedto occipital non-balding follicles, but to alesser extent in women.33 DHT levels are in-creased in balding scalp when compared tonon-balding scalp.35,38–40 Women have 3.0–3.5times less 5α-reductase (I and II) than men,33

and this may explain why female AGA is usu-ally less severe than male AGA. Individualswith a genetic deficiency of 5a-reductase typeII isoenzyme do not develop AGA,41–43 furthersupporting the DHT requirement for AGA ex-pression. A recent case report by Orme et al.44

described a young women with hypopituitar-ism who presented with clinical and histologicfeatures of female AGA in the absence of de-tectable androgens or other signs of post-pu-bertal androgenization, showing that thispattern of hair loss is not necessarily andro-gen-dependent. Shapiro has seen a femaleteenager with androgen-insensitive syndrome,lacking androgen receptors, with typical fe-male AGA (unpublished personal observa-


tion). These findings are intriguing. Norwoodand Lehr45 have proposed that female AGAmay be a separate entity. However, they admitthat it is impossible to distinguish male fromfemale hair shaft miniaturization either clini-cally or histologically.

The cytochrome P450 aromatase enzyme isalso part of normal androgen metabolism, andmay have a protective effect on hair follicles.33

Aromatase results in the conversion of T toestradiol and estrone, and therefore the result-ing shift will lessen conversion of T to DHT.Aromatase is significantly higher in the hairfollicles of women. There is 6 times morearomatase in the frontal follicles and 4 timesmore in the occipital follicles of women thanin those of men. This likewise helps explainwhy women with AGA usually retain theirfrontal hairline and have less hair loss thanmen with AGA.17,33

Androgen receptor proteins (ARP) are foundin the outer root sheath and dermal papillafibroblasts of scalp hair follicles.8,13,32,33 Thereceptor levels were found to be 30% greaterin balding frontal hair follicles than in non-balding occipital follicles in both men andwomen with AGA, but the total receptor con-tent is 40% less in women than in men.33 Thebinding of androgens to ARP results in modifi-cation of signal transduction between the mes-enchymal-derived dermal papilla and theepithelial-derived follicular cells. Theseevents within the follicle result in the transfor-mation of terminal to miniaturized hair folli-cles on the scalp in AGA. Paradoxically, inother androgensensitive areas such as thebeard and mustache, androgens upsize, ratherthan downsize, hair follicles at puberty. Theexplanation for this bifurcated action is notknown.17

Studying the quail-chick model, Ziller46

found differences of embryonic origin of the

dermis of the fronto-parietal scalp comparedto the occipital scalp. Dermis of the frontopa-rietal scalp is derived from the neural crest,whereas dermis of the occipital/temporal scalpis derived from the mesoderm. One can specu-late that this difference in embryonic originmay influence the well-known differential re-sponse of follicles in the occipital region asagainst the rest of the scalp in AGA.

Clinical features ofAGA

History

Thinning of the hair can occur as early as theage of 12 (Figure 3.2a) and as late as the age of45 in both sexes. However, AGA usually mani-fests at an early age and progresses slowly.Most cases start between the ages of 15 and25.47 The clinical course is gradual, consistingof acute episodic phases with increased loss oftelogen hair, alternating with periods whenthere is little shedding. The shedding may beseasonal in a small number of individuals.47

For many individuals, the condition may seemstable for years.47 Many men reach their maxi-mum pattern by their forties, although hairdensity does decrease as they age further.

Usually there is a positive family history.However, 12% in one study showed a com-pletely negative family history.25

Hair loss in women may be triggered by hor-monal changes, including starting or stoppingthe oral contraceptive pills and post-partumand peri- and post-menopausal states. Theseevents, which can elicit a telogen effluvium,may unmask a tendency for AGA. Women


must be questioned about the regularity oftheir periods and the presence or absence ofhirsutism in an attempt to determine if hyper-androgenism is a problem. SAHA syndrome,standing for seborrhea, alopecia, hirsutism andacne, frequently indicates an androgen excessin the female patient. However, in the vastmajority of women with AGA, hyper-androgenism is not a problem.48

An increased risk for coronary artery dis-ease has recently been correlated to vertexbalding in men.49–51 In one study there ap-peared to be lipoprotein and triglyceride leveldifferences between males with vertex thin-ning and non-balding men,50 with an increasedrisk for atherosclerotic and coronary heart dis-ease in balding men. Lotufo et al.52 showed thatvertex pattern balding appears to be a markerfor increased risk of coronary heart disease,especially among men with hypertension orhigh cholesterol levels. The biologic mecha-

nisms for this relationship are unknown. It wasfelt by these authors that early vertex baldingmay be a useful marker to identify men at in-creased risk who may benefit from aggressivescreening and primary prevention efforts di-rected toward other known modifiable risk fac-tors for coronary heart disease.

Herrera et al.53 assessed the relation betweenthe extent and progression of baldness and coro-nary heart disease. Baldness was assessedtwice, in 1956 and in 1962, in a cohort of 2,017men from Framingham, Massachusetts. Thecohort was followed for up to 30 years for newoccurrences of coronary heart disease, coronaryheart disease death, cardiovascular disease, anddeath due to any cause. The relations betweenthe extent and progression of baldness and theaforementioned outcomes were assessed usinga Cox proportional hazards model, adjusting forage and other known cardiovascular diseaserisk factors. Extent of baldness was not associ-

Figure 3.2(a) Male androgenetic alopecia can appear early. This is a 13-year-old boy showing frontotem-poral thinning and hair miniaturization. (b) The presence of miniaturized hairs helps toconfirm a diagnosis of AGA. A contrast paper is placed in a parted area of the scalp. The hairis then closely examined against this backdrop.


ated with any of the outcomes. However, theamount of progression of baldness was associ-ated with coronary heart disease occurrence(relative risk (RR)=2.4, 95% confidence inter-val (CI) 1.3–4.4), coronary heart disease mor-tality (RR=3.8, 95% CI 1.9–7.7), and all-causemortality (RR =2.4, 95% CI 1.5–3.8). It was con-cluded that rapid hair loss may be a marker forcoronary heart disease.

A practice-based case-control study in menaged 19–50 years showed a strikingly in-creased risk of hyper-insulinemia and insulin-resistance-associated disorders such asobesity, hypertension, and dyslipidemia inmen with early onset of AGA (< 35 years),when compared to age-matched controls.54

This finding supports the hypothesis that earlyAGA could be a clinical marker of insulin re-sistance. These authors suggest that men withearly AGA might benefit from screening forcardiovascular risk factors and for insulin re-sistance.

On the other hand, in a study of 478 men,no association between coronary heart diseaseand androgenetic alopecia was found.55

A total of 3,421 men age 25–75 years (me-dian age at baseline 55) without a history ofprostate cancer were examined for AGA in theEpidemiologic Follow-up Study of the firstNational Health and Nutrition ExaminationSurvey.56 Participants were followed frombaseline (1971–4) through to 1992. Incidentcases of prostate cancer were identified by in-terviews, medical records and death certifi-cates. Prostate cancer was diagnosed in 214subjects over 17–21 years of follow-up. Theinvestigators noted that the age-standardizedincidence of prostate cancer was greateramong men with baldness at baseline (17.5 vs12.5 per 10,000 person years). Men with AGAhad a consistently higher incidence of pros-tate cancer compared with those without

AGA, beginning at approximately 60 years ofage. The adjusted relative risk for prostatecancer among men with any degree of bald-ness was 1.5, and was similar regardless ofthe severity of baldness at baseline and wasindependent of other risk factors, includingrace and age. The authors concluded that menwith AGA had a 50% excess risk for clinicalprostate cancer. The major strengths of thisstudy included its prospective design, largesample size, extended follow-up, and na-tional representative sampling. A drawbackwas that approximately 1/3 of their cohorthad not yet reached the advanced age-rangein which clinical prostate cancer is typicallypresent, thus limiting the effective power oftheir study. Hawk et al.56 further hypothesizethat AGA in men may predict other age-re-lated pathological processes, such as athero-genesis, that tend to remain clinically silentuntil they are advanced.

In some women with AGA, and occasion-ally in men, AGA may unmask a psychologi-cal lability and/or psychiatric disturbance.47 Insome individuals, AGA becomes a preoccupa-tion, and is blamed for all social and profes-sional problems. Psychoneurotic attitudes mayensue, in which the alopecia is merely a symp-tom that the patient may clutch on to.47

Physical examination

Hair loss is patterned and non-scarring, withpreservation of follicular ostia. A hair pull testis usually negative, although there may be amild increase in telogen hairs, though only ininvolved areas of the scalp. Miniaturizedvellus-like hairs can usually be seen with con-trast paper placed over a part (Figure 3.2b).

In terms of the pattern of hair loss, womenusually have less severe hair loss than men and


retain their frontal hairline (Figure 3.3). Thehair thinning is mostly on the crown. This pat-tern is recognized as the Ludwig pattern, andis divided in 3 stages according to severity(Figures 3.4–3.8).57 Ludwig Stage I is the mostcommon pattern. Hair loss may only be evi-dent when one compares the relative widths

of the division of bare scalp between areas ofcombed hair (‘part’, ‘parting’) in the centro-pa-rietal area with that in the occipital area.Ludwig Stage III is rare, and women affectedmay require an endocrine work-up if theyshow other signs of androgen excess.

In a significant percentage of female pa-tients with AGA, diffuse hair thinning maybe present (Figure 3.9a and b). Olsen58 feelsthat 5% show a global decrease in scalp hairdensity. Shapiro feels that approximately30% of women have a more global thinning.This generally occurs in those women withmore advanced hair loss, and usually in thosewith early-onset AGA. Even with this diffuseloss, there still remains a variance of hairdensity on the top of the scalp versus thesides or the back of the scalp. The presence ofglobal thinning clearly decreases the chancesof being a successful female hair transplantcandidate.

In men, there is a frontal hairline recessionassociated with thinning or balding on the

Figure 3.3In female AGA, most women present with anintact frontal hair line.

Figure 3.4(a) Ludwig classification of female AGA, showing the three different stages of severity. (b)The characteristically narrow division of bare scalp between areas of combed hair (‘part’,‘parting’) found in a woman without AGA. Reproduced with permission from the BritishJournal of Dermatology 1977; 97:247–54.


crown or vertex. There are exceptions, withcertain individuals showing no recession andonly vertex thinning, as in Figure 3.10a and b.Hamilton originally classified male AGA onthe basis of fronto-parietal/fronto-temporal re-cession and vertex thinning.59 Norwood,60

more than 25 years later, improved on this pic-torial classification. This pattern is known asthe Norwood-Hamilton pattern, and is divided

Figure 3.5Ludwig Stage I: A widening of the division ofbare scalp between areas of combed hair(‘part’, ‘parting’) may be the first complaint ofthe female patient. She will also notice herponytail diameter may be reduced one-thirdto one-half of what it used to be. The elasticband that she usually uses to tie up herponytail can now be wound several timesaround her hair in contrast to only once ortwice, as before.

Figure 3.6Ludwig Stage II: The width of the division ofbare scalp (‘part’, ‘parting’) is now consider-ably more evident than in Ludwig I.

Figure 3.7Mother (left) with Ludwig Stage II anddaughter (right) with Ludwig Stage I.

Figure 3.8Ludwig Stage III: Considerable loss of hair.


most men, does not necessarily herald the ex-pression of AGA, and is unlikely to reversewith current therapies. However, a deeper bi-temporal recession of greater than 1 inch fromthe frontal hair line is part of the AGA pheno-type, and, if treated early, may respond totherapy.40

Figure 3.9Female AGA may be totally diffuse, involving not only (a) the centro-parietal area but also (b)the sides and the back of the scalp.

Figure 3.10a and bA rare case of a 55-year-old male with absolutely no recession and simply vertex thinning.

into 7 stages according to severity (Figures3.11–3.16).60 The first change is bitemporal re-cession, which is seen in 96% of sexually ma-ture Caucasian males, including those men notdestined to progress to further hair loss. Re-sculpturing of the frontal hairline with somebi-temporal recession, seen post-puberty in


These patterns are not restrictive, and somewomen can present with the Norwood-Hamil-ton pattern (Figures 3.17–3.19) and some menwith the Ludwig pattern (Figures 3.20 and3.21). Norwood and Lehr45 feel that 10% oftheir male AGA patients present with a femaleAGA pattern. Venning and Dawber48 whenthey examined 564 women aged over 20 yearsfound that 80% of pre-menopausal women hadthinning in the Ludwig pattern and 13% hadHamilton Type II–IV patterns. After meno-pause the proportion exhibiting the male pat-tern increased to 37%, and, although they didnot progress to beyond Hamilton Stage IV,some had marked M-shaped recession at bothtemples.

Figure 3.11Norwood-Hamilton Classification of HairLoss based on severity.

Figure 3.12(a) A 33-year-old male showing the classic M hairline with fronto-temporal recession. (b) Healso has vertex thinning, making him a Norwood-Hamilton Stage III. Reproduced with per-mission from Southern Medical Journal 1975; 68:1359–65.


Figure 3.13Early Norwood-Hamilton Stage IV, with theemergence of a bridge connecting lateralportions of the scalp.

Figure 3.14Late Norwood-Hamilton Stage IV, with thebridge less intact.

Figure 3.15Norwood-Hamilton Stage V, with the bridgegone but still a significant number of mini-aturized hairs on the top of the scalp.

Figure 3.16Norwood-Hamilton Stage VI, with very littlehair on the top of the scalp.

Differential diagnosis

Usually the diagnosis of AGA is not a difficultone in men. However, in women, the diagno-sis may be more difficult.

The diagnosis of AGA is usually supportedwith the following cardinal features:

• usual focal balding pattern with miniatur-ized hairs

• gradual onset with progression• thinning with or without gradually devel-

oping bare patches• onset after puberty• negative pull test


Figure 3.17Norwood-Hamilton Stage VII, with preserva-tion of the ‘horseshoe’ of hair at the sides andback of the scalp.

Figure 3.18Women can show the Norwood-Hamiltonpattern. A 40-year-old female with Norwood-Hamilton Stage II AGA with fronto-temporalrecession. (a) Frontal view (b) Lateral view,with miniaturized hairs.

Figure 3.19A female with AGA with a Norwood-Hamil-ton Stage V pattern.

Figure 3.20A female with AGA with a Norwood-Hamiltion Stage VI pattern.


Figure 3.21Two male teenagers with the Ludwig Stage Ipattern. (a) A fourteen-year-old male withLudwig Stage I. (b) A seventeen-year-oldmale with the Ludwig Stage I pattern.

Figure 3.22aA 40-year-old male with Ludwig Stage II.

Figure 3.22bPatterns of hair loss can intermix within thesame family and within the same sex.Norwood-Hamilton Stage VII in a 48-year-oldfather (right) and Ludwig Stage I occurring inhis 20-year-old son (left).

The other two diagnoses that may be diffi-cult to distinguish are telogen effluvium andalopecia areata. Both these entities are dis-cussed at length in other chapters. Telogen ef-fluvium is usually generalized (Figure 3.23a),with an abrupt onset, frequently with an iden-


Figure 3.23a and bTelogen effluvium consists of hair thinning in a generalized manner not only (a) on top of thescalp but also (b) on the sides.

Figure 3.23cPatients with telogen effluvium frequentlypresent with bag of hair to show the physi-cian. This is unusual with AGA.

tifiable trigger. There is thinning, with no barepatches. Shedding is prominent. Onset is atany age, but usually not childhood. The pulltest is positive with telogen hairs. Alopeciaareata (AA) is usually randomly patchy, butcan be generalized. Onset is usually abrupt,

Figure 3.23dA 28-year-old female with telogen effluviumwho kept a diary of hair loss for 5 years. Thisamount of hair loss would not be seen inAGA.

with remissions and relapses. Onset is at anyage, with over 60% presenting under the ageof 20. Shedding is prominent, with a positivepull test for both dystrophic anagen andtelogen hairs. Overlapping of AGA and alo-pecia areata can occur. (Figure 3.24). It is ex-


respect to anagen/telogen and terminal/vellusratios, but also more information on hair den-sity and inflammatory perifollicular changes.The meticulous ‘unit area trichogram’ intro-duced by Rushton61 will also give informationon hair density. However, it requires specialskill and is fairly labor-intensive.

Laboratory tests

In men, no laboratory work-up is necessary un-less there is concomitant diffuse hair loss. In

pected that 1.7% of patients with AGA havehad, have, or will have AA. This may havegreat significance if one is contemplating hairtransplantation surgery for AGA. If an AGApatient has a previous recent or remote historyof AA, he or she must be warned that that itcould recur after surgery.

The 4.0 mm scalp biopsy with transversesectioning is the best laboratory test to distin-guish AGA from AA or telogen effluvium.Standard trichograms, involving the hairpluck, are very popular in Europe and are use-ful. However, the scalp biopsy will give thephysician not only the same information with

Figure 3.24a and bOverlapping of AGA and alopecia areata(AA) can occur. It is expected that almost2% of patients with AGA have had, have, orwill have AA. This may have great signifi-cance if one is contemplating hair transplan-tation surgery for AGA. If an AGA patienthas a previous, recent or remote history ofAA, he or she must be warned that that itcould recur after surgery. (a) A 25-year-oldfemale with female AGA with a 6-monthhistory of a patch of AA. (b) A 35-year-oldmale with AGA with a 3-month history of apatch of AA.


papillary dermis.62–64 (Stelae are the residualfibrous tracts that mark the upward migrationof the catagen, telogen or miniaturizing hairshaft and bulb (Figure 3.25).) Horizontal sec-tions show distinctive changes in papillaryand reticular dermis and in the deeper subcu-taneous sections. In papillary dermis, both ter-minal, vellus, and vellus-like hairs areidentified. Vellus and vellus-like hairs are lessthan 0.03 mm in diameter. Primary vellus hairsare small hairs, have a thin outer root sheath,and originate in the upper half of the dermis(Figure 3.26). Vellus-like hairs are miniatur-ized hairs that have a thick outer root sheathand originate from a terminal hair rooted inreticular dermis or subcutaneous fat with un-derlying stelae (Figure 3.27). Usually, hairs onhorizontal section are arranged in follicularbundles of 2–4 hairs with sebaceous glandsand arrector pili muscle63 (Figure 3.28). Thispatterning is typical of scalp hair. In reticulardermis there are no vellus or vellus-like hairs.Terminal hair bulbs predominate in anagenphase. Catagen and telogen terminal hairs arenoted as well (Figure 3.29). In fat, only the

women, this author recommends a routine thy-roid stimulating hormone test (TSH), becauseof the frequency of thyroid abnormalities andthe difficulty of distinguishing AGA fromtelogen effluvium. Ferritin levels are also or-dered routinely on menstruating females, aslow iron levels can trigger a telogen effluviumthat may mimic AGA. Androgen levels shouldonly be ordered in those women who appearclinically to have an androgen excess. The vastmajority of women with AGA do not displayhyper-androgenism, and therefore an androgenwork-up is not indicated. If one suspects anandrogen excess, a free testosterone anddehydroepiandrosterone sulfate (DHEAS) testshould be ordered.

Pathology

The histologic features of AGA are similar inmales and females.62 Vertical sections showterminal hairs and follicular stelae in the sub-cutaneous tissue and reticular dermis and ter-minal and vellus hairs and stelae in the

Figure 3.25a and bStelae or fibrous streamers (FSt) commonly seen in AGA (courtesy of Dr MagdalenaMartinka).


reticular dermis the number is usually reducedto 35, and in the fat is usually around 30. Thedifference of counts between papillary dermisand reticular dermis represents the number of

Figure 3.26Primary vellus hair (V) with a small hairshaft and small outer root sheath (ORS)(courtesy of Dr Magdalena Martinka).

Figure 3.27Secondary vellus hair (V) with small hairshaft and large outer root sheath (ORS),indicating true miniaturization (courtesy ofDr Magdalena Martinka).

Figure 3.28Follicular bundles with miniaturized hairs(courtesy of Dr Magdalena Martinka).

Figure 3.29A close-up of a follicular bundle in AGA,showing a vellus hair (V) and a telogen hair(T). Note the prominence of the sebaceousglands (SG) when hairs are miniaturized(courtesy of Dr Magdalena Martinka).

deeper anagen terminal hairs are present (Fig-ure 3.30). Follicular counts vary from level tolevel. Normally, in the upper papillary dermiscounts are usually around 40–50. In the


vellus hairs present in the papillary dermis.The difference in follicular counts betweenreticular dermis and fat represents the numberof terminal telogen hairs. In AGA, the totalnumber of follicular counts is usually normalin the papillary dermis. However, Whiting hasseen a reduction in 10% of cases of AGA, indi-cating a decreased capacity for follicularregrowth in this small number of AGA pa-tients.63 Ratios of anagen to telogen and termi-nal to vellus change in AGA. Normally90–94% of hairs are in anagen and 6–10% intelogen. In AGA, as few as 80% of hairs are inanagen and up to 20% in telogen. In AGA,since miniaturization is due to the shorteningof the anagen phase, with no decrease intelogen, there is clearly an increase in telogenhairs. The terminal to vellus ratio is normally7:1. In AGA, the ratio is 2:1, indicating amarked shift to miniaturization in AGA. Acharacteristic microscopic finding in AGA isvolumetric reduction of terminal follicles. Ini-tially the follicles are only minimally de-

creased in diameter, but eventually a mixtureof follicular sizes is apparent. Sebaceousglands seem enlarged in relation to these mini-aturized follicles (Figure 3.26). Arao-Perkinsbodies may be seen. These are small clustersof elastic fibers in the neck of dermal papillae.They are clumped in catagen and located atthe lowest point of origin of the follicular stela.Stacks of these Arao-Perkins bodies may beseen, like rungs of ladders, in these stelae ofminiaturized anagen hairs. One-third of pa-tients with AGA show mild inflammation, justas one-third of normal controls do. Forty percent of patients with AGA show moderatelymphohistiocytic inflammation, compared toonly 10% of normal controls.62 (Figure 3.31).The role of inflammation is controversial. Pos-sible causes for inflammation include sebor-rheic dermatitis, actinic damage, and theapplication of comedogenic, irritant, sensitiz-ing or otherwise toxic cosmetics and groomingagents to the scalp. Even porphyrins elabo-rated by follicular bacteria and activated by UV

Figure 3.30In AGA, subcutaneous fat (F) containsanagen hairs (AH) (courtesy of Dr MagdalenaMartinka).

Figure 3.31Inflammatory infiltrate in AGA is not uncom-mon. Note the perifollicular lymphocyticinfiltrate around this follicular bundle, whichcontains a miniaturized hair (MH) (courtesyof Dr Magdalena Martinka).


light could cause some inflammation. Thesecauses may be more pronounced in the lessprotected scalp.62

TreatmentThe whole raison d’être for treating AGA is thepsycho-social aspect. Hair loss can truly de-tract from an individual’s holistic sense ofwell-being. It is important to address AGA inthe context of overall patient health by takingthe time to discuss the impact that AGA hason the patient’s life. Balding men are per-ceived as older and less physically and so-cially attractive.4–6 Some balding men feel lessattractive, and struggle to cope with hair loss.4–

6 They worry and search for ways to compen-sate or restore body image. Behavioral copingmechanisms include changing hairstyle, im-proving physique or growing a beard ormustache.4–6 Women also experience greatstress from AGA, which can affect their livessignificantly.5 These psycho-social issuesshould be addressed before the implementa-tion of medical or surgical therapy.

Treatment options

Two decades ago hair-growth promoters werenon-existent. From a medical perspective, lit-tle could be offered to patients with AGA. To-day there are new classes of evidence-basedhair-growth promoters with unquestionableproven efficacy.

A hair-growth promoting agent must eitherprolong the anagen phase or increase matrixgirth by influencing follicular growth controls.For example, in AGA, drug targets may includesteroid receptors, steroid metabolizing en-

zymes and growth factors or cytokines that areimplicated in controlling cell cycling and con-version of terminal to miniaturized hairs. Weare currently just beginning to unravel themolecular control mechanisms and their loca-tion within the hair follicle. Further under-standing of this cascade of orchestrated eventsis crucial for the development of more effec-tive agents.

Hair-growth promoters can be classified ac-cording to their mode of action: hormonemodifiers versus biologic response modifiers.Hormone modifiers for AGA alter the perifol-licular endocrine milieu by blocking either 5a-reductase or androgen receptor proteins.Biologic response modifiers have a non-endo-crine effect on follicular cycling. The aim ofall these agents is to prevent the apoptoticevents precipitating catagen/telogen and tomaintain a longer anagen state, so that geneti-cally programmed miniaturization will be de-layed or prevented. Another aim is to reverseminiaturization by providing the appropriatehormonal and cytokine factors that nurturehair growth and inhibit factors that have anegative effect on hair growth.

There is still no cure for AGA and, withoutany treatment, those affected by AGA can ex-perience a mean steady decrease in hair weightof about 6% per year.65 If treatment is desired,options can be summarized as follows: Formen, options include finasteride, minoxidil,hair transplantation (HT) or a hairpiece. Forwomen, options include minoxidil, spironol-actone, cyproterone acetate, hair transplanta-tion or a hairpiece. It is important that patientshave realistic expectations regarding theirmedical treatment outcome, and the emphasisshould be placed on the prevention of furtherhair loss. Medical treatments will only be ef-fective if there is sufficient hair to salvage,with at least miniaturized hairs to convert intoterminal hair. For those with more advanced


hair loss, surgery or hairpiece may be the onlyoptions. Each option will be discussed in de-tail on the basis of classification.

Hormone modifiers

Androgen blockade

5a-reductase inhibitorFinasteride: Finasteride (Propecia™) is a syn-thetic 4-azasteroid compound that is a specificinhibitor of type II 5a-reductase, an intracellu-lar enzyme that converts T into DHT.38,40,66

Finasteride does not have any hormonal prop-erties in itself,38,40 and has no estrogenic, anti-estrogenic or progestational effects. Byinhibiting type II 5a-reductase, it blocks the pe-ripheral conversion of T to DHT, resulting insignificant decreases in serum and tissue DHTconcentrations.38,40,67–71 A recent study by Drakeet al.69 showed that median scalp DHT levelsdecreased by 13% with placebo and by 64.1%and 69.4% with 1 mg and 5 mg of finasteride,respectively, after 42 days of treatment. Medianserum DHT levels decreased by 71.4% and72.2% with 1 mg and 5 mg on the same sched-ule. This study also showed that doses as lowas 0.2 mg daily decreased .scalp and serumDHT. The study by Roberts et al.70 confirmedthat finasteride 1 mg daily was the optimaldose, with 1 mg and 5 mg superior to lowerdoses such as 0.2 mg/daily. The daily 5 mg dosewas not more efficacious than the 1 mg dose.

In 1997 the FDA approved finasteride for usein the United States at a dose of 1 mg/day in menwith AGA. Three double-blind, randomized, pla-cebo-controlled studies were conducted in 1879men ages 18 to 41 years with mild to moderatehair loss.40,72 Two of the studies enrolled menwith predominantly vertex hair loss40 and one

study enrolled men with predominantly frontalhair loss.72 Finasteride 1 mg oral tablets or pla-cebo tablets were taken once daily for 24 monthsin the vertex studies and 12 months in the fron-tal study. All three studies showed a significanthair count increase at 6 and 12 months in mentreated with finasteride, while a significant de-crease in hair counts was demonstrated in mentreated with placebo. In the second year, haircounts remained stable at the increased level inthe men who continued to receive finasteride. Inthe vertex studies, those individuals who werecrossed over after 12 months from finasteride toplacebo showed loss of the benefit achieved inthe first 12 months by hair count, and those whowere switched from placebo to finasterideshowed significant gains. A histologic study byWhiting et al.73 showed a significant increase interminal anagen hairs from baseline in scalp bi-opsies taken from men at baseline and after 12months of finasteride. This was also significantlydifferent from the placebo group. Histologically,vellus-like hairs decreased, and the terminal tovellus ratio increased, in the finasteride groupcompared with the placebo group, suggestingreversal of the miniaturization process.

Therapeutic efficacy was assessed with ablinded rating of standardized photographs,patient self-assessment and investigator as-sessment. From these studies, it can be con-cluded that finasteride can stabilize hair lossin 83% of the cases with vertex hair loss after 2years, and in 70% of cases with frontal hairloss after 1 year. The chances of mild to mod-erate regrowth are 61% on the vertex after 2years and 37% on the frontal area after 1 year.Continued daily use of 1 mg oral finasteride isneeded for sustained benefit.

In two studies in men with vertex hair loss,treatment with finasteride 1 mg/day or placebowas continued for 5 years. Based on photo-graphic assessment, treatment with finasteridefor 5 years resulted in stabilization of hair loss


in up to 90% of men, compared with 25% onplacebo. Based on hair counts, regrowth was ob-served in 65% of men treated with finasteridefor 5 years compared to gradual hair loss ob-served in 100% of men treated with placebo,leading to a net improvement in hair count of277 hairs (31%) for men treated with finasteridecompared with placebo after 5 years. While im-provement for finasteride-treated men com-pared to baseline was greater at 24 months, thedifference between the group treated withfinasteride and the placebo group continued toincrease throughout the 5 years of the study.74

In a study of hair weights done by Price, sig-nificant differences between finasteride andplacebo were seen with small numbers of sub-jects. Sixty-six men aged 18–40 years withNorwood-Hamilton Stage III and IV were en-rolled in a randomized, double-blind, placebo-controlled study. Thirty-three men receivedfinasteride 1 mg daily and 33 received placebofor 48 weeks. The study was extended for 48weeks for a total of 96 weeks. In the extensionstudy, 26 men continued to receive finasteride1 mg and 23 men remained on placebo. At 6-week intervals, hair in a marked site was hand-clipped using a magnifying light. All hairsamples were weighed in a single session by atechnician who was blinded to patient, visitnumber and treatment. After 96 weeks, the totalhair weight showed a statistically significant in-crease from baseline weight in the finasteride-treated subjects. The hair weight studydemonstrated that treatment with finasteride 1mg provides continued maintenance and im-provement of hair growth over 96 weeks.75

Van Neste et al.,76 using the phototric-hogram method, provided direct evidence thatfinasteride 1 mg daily promotes the conversionof hairs into the anagen phase. This study en-rolled 212 men age 18–40 years with AGA.Patients were randomized to receive eitherfinasteride 1 mg daily or placebo for 48 weeks.

Macrophotographs were taken to measure to-tal as well as anagen hair counts in a 1 cm2

target area of the scalp. In this study, treatmentwith finasteride 1 mg per day for 48 weeks sig-nificantly increased both total and anagen haircounts and improved anagen to telogen ratioscompared to placebo. Treatment withfinasteride resulted in a net improvement inthe anagen to telogen ratio of 47%.

Finasteride may show improvement inolder men. A small 24-month double-blindplacebocontrolled study on 28 men aged 53–76 years taking finasteride 5 mg per day forbenign prostatic hypertrophy showed statisti-cally significant improvement in hair countsin a circular balding 1-inch target area in thefinasteride group compared to the placebogroup.77 A 2-year study in balding men be-tween the ages of 41 and 60 years is ongoing.

A study of finasteride in 136 postmenopau-sal women with AGA showed no benefit com-pared with placebo.78,79 In this 1-year,double-blind, placebo-controlled, random-ized, multicenter trial, 136 postmenopausalwomen (41–60 years of age) with AGA re-ceived finasteride 1 mg/day or placebo. Effi-cacy was evaluated by scalp hair counts,patient and investigator assessments, blindedratings of standardized photographs by an ex-pert panel, and histologic analysis of scalp bi-opsy specimens. After 1 year of therapy, therewas no significant difference in the change inhair count between the finasteride and placebogroups. Both treatment groups had significantdecreases in hair count in the frontal/parietal(anterior/mid) scalp during the 1-year studyperiod. Similarly, patient, investigator, andphotographic assessments did not demonstrateany improvement in slowing hair thinning,increasing hair growth, or improving the ap-pearance of the hair in finasteride-treated sub-jects compared with the placebo group.Finasteride was generally well tolerated. In


post-menopausal women with AGA,finasteride 1 mg/day taken for 12 months didnot increase hair growth or slow the progres-sion of hair thinning. This was confirmed byhistologic analysis on 94 women with AGA.73,79

Propecia™ 1 mg is to be taken every day, ona regular schedule, with or without food. Thebioavailability after oral intake is 65%.80

Ninety per cent of circulating finasteride isbound to plasma proteins and can cross theblood-brain barrier.80 Finasteride is metabo-lized in the liver, and therefore caution shouldbe taken in patients with liver function abnor-malities.80 Dosage does not need to be adjustedin case of renal insufficiency.80 Finasteridedoes not affect the cytochrome P450 metabo-lizing enzyme system, and no drug interac-tions have been reported.80

Finasteride is well tolerated, and side-effectsoccur in less than 2% of patients.40,72 Side-ef-fects include 1.8% decreased libido (1.3% pla-cebo), 1.3% erectile dysfunction (0.7% placebo)and 0.8% decreased ejaculate volume (0.4%placebo).40,72 There was no significant differ-ence from the placebo group for each of theseside-effects taken alone, but there is a statisticaldifference when all side-effects are consideredtogether (3.8% vs 2.1%).40 Side-effects will sub-side spontaneously in 58% of those who decideto continue the treatment, and are reversibleupon cessation of treatment.1 A recent study byOverstreet et al.81 confirmed that finasteride 1mg daily for 48 weeks did not effect sperma-togenesis or semen production in men aged 19–41 years. The effect on prostate volume andserum PSA in this young population withoutbenign prostate hypertrophy was small and re-versible upon discontinuation of the drug.81

Finasteride can decrease PSA levels by 50% inolder men.82 At the University of British Colum-bia Hair Research and Treatment Centre, it isrecommended a baseline PSA be taken for older

men prior to initiation of therapy withfinasteride. We also advise the patient’s familydoctor to double the PSA value while patientsare taking finasteride.

Women who are or potentially may be preg-nant should not take finasteride or handlecrushed or broken tablets.80 Finasteride tabletsare coated to prevent contact with the activeingredients during manipulation. The risk ofteratogenicity in humans has not been directlyevaluated,80 but there is a risk that finasterideexposure during pregnancy may cause hypos-padias in the developing male fetus.17 Expo-sure to semen of men who are takingfinasteride does not pose a risk to a pregnantwoman’s male fetus.

Androgen-receptor blockers (ARP inhibitors)

Systemic ARP inhibitors decrease both T andDHT by binding to the androgen receptor. Theyare suitable only in women and are contrain-dicated in men because of side-effects such asimpotence, decreased libido, gynecomastiaand feminization.

Cyproterone acetate: Cyproterone acetate(CPA) is a potent progestin and an androgenreceptor antagonist. CPA is available in Eu-rope, Asia and Canada, but not in the UnitedStates. CPA is an effective treatment for hir-sutism and acne.83–85 There are no large con-trolled clinical studies in AGA with CPA. Itmay have some effect on stabilization of hairloss, although regrowth is quite rare in thisauthor’s experience.83,86–88

Fifty to 100 mg per day of CPA taken on days5 to 14 of the menstrual cycle can be used incombination with an oral contraceptive toregulate menstrual cycles and to avoid preg-nancy.17 Diane-35 contains 2 mg of CPA. Thisis adequate for the treatment of acne, but maybe too low for female AGA.


Side-effects include depression, nausea,menstrual irregularity, weight gain, breast ten-derness and loss of libido.17 Women of child-bearing potential must use an effective birthcontrol method and be warned of the potentialfor feminization and the unknown teratogeni-city risk if they become pregnant.17

Spironolactone: Spironolactone is an aldos-terone antagonist, and its anti-androgenic ef-fect is only mild. It is a competitive inhibitorof androgen receptor protein binding, and in-terferes with the translocation of this complexinto the cell nucleus.85,89,90 It also depletes thecytochrome P450 enzyme (CYP 450) complex,which weakly inhibits androgen biosynthesisin the adrenal glands.89,90

Spironolactone is effective mostly for hir-sutism.84,85 The drug is less effective in femaleAGA, and 200 mg per day is usually required.Small open trials have shown some clinical ef-fect in AGA,91,92 but Spironolactone rarely of-fers the benefit of hair regrowth.

The main side-effect is menstrual irregulari-ties. Minimal increases in serum potassium mayoccur, but are uncommon.89 Women of childbear-ing age must use acceptable birth control meth-ods and be aware there is a risk for feminizationof a male fetus if they become pregnant.

Estrogen mediated: Estrogens increase lev-els of sex hormone binding globulin (SHBG),thereby reducing circulating free T. They alsoinhibit secretion of luteinizing hormonere-leasing hormone (LH-RH) by the hypoth-alamus, reducing androgen synthesis by thegonads. Estrogens are weak 5a-reductase in-hibitors.

Topical and oral estrogens have been usedin women with AGA. Clinically, estrogens mayhelp to maintain the status quo and to slow theprogression of AGA,93 but appear to have littleeffect on stimulating regrowth, although nocontrolled studies have been done.

Biologic response modifiers

Minoxidil

Minoxidil (Rogaine™) was the first agentshown to promote hair regrowth. It is apiperidinopyrimidine derivative that is usedorally as an antihypertensive drug.66 Since oneof its sideeffects is hypertrichosis, a topical so-lution was developed to treat hair loss. Its ex-act mechanism of action is still unclear. It doesnot appear to have either a hormonal or an im-munosuppressant effect.94 Minoxidil increasesduration of anagen and enlarges miniaturizedand suboptimal hair follicles.1 It has beenshown to have a direct mitogenic effect on epi-dermal cells both in vitro and in vivo;95

plucked anagen hair bulbs from men applyingminoxidil show a significant increase in pro-liferation index as measured by DNA flowcytometry.96 It has also been shown to prolongthe survival time of keratinocytes in vitro.95

Another possible mechanism of action is theopposition to intracellular calcium entry. Cal-cium normally enhances epidermal growthfactors (EGF) and inhibits hair growth.97

Minoxidil is converted to minoxidil-sulfate,which is a potassium channel agonist and en-hances potassium ion permeability, thus op-posing the entry of calcium into cells.97,98 Thiswould decrease EGF and subsequently en-hance hair growth. Local vasodilatation doesnot seem to play a major role in hair growth.98,99

Minoxidil was approved for men by the FDAas a 2% solution in 1988 and as a 5% solutionin 1997. For women, the 2% solution was ap-proved in 1991. The 5% solution has not yetbeen approved for women, but it has been usedworldwide by many dermatologists for manyyears. Both solutions are available without aprescription in the United States. In men withAGA, a double-blind, placebo-controlled trial,


using hair weight measurements, found thattopically minoxidil solutions of both 2% and5% were significantly more effective than a pla-cebo lotion or no treatment.65 The 5% solutionproduced a 35% increase in hair weights, com-pared to 25% with the 2% solution.65 The majorincrease in hair weight was observed within thefirst 20 weeks following initiation of therapy.Minoxidil application halted hair loss over the96 weeks, while both the placebotreated menand the untreated men had an approximately6% decrease in hair weight per year.65 Discon-tinuation of therapy results in loss of hairweight over 6 months to match the level in theplacebo-treated group and untreated men.65 Inwomen, one study of 32 weeks used hairweights to assess efficacy, and a 42.5% increasewas found with the 2% solution compared to1.9% with placebo.100 Clinically, loss of hair isevident once treatment with topical minoxidilis discontinued. Thus, topical minoxidil solu-tion must be continued indefinitely.101–107 Therapid loss of hair weight after treatment con-firms its trichogenic effects.

Minoxidil can be used for either frontal orvertex scalp thinning.108 The increase in den-sity is mostly due to miniaturized hairs thatare converted into terminal hairs rather than ade novo regrowth.1 The major increase is usu-ally seen within the first 4 months oftherapy.104 The hair loss becomes stabilized af-ter the initial period of regrowth.103 In a multi-center, double-blind study involving 2294 menbetween the ages of 18 and 50, approximately30–35% of patients, applying 2% topicalminoxidil solution twice daily, showed mod-erate to dense regrowth as assessed by haircounts using macro-photographs.108 Twice-daily application is needed for efficacy. In amulti-center, double-blind placebo-controlledstudy of 256 women between the ages of 18and 45 with AGA, 63% who applied 2% topi-cal minoxidil solution twice daily showed

minimal to moderate regrowth using haircounts in macrophotographs for assessment.109

One study in the stump-tailed macaqueshowed additive benefit in using bothminoxidil and finasteride,110 but there are nodata on this combination therapy in humans.Practically, if one starts both medications si-multaneously in a male patient, he will notknow whether it is either minoxidil,finasteride or the combination that is havingthe effect. For some patients, this may not bean issue, and combination therapy, if afford-able, is a reasonable option. For those male pa-tients already using minoxidil and wanting toswitch to finasteride, it is important to con-tinue using minoxidil for at least 4 months af-ter starting finasteride to prevent the loss ofhair that occurs with the discontinuation ofminoxidil.1

Minoxidil should be used for one full yearbefore its efficacy is assessed. Therapeutic ef-ficacy is evaluated by patient satisfaction andphysician comparison with a baseline photo-graph. In patients with very early AGA, it ishard to appreciate any regrowth or hair lossbecause of the great hair density. In thosecases, physicians must rely mostly on the pa-tient’s impression.

One millilitre of minoxidil solution must beused twice daily, every day in order to be ef-fective. Twenty-five drops (1 ml) must be ap-plied directly on to a dry scalp and thenslightly spread with the fingers.17 No morethan 2 ml should be applied every day, regard-less of the extent of the affected area. For some-one with moderate amounts of hair, the bestmode of application is to divide it into 5 partsand apply 5 drops to each part. The spray ap-plicator is not recommended, since most of thesprayed solution will be applied on the hairs,where it is ineffective and thus wasted.17 Pa-tients must be told that minoxidil solution is ascalp lotion, not a hair lotion.


Minoxidil is poorly absorbed after topicalapplication on normal intact skin.80 Only 0.3to 4.5% reaches the systemic circulation.80 Theeffects of concomitant occlusion or abnormalskin are unknown80. The percentage ofminoxidil that is absorbed is eliminated within4 days.80 It is metabolized in the liver and ex-creted in the urine. Studies have not shownany change in blood pressure or any otherhemodynamic effect, but minoxidil solutionshould be used with caution in patients withcardiovascular disease.80,103 Minoxidil shouldnot be used by pregnant or nursing women.80

There is no evidence of teratogenicity in ratsand rabbits, but in humans data are lacking.80

Minoxidil is secreted in human milk.80 Acci-dental ingestion of topical minoxidil couldlead to serious adverse effects. Each ml of the5% solution contains 50 mg of minoxidil. Themaximum oral daily dose for the treatment ofhypertension is 100 mg.80

Topical minoxidil solution is very safe, andside-effects are mainly dermatologic. The mostfrequent side-effect is an irritant contact der-

matitis, probably due to the propylene glycolin the vehicle.1,17 Occasionally, minoxidil itselfcauses an allergic contact dermatitis.111–113 In-cidence of scalp irritation is approximately 7%with the 2% solution, and may be slightlyhigher with the 5% solution.1,17,103 Contact withany mucosal surface (usually the eyes) shouldbe avoided, because it will cause burning andirritation. If such an event occurs, thoroughlyrinse the eyes with cool tap water.80

If patients experience an irritant contactdermatitis due to the 5% solution, they shouldstop the treatment until all symptoms have re-solved. If they again develop dermatitis on thesecond trial, the concentration should be low-ered to 2%. Patients will be unlikely to de-velop a tolerance to this side-effect, and thetreatment may have to be discontinued alto-gether.

Facial hypertrichosis (Figure 3.32) may oc-cur in 3–5% of women, and is usually not aproblem in men.17 It is not clear yet why thehypertrichosis occurs; but it is possibly eitherthrough a systemic effect or via a transfer of

Figure 3.32Hypertrichosis of the face can occur in women using topical minoxidil solution. (a) Frontalview. (b) Lateral view.


the drug.17 It affects mostly the forehead, ma-lar areas, and sides of the face.17 Those womenwho, prior to treatment, already have mild hir-sutism are more likely develop this side-effect.Hypertrichosis is totally reversible upon dis-continuation of the drug. Those patients whoare affected and continue with the treatmentusually notice a decrease in and even a disap-pearance of the facial hair within a year.17

Thorough hand-washing after each use mayminimize irritation and possibly hypertricho-sis in other body areas.

Tretinoin

Tretinoin (all-trans-retinoic acid) is a biologicresponse modifier. It is a potent cell mitogenthat promotes and regulates epithelial cellgrowth and differentiation.114 It promotes ang-iogenesis115 and increases percutaneous ab-sorption by affecting the fluidity and the lipidcomposition of cell membranes.114

It has been proposed that tretinoin may havean effect on AGA by stimulating the growth ofsuboptimal hairs and could also actsynergistically with minoxidil to producemore dense hair regrowth than either com-pound alone.116 A small study on men withAGA showed some hair regrowth when treatedfor 1 to 2 years with a combination solution of0.025% tretinoin and 0.5% minoxidil, formu-lated using generic powder forms.116 However,Rogaine® and Retin-A®, the proprietary prod-ucts, are incompatible and become ineffectiveif compounded in the same solution.17 Theymust either be mixed using generic powderforms or be applied as separate treatments.Rogaine® must be applied every morning andnight and Retin-A® during the day. Eventhough there seems to be some benefit in usingthe combination, most patients are not com-pliant with the need for an extra application

during the day, making this combination animpractical option for most patients. In addi-tion, the irritation of tretinoin is not alwayswell tolerated.

Treatment of AGA in women

Many factors must be considered in the treat-ment of AGA. An algorithmic approach toAGA in women, structured about the Ludwigclassification, is presented in Figure 3.33. Inwomen with stage I or II hair loss, topical 5%minoxidil solution is offered and continued for1 year (Figures 3.34, 3.35). If patients respondto treatment, then it is continued for as long ashair loss is perceived to be important to thepatient. If ongoing hair loss is detected after 1year, patients may be offered androgen block-ade with CPA or spironolactone, or hair trans-plantation if the patient has a good occipitalscalp donor area. Hair transplantation in fe-male AGA will be discussed in Chapter 4. Forthose with more advanced hair loss and a poordonor area, a hairpiece is suggested. Patientsshould be reassured on the cosmetic appear-ance of hairpieces, as they can give excellentresults. A partial hairpiece may also give anatural and satisfying appearance. Patients of-ten need guidance as to where to get hair-pieces, and it is most appreciated when theyare given a few options.

For women with Ludwig stage III, topicaltherapies are usually ineffective. Hyper-andro-gen excess should be checked by history andphysical examination. If there is any sign ofvirilization (i.e. severe acne, hirsutism, sebor-rheic dermatitis, menstrual irregularities, orinfertility), serum testosterone anddehydroepiandrosterone-sulfate (DHEAS)tests should be ordered and referral to anendocrinologist may be indicated.


Hamilton classification, is outlined in Figure3.36. In those with less severe hair loss andnumerous miniaturized hairs, medical thera-peutic options include finasteride orminoxidil (Figure 3.37). Therapeutic efficacyis evaluated at 1 year (Figure 3.38). If evalua-tion reveals stabilization or regrowth, thenpatients are counseled to continue with treat-ment for as long as they feel hair loss is im-

Figure 3.33An algorithmic approach on the treatment of female AGA: UCSF-UBC Treatment Protocol forandrogenetic alopecia in women (courtesy of Jerry Shapiro, MD, Vera H.Price, MD and HarveyLui, MD).

Treatment of AGA in men

For men, the final decision is based on manyfactors, such as the extent of hair loss, thepresence or absence of miniaturized hairs,patient age, preference for topical or systemictherapy, financial considerations and patientexpectations. An algorithmic approach tomale AGA, structured around the Norwood-


very motivated patients. In those with moreadvanced hair loss and few miniaturizedhairs, medical therapy is unlikely to work,and a surgical approach or a hairpiece is rec-ommended. Studies are currently under wayevaluating the effect of finasteride on thenumber of hair transplantation sessions. It is

Figure 3.34A 40-year-old female with AGA (a) before topical minoxidil solution; and (b) after 6 monthsof use of topical minoxidil, showing marked improvement, with narrowing of her part/parting.

Figure 3.35A 53-year-old female with AGA (a) before topical minoxidil solution; and (b) after 8 monthsof topical minoxidil solution, showing marked improvement.

portant to them. If ongoing hair loss occursdespite treatment, then a surgical approach ora hairpiece should be discussed. Combinationtherapy with both finasteride and minoxidilhas been shown to have additive hairregrowth effects in a balding stump-tailmacaque model,110 and can be prescribed to


Figure 3.37A good candidate for medical treatment of maleAGA (note the presence of miniaturized hair).

Figure 3.36An algorithmic approach on the treatment of male AGA: the UCSF-UBC Treatment Protocolfor androgenetic alopecia in men (courtesy of Jerry Shapiro, MD, Vera H.Price, MD andHarvey Lui, MD).


likely that the combination of the two will re-duce the number of sessions. This author rec-ommends finasteride on all patientsundergoing hair transplants if they are StageIIIV–V pre-transplantation (Figure 3.39).

Patient monitoring

How is response to therapy assessed, and whatmethods can be used to determine treatmentsuccess or failure? First, patient impressions

A 33-year-old male with AGA (c) before the use of finasteride 1 mg/day and (d) after 11months of therapy, showing improvement.

Figure 3.38A 24-year-old male with AGA (a) before theuse of finasteride 1 mg/day and (b) one yearlater, showing improvement.


are determined. Unfortunately, many patientsare often unreliable and unsatisfied with sub-jective estimates. Ideally, each patient has dig-ital photography taken at a standardizeddistance and position (Figure 3.40). If one does

not have a digital set-up with a stereotacticdevice, then an ordinary photograph should betaken. Both patient and physician should real-ize that these uncontrolled snapshots are notaccurate, but do give a general impression ofthe kind of coverage present at baseline. Thephotograph is reviewed with the patient ateach follow-up and compared to current hair-growth status, thereby imparting some kind ofobjective measurement of response. Photo-graphs do not need to be taken annually. Fi-nally, serial part diameters can be taken fromthe same areas of the scalp with each visit.

Matching therapy to patient

expectations

Patient expectations are an important factorwhen discussing therapeutic options and goals.The key features to distinguish between are pre-vention and regrowth. Expectations are largelydictated by the extent of hair loss. In men, those

Figure 3.39(a) A 35-year-old male with two previoussessions of hair transplants, the last trans-plant four years before the photo. He wasconsidering another session. (b) The sameindividual 12 months after the use offinasteride 1 mg/day, showing significantimprovement. This patient felt he did notneed another transplant session.

Figure 3.40Digital photography with a stereotacticdevice (Canfield Scientific, New Jersey, USA)is ideal as a means for monitoring patients.


with stage II or III hair loss have lower expecta-tions and are primarily seeking prevention. It isalso important to reset these expectations, em-phasizing that regrowth can be difficult to per-ceive and only stabilization may be detected.Those with more advanced balding have higherexpectations and are hoping for regrowth. If ex-pectation levels are high, they may less likelyto be satisfied with medical therapy. It is impor-tant to keep the expectations of this group low,emphasizing prevention and minimizing ex-pectations of regrowth. Those seeking hairtransplants all have high expectations and areusually satisfied.

ConclusionsThe treatment of AGA has advanced tremen-dously in the last 10 years. The consultationprocess is no longer a disappointing meetingwith the physician, but consists of an interac-tive session with choices and discussion. Thealgorithmic approach to AGA allows the clini-cian to select an appropriate therapeutic mo-dality based on stage of hair loss. It isimportant to present patients with all thera-peutic options, while addressing realistic ex-pectations.

Outlook for the futureThere are currently two treatment modalitiesfor AGA: androgen blockade and biologic re-sponse modifiers. It is expected that moreagents will be developed in both categories.Dual inhibitors, such as combined type I andtype II 5a-reductase inhibitors, will probablybe evaluated. Topical androgen receptor pro-tein inhibitors and new biologic responsemodifiers will also undoubtedly be available.Targeted follicular gene therapy has the poten-tial to block or intercept the synthesis of 5a-

reductase or the androgen receptor protein.Follicular stem-cell gene therapy will also beexplored in the future, and would allow altera-tion of specific DNA transcription, RNA trans-lation and modified synthesis of putativeenzymes and receptors involved in the proc-ess of hair follicle miniaturization.

References1. Price V.H. Treatment of hair loss. New Engl J

Med, 1999; 341(13):964–73.2. Rhodes T., Girman C.J., Savin R.C., et al.

Prevalence of male pattern hair loss in 18–49year old men. Dermatol Surg, 1998; 24(12):1330–2.

3. Bergfeld W.F. Androgenetic alopecia: anautosomal dominant disorder. Am J Med,1995; 98(1A):95S–98S.

4. Cash T.F. The psychosocial consequences ofandrogenetic alopecia: a review of theresearch literature. Br J Dermatol, 1999;141(3):398–405.

5. Cash T.F., Price V.H. and Savin R.C. Psycho-logical effects of androgenetic alopecia onwomen: comparisons with balding men andwith female control subjects. J Am AcadDermatol, 1993; 29(4):568–75.

6. Cash T.F. The psychological effects ofandrogenetic alopecia in men. J Am AcadDermatol, 1992; 26(6):926–31.

7. Randall V.A. The use of dermal papilla cellsin studies of normal and abnormal hairfollicle biology. Dermatol Clin, 1996;14(4):585–94.

8. Hibberts N.A., Howell A.E. and Randall V.A.Balding hair follicle dermal papilla cellscontain higher levels of androgen receptorsthan those from non-balding scalp. JEndocrinol, 1998; 156(1):59–65.

9. Randall V.A., Hibberts N.A. and Hamada K.A comparison of the culture and growth ofdermal papilla cells from hair follicles fromnon-balding and balding (androgeneticalopecia) scalp. Br J Dermatol, 1996; 134(3):437–44.


10. Randall V.A. Androgens and human hairgrowth. Clin Endocrinol (Oxf), 1994; 40(4):439–57.

11. Randall V.A., Thornton M.J., Hamada K. andMessenger A.G. Androgen action in cultureddermal papilla cells from human hairfollicles. Skin Pharmacol, 1994; 7(1–2):20–6.

12. Randall V.A. Role of 5 alpha-reductase inhealth and disease. Baillière’s ClinEndocrinol Metab, 1994; 8(2):405–31.

13. Randall V.A., Thornton M.J. and MessengerA.G. Cultured dermal papilla cells fromandrogen-dependent human hair follicles(e.g. beard) contain more androgen receptorsthan those from non-balding areas of scalp. JEndocrinol , 1992; 133(1):141–7.

14. Randall V.A., Thornton M.J., Hamada K. andMessenger A.G. Mechanism of androgenaction in cultured dermal papilla cellsderived from human hair follicles withvarying responses to androgens in vivo. JInvest Dermatol, 1992; 98(6 Suppl):86S–91S.

15. Randall V.A., Thornton M.J., Hamada K., et al.Androgens and the hair follicle. Culturedhuman dermal papilla cells as a model system.Ann N Y Acad Sci, 1991; 642: 355–75.

16. Thornton M.J., Messenger A.G., Elliott K.and Randall V.A. Effect of androgens on thegrowth of cultured human dermal papillacells derived from beard and scalp hairfollicles. J Invest Dermatol, 1991;97(2):345–8.

17. Shapiro J. and Price V.H. Hair regrowth.Therapeutic agents. Dermatol Clin, 1998;16(2):341–56.

18. Rushton D.H., Ramsay I.D., Norris M.J. andGilkes J.J. Natural progression of malepattern baldness in young men. Clin ExpDermatol , 1991; 16(3):188–92.

19. Kuster W. and Happle R. The inheritance ofcommon baldness: two B or not two B? J AmAcad Dermatol, 1984; 11(5 Pt 1):921–6.

20. Sybert V. Genetic Skin Disorders, pp. 165–7.1997; New York: Oxford University Press.

21. McKusick V. Mendelian Inheritance in Man.Catalogs of Human Genes and Genetic

Disorders. 1998; Baltimore, MD: JohnsHopkins University Press.

22. Osborn D. Inheritance of baldness. J Hered,1919; 7:347–55.

23. Smith M. Male type alopecia, alopecia areataand normal hair in women: family histories.Arch Dermatol, 1964; 89:95–8.

24. Harris D. The inheritance of prematurebaldness in men. Ann Eugen, 1946; 13:172–81.

25. Salamon T. Genetic factors in male patternalopecia. In Biopathology of Pattern Alo-pecia, ed. G.M.A.Baccaredda-Boy andJ.R.Frey, pp. 39–49. 1968; New York: Karger.

26. Verbov J.L. Common baldness occurring infemales only, in one generation. Br J ClinPract, 1978; 32(9):261–2.

27. Carey A.H.,Chan K.L., Short F., et al.Evidence for a single gene effect causingpolycystic ovaries and male pattern bald-ness. Clin Endocrinol (Oxf), 1993;38(6):653–8.

28. Carey A.H., Waterworth D., Patel K., et al.Polycystic ovaries and premature malepattern baldness are associated with oneallele of the steroid metabolism gene CYP17.Hum Mol Genet, 1994; 3(10):1873–6.

29. Konig A., Happle R., Tchitcherina E., et al.An X-linked gene involved in androgeneticalopecia: A lesson to be learned fromadrenoleukodystrophy. [In Process Citation].Dermatology, 2000; 200(3):213–18.

30. Sprecher E., Shalata A., Dabhah K., et al.Androgenetic alopecia in heterozygouscarriers of a mutation in the human hairlessgene. J Am Acad Dermatol, 2000; 42(6):978–82.

31. Sreekumar G.P., Pardinas J., Wong C.O., etal. Serum androgens and genetic linkageanalysis in early onset androgeneticalopecia [letter]. J Invest Dermatol, 1999;113(2): 277–9.

32. Sawaya M.E. Purification of androgenreceptors in human sebocytes and hair. JInvest Dermatol, 1992; 98(6 Suppl): 92S–96S.


d33.Sawaya M.E. and Price V.H. Different levelsof 5alpha-reductase type I and II, aromatase,and androgen receptor in hair follicles ofwomen and men with androgenetic alopecia.J Invest Dermatol, 1997; 109(3):296–300.

34. Chen W., Zouboulis C.C. and Orfanos C.E.The 5 alpha-reductase system and itsinhibitors. Recent development and itsperspective in treating androgen-dependentskin disorders. Dermatology, 1996; 193(3):177–84.

35. Bingham K.D. and Shaw D.A. The metabo-lism of testosterone by human male scalpskin. J Endocrinol, 1973; 57(1): 111–21.

36. Itami S., Kurata S., Sonoda T. and TakayasuS. Mechanism of action of androgen indermal papilla cells. Ann N Y Acad Sci,1991; 642:385–95.

37. Itami S., Kurata S., Sonoda T. and TakayasuS. Characterization of 5 alpha-reductase incultured human dermal papilla cells frombeard and occipital scalp hair. J InvestDermatol, 1991; 96(1):57–60.

38. Kaufman K.D. Androgen metabolism as itaffects hair growth in androgenetic alopecia.Dermatol Clin, 1996; 14(4):697–711.

39. Schweikert H.U. and Wilson J.D. Regulationof human hair growth by steroid hormones.I. Testerone metabolism in isolated hairs. JClin Endocrinol Metab, 1974; 38(5):811–19.

40. Kaufman K.D., Olsen E.A., Whiting D., et al.Finasteride in the treatment of men withandrogenetic alopecia. Finasteride MalePattern Hair Loss Study Group. J Am AcadDermatol, 1998; 39(4 Pt 1):578–89.

41. Imperato-McGinley J. 5-alpha-reductasedeficiency. Curr Ther Endocrinol Metab,1994; 5:351–4.

42. Imperato-McGinley J., Guerrero L., Gautier T.and Peterson R.E. Steroid 5alpha-reductasedeficiency in man: an inherited form of malepseudohermaphroditism. Science, 1974;186(4170):1213–15.

43. Price V.H. Testosterone metabolism in theskin. A review of its function inandrogenetic alopecia, acne vulgaris, and

idiopathic hirsutism including recentstudies with antiandrogens. Arch Dermatol,1975; 111(11):1496–1502.

44. Orme S., Cullen D.R. and Messenger A.G.Diffuse female hair loss: are androgensnecessary? Br J Dermatol, 1999;141(3):521–3.

45. Norwood O.T. and Lehr B. Femaleandrogenetic alopecia: a separate entity.Dermatol Surg, 2000; 26(7):679–82.

46. Ziller C. Pattern formation in neural crestderivatives. In Hair research for the nextmillenium, ed. V.R.D.Van Neste, p. 1. 1996;Amsterdam: Elsevier Science.

47. Orfanos C. Androgenetic alopecia: clinicalaspects and treatment. In Hair and HairDiseases, ed. C.Orfanos, pp. 485–527. 1990;Berlin: Springer-Verlag.

48. Venning V.A. and Dawber R.P. Patternedandrogenic alopecia in women. J Am AcadDermatol, 1988; 18(5 Pt 1):1073–7.

49. Lesko S.M., Rosenberg L. and Shapiro S. Acase-control study of baldness in relation tomyocardial infarction in men [publishederratum appears in JAMA 1993 May 19;269(19):2508] [see comments]. JAMA, 1993;269(8):998–1003.

50. Sasmaz S., Senol M., Ozcan A., et al. Therisk of coronary heart disease in men withandrogenetic alopecia. J Eur Acad DermatolVenereol, 1999; 12(2):123–5.

51. Ford E.S., Freedman D.S. and Byers T.Baldness and ischemic heart disease in anational sample of men [see comments]. AmJ Epidemiol, 1996; 143(7):651–7.

52. Lotufo P.A., Chae C.U., Ajani U.A., et al.Male pattern baldness and coronary heartdisease: the Physicians’ Health Study. ArchIntern Med, 2000; 160(2):165–71.

53. Herrera C.R., D’Agostino R.B., GerstmanB.B., et al. Baldness and coronary heartdisease rates in men from theFramingham Study. Am J Epidemiol,1995; 142(8): 828–33.

54. Matilainen V., Koskela P. andKeinanenKiukaanniemi S. Early


androgenetic alopecia as a marker of insulinresistance [letter] [in process citation].Lancet, 2000; 356(9236): 1165–6.

55. Cooke N.T. Male pattern alopecia andcoronary artery disease in men. Br JDermatol, 1979; 101(4):455–8.

56. Hawk E., Breslow R.A. and Graubard B.I.Male pattern baldness and clinical prostatecancer in the epidemiologic follow-up of thefirst National Health and Nutrition Examina-tion Survey. Cancer Epidemiol BiomarkersPrev, 2000; 9(5):523–7.

57. Ludwig E. Classification of the types ofandrogenetic alopecia (common baldness)occurring in the female sex. Br J Dermatol,1977; 97(3):247–54.

58. Olsen E. Disorders of Hair Growth, ed. E.Olsen, pp. 257–279. 1994; New York:McGraw-Hill, Inc.

59. Hamilton J. Patterned loss of hair in men:Types and incidence. Ann NY Acad Sci,1951; 53:708–28.

60. Norwood O.T. Male pattern baldness:classification and incidence. South Med J,1975; 68(11):1359–65.

61. Rushton H., James K.C. and Mortimer C.H.The unit area trichogram in the assessmentof androgen-dependent alopecia. Br JDermatol, 1983; 109(4):429–37.

62. Whiting D. Scalp biopsy as a diagnostic toolin androgenetic alopecia. Dermatol Ther,1998; 8:24–33.

63. Whiting D.A. Diagnostic and predictivevalue of horizontal sections of scalp biopsyspecimens in male pattern androgeneticalopecia [published erratum appears in J AmAcad Dermatol, 1993 Oct; 29(4):554]. J AmAcad Dermatol, 1993; 28(5 Pt 1):755–63.

64. Headington J.T. Transverse microscopicanatomy of the human scalp. A basis for amorphometric approach to disorders of thehair follicle. Arch Dermatol, 1984; 120(4):449–56.

65. Price V.H., Menefee E. and Strauss P.C.Changes in hair weight and hair count inmen with androgenetic alopecia, after

application of 5% and 2% topical minoxidil,placebo, or no treatment. J Am AcadDermatol, 1999; 41(5 Pt 1):717–21.

66. Sawaya M.E. Novel agents for the treatmentof alopecia. Semin Cutan Med Surg, 1998;17(4):276–83.

67. Gormley G.J., Stoner E., Bruskewitz R.C., etal. The effect of finasteride in men withbenign prostatic hyperplasia. TheFinasteride Study Group [see comments].New Engl J Med, 1992; 327(17):1185–91.

68. Stoner E. The clinical development of a 5alpha-reductase inhibitor, finasteride. J SteroidBiochem Mol Biol, 1990; 37(3): 375–8.

69. Drake L., Hordinsky M., Fiedler V., et al. Theeffects of finasteride on scalp skin and serumandrogen levels in men with androgeneticalopecia. J Am Acad Dermatol, 1999;41(4):550–4.

70. Roberts J., et al. Clinical dose ranging studieswith finasteride, a type 2 5 alpha reductaseinhibitor in men with male pattern hair loss.J Am Acad Dermatol, 1999; 41(4):555–63.

71. Dallob A.L., Sadick N.S., Unger W., et al.The effect of finasteride, a 5 alpha-reductaseinhibitor, on scalp skin testosterone anddihydrotestosterone concentrations inpatients with male pattern baldness. J ClinEndocrinol Metab, 1994; 79(3):703–6.

72. Leyden J., Dunlap F., Miller B., et al.Finasteride in the treatment of men withfrontal male pattern hair loss [see com-ments]. J Am Acad Dermatol, 1999; 40(6 Pt1):930–7.

73. Whiting D.A., Waldstreicher J., Sanchez M.and Kaufman K.D. Measuring reversal ofhair miniaturization in androgeneticalopecia by follicular counts in horizontalsections of serial scalp biopsies: results offinasteride 1 mg treatment of men andpostmenopausal women. J Invest DermatolSymp Proc, 1999; 4(3):282–4.

74. Abstract. Propecia: New Clinical Data—FiveYear Experience. In European Academy ofDermatovenereology Annual Meeting. Oct2000. Geneva.


75. Price V.H. Changes in hair weight in menwith androgenetic alopecia after takingfinasteride. Presentation at EuropeanAcademy of Dermatology. 1999. Amsterdam.

76. Van Neste D., et al. Finesteride increasesanagen hair in men with androgeneticalopecia. Br J Dermatol 2000; 143(4):804–10.

77. Brenner S. and Matz H. Improvement inandrogenetic alopecia in 53–76-year-oldmen using oral finasteride. Int J Dermatol,1999; 38(12):928–30.

78. Roberts J., Price V.H., Olsen E., et al. Theeffects of finasteride on post-menopausalwomen with androgenetic alopecia. In HairWorkshop. 1998. Brussels, Belgium.

79. Price V.H., Roberts J.L., Hordinsky M., et al.Lack of efficacy of finasteride in postmeno-pausal women with androgenetic alopecia. JAm Acad Dermatol, 2000; 43(5): 768–76.

80. Canadian Pharmacists AssociationMonography, Minoxidil and Finasteride. InCompendium of Pharmaceuticals andSpecialties (CPS) 34th Edition. 1999;Ottawa, Canada.

81. Overstreet J.W., Fuh V.L., Gould J., et al.Chronic treatment with finasteride dailydoes not affect spermatogenesis or semenproduction in young men. J Urol, 1999;162(4):1295–300.

82. Matzkin H., Barak M. and Braf Z. Effect offinasteride on free and total serumprostatespecific antigen in men with benignprostatic hyperplasia. Br J Urol, 1996;78(3):405–8.

83. Hammerstein J., Meckies J., Leo-Rossberg I.,et al. Use of cyproterone acetate (CPA) in thetreatment of acne, hirsutism and virilism. JSteroid Biochem, 1975; 6(6):827–36.

84. Namer M. Clinical applications ofantiandrogens. J Steroid Biochem, 1988;31(4B):719–29.

85. Shaw J.C. Antiandrogen therapy in derma-tology. Int J Dermatol, 1996; 35(11): 770–8.

86. Ekoe J.M., Burckhardt P. and Ruedi B.Treatment of hirsutism, acne and alopecia

with cyproterone acetate. Dermatologica,1980; 160(6):398–404.

87. Mortimer C.H., Rushton H. and James K.C.Effective medical treatment of commonbaldness in women. Clin Exp Dermatol,1984; 9(4):342–50.

88. Neumann F. Pharmacology and potential useof cyproterone acetate. Horm Metab Res,1977; 9(1):1–13.

89. Lobo R.A., Shoupe D., Serafini P., et al. Theeffects of two doses of spironolactone onserum androgens and anagen hair in hirsutewomen. Fertil Steril, 1985; 43(2): 200–5.

90. Menard R.H., Guenthner T.M., Kan H. andGillette J.R. Studies on the destruction ofadrenal and testicular cytochrome P-450 byspironolactone. Requirement for the 7alpha-thio group and evidence for the loss of theheme and apoproteins of cytochrome P-450.J Biol Chem, 1979; 254(5): 1726–33.

91. Rushton D. Quantitative assessment ofspironolactone treatment in women withdiffuse androgen-dependent alopecia. J SocCosmet Chem, 1991; 42:317.

92. Burke B.M. and Cunliffe W.J. Oral spironol-actone therapy for female patients with acne,hirsutism or androgenic alopecia [letter]. Br JDermatol, 1985; 112(1):124–5.

93. Orfanos C.E. and Vogels L. Local therapy ofandrogenetic alopecia with 17 alpha-estradiol. A controlled, randomized double-blind study. Dermatologica, 1980; 161(2):124–32.

94. Khoury E.L., Price V.H., Abdel-Salam M.M.,et al. Topical minoxidil in alopecia areata:no effect on the perifollicular lymphoidinfiltration. J Invest Dermatol, 1992;99(1):40–7.

95. Baden H.P. and Kubilus J. Effect of minoxidilon cultured keratinocytes. J Invest Dermatol,1983; 81(6):558–60.

96. Kiesewetter F., Langer P. and Schell H.Minoxidil stimulates mouse vibrissaefollicles in organ culture [letter; comment]. JInvest Dermatol, 1991; 96(2):295–6.


97. Ohtsuyama M. Minoxidil sulfate effect ofinternal calcium of cell in the epidermisand epidermal appendages. In Hair Reseachfor the Next Millennium, ed. V.R.D.VanNeste, p. 481. 1996; Amsterdam: ElsevierScience.

98. Buhl A.E. Minoxidil’s action in hairfollicles. J Invest Dermatol, 1991; 96(5):73S–74S.

99. Philpott M.P., Sanders D.A. and Kealey T.Whole hair follicle culture. Dermatol Clin,1996; 14(4):595–607.

100. Price V.H. and Menefee E. Quantitativeestimation of hair growth. I. androgeneticalopecia in women: effect of minoxidil. JInvest Dermatol, 1990; 95(6): 683–7.

101. Olsen E.A. Topical minoxidil in the treat-ment of androgenetic alopecia in women.Cutis, 1991; 48(3):243–8.

102. Olsen E.A., Buller T.A., Weiner S., DeLongE.R. Natural history of androgeneticalopecia. Clin Exp Dermatol, 1990; 15(1):34–6.

103. Olsen E.A., Weiner M.S., Amara I.A. andDeLong E.R. Five-year follow-up of menwith androgenetic alopecia treated withtopical minoxidil. J Am Acad Dermatol,1990; 22(4):643–6.

104. Olsen E.A. and Weiner M.S. Topicalminoxidil in male pattern baldness: effectsof discontinuation of treatment. J Am AcadDermatol, 1987; 17(1):97–101.

105. Olsen E.A., DeLong E.R. and Weiner M.S.Long-term follow-up of men with malepattern baldness treated with topicalminoxidil. J Am Acad Dermatol, 1987; 16(3Pt 2):688–95.

106. Olsen E.A., Weiner M.S., DeLong E.R. andPinnell S.R. Topical minoxidil in early male

pattern baldness. J Am Acad Dermatol,1985; 13(2 Pt 1):185–92.

107. Kidwai B.J. and George M. Hair loss withminoxidil withdrawal [letter]. Lancet, 1992;340(8819):609–10.

108. Olsen E. Treatment of androgenetic alopeciawith topical minoxidil solution. Res StaffPhys, 1989; 35:53.

109. DeVillez R.L., et al. Androgenetic alopecia inthe female. Treatment with 2% topicalminoxidil solution. Arch Dermatol, 1994;130(3):303–7.

110. Diani A.R., Mulholland M.J., Shull K.L., etal. Hair growth effects of oral administrationof finasteride, a steroid 5 alpha-reductaseinhibitor, alone and in combination withtopical minoxidil in the balding stumptailmacaque. J Clin Endocrinol Metab, 1992;74(2):345–50.

111. Wilson C, Walkden V., Powell S., et al.Contact dermatitis in reaction to 2% topicalminoxidil solution. J Am Acad Dermatol,1991; 24(4):661–2.

112. Ebner H. and Muller E. Allergic contactdermatitis from minoxidil. Contact Dermati-tis, 1995; 32(5):316–17.

113. Tosti A., Bardazzi F., De Padora M.P., et al.Contact dermatitis to minoxidil; ContactDermatitis, 1985; 13(4):275–6.

114. Elias P.M. Epidermal effects of retinoids:supramolecular observations and clinicalimplications. J Am Acad Dermatol, 1986;15(4 Pt 2):797–809.

115. Sporn M.B., Roberts A.B., Roche N.S., et al.Mechanism of action of retinoids. J AmAcad Dermatol, 1986; 15(4 Pt 2):756–64.

116. Bazzano G.S., Terezakis N. and Galen W.Topical tretinoin for hair growth promotion.J Am Acad Dermatol, 1986; 15(4 Pt 2):880–3,890–3.

Most follicles at the occiput of the scalp havebeen ‘genetically programmed’ to persist asnon-miniaturized terminal hairs throughoutthe life of a patient with AGA. These hairs are

unlikely ever to become vellus-like. These fol-licles can be transplanted anywhere on thesame individual and will produse coarce ter-minal hairs for the lifetime of the individual.

4 Surgical management ofandrogenetic alopecia

Figure 4.1Hair transplantation two decades ago: (a), (b), (c). Note the unnatural corn-row tufting of hairsurgery performed in the 1960s and 1970s. (d). This patient requested laser hair removal toremove his grafts from twenty years ago.


This is termed donor dominance of the grafts,and is the basis for the success of hair trans-plantation.

The chapter will deal solely with hair trans-plantation, as this is the most commonly per-formed surgical procedure for androgeneticalopecia (AGA). The field of hair transplanta-tion has changed markedly within the past 10years (Figure 4.1). The advent of (1) strip har-vesting for the donor area; (2) the introductionof finer, more natural-appearing grafts; and (3)the use of slits for the recipient area have revo-lutionized the field of hair transplantation.There are many differing approaches to hairtransplantation, and these are discussed thor-oughly elsewhere.1,2 This chapter will discusshair transplantation as it is performed at theUniversity of British Columbia Hair Clinic.

The donor siteThe selected donor area is initially trimmed(Figures 4.2, 4.3) and anesthetized using the

tumescent technique (Figure 4.4). The tumes-cent technique involves the injection of largevolumes of very dilute lidocaine andepinephrine. This anesthetic approach wasfirst developed for patients undergoingliposuction.3 It has been shown that tumescentanesthesia significantly reduces the total

Figure 4.2Donor area is chosen in the occipital portionof the scalp.

Figure 4.3Donor area at the back of the scalp istrimmed.

Figure 4.4Donor area is injected with tumescentanesthesia.

Surgical management of androgenetic alopecia 123

number of milligrams of lidocaine requiredand maximizes the vasoconstrictive benefits ofepinephrine, thus decreasing bleeding.4 A so-lution prepared by adding 25 ml of 2% lido-caine without epinephrine, 2.5 ml of 8.4%sodium bicarbonate solution and 0.4 ml of1:1000 epinephrine is added to a 250 ml IV bagof saline. Approximately 6–7 injections areperformed with an action pump syringe and a25 gauge needle into the trimmed occipitalarea. A mandatory period of 20 minutes is re-quired for the anesthetic to have its full effectin terms of anesthesia and vasoconstriction.Just before excision, repeat injections ofanesthesia are given to the patient’s donorarea. This increases skin turgor in the area andallows easier visualization and excision of thedonor area. Any curly hairs will also becomemore ‘straightened’ with this increased turgor,

and as a result are less likely to be latertransected. Any ‘hot spots’ that are not com-pletely anesthetized can be furtheranesthetized with small amounts of 2% lido-caine.

The hair follicle with its dermal papilla usu-ally extends to a depth of 4–6 mm. Tissue morethan 1 mm below the dermal papilla is not nec-essary for transplanting. It is important to keepthis in mind when harvesting strips. If an exci-sion is too deep, it can cause unnecessary harmto underlying arteries and veins.

Harvesting with strips as opposed topunches allows for more efficient harvestingand better cosmesis. Strip harvesting has trulyreplaced the older punch-harvesting methods.A multi-bladed knife with #10 Personna bladesis angled parallel to the hair shafts (Figures4.5a and 4.5b). This angle is crucial and variesfrom 100 to 120 degrees. If the angle is not pre-

Figure 4.5(a) Multiple-bladed knife is prepared. (b) The blades are angled in the direction of the hairs.Constant monitoring of the angle is necessary. This angle is crucial, and varies from 100 to120 degrees. If the angle is not precise there will be considerable follicular transection andsubsequent follicular wastage.


cise there will be considerable folliculartransection and subsequent follicular wastage.After the stab incision, blades are maintainedat a constant depth, with avoidance of any kindof ‘sawing’ motions. Most strips are 12–16 cmin length. The width of each strip varies foreach individual. For an average regular ses-sion, at the University of British Columbia(UBC) Hair Clinic, three strips of 2.25 mm eachfor a total of 6.75 mm width are excised. Thiswill yield an average total of 600–800 grafts.For an average megasession involving consid-erably more harvesting, the strips will usuallybe longer and wider, with four 2.5 mm stripstaken for a total width of 1 cm. This will usu-ally yield 1100–1350 grafts on average. Thestrips are released at the ends with a V shapeand from underlying tissue with a #15

Figure 4.6Strips are excised from the donor area. Stripsvary in size depending on whether it is aregular or a megasession. Usually three stripsof 2.25 mm are removed with a regularsession or four strips of 2.5 mm for amegasession. The surgical defect will rangefrom 6.75 mm-1.0 cm in width. Length isusually 10–14 cm.

Figure 4.7Strips are released from the rest of the scalpwith a #15 blade.

Figure 4.8Strips are removed with a V shape at theends.

Personna scalpel blade (Figures 4.6, 4.7, 4.8).This is done meticulously, so as not to harmthe lower portions of the follicle as well as notinjure any underlying blood vessels. Smallbleeders can be cauterized or tied off with 3–0Vicryl absorbable sutures.


The size of the strips taken varies accordingto how much area needs to be covered, hairdensity, ethnicity and scalp elasticity. Largerareas of alopecia will require greater coverageand thus larger strips. If donor follicular den-sity is low, wider strips are necessary. African-Americans in particular usually have a lowerscalp follicular density and frequently requirea greater total width of strips. However, if anindividual’s scalp is too tight, the total widthof strips removed will be lessened.

The donor site is sutured with blue nylon3–0 Novafil. We have found that sutures aremore confortable than staples for the patient,and as a result prefer closure by a continuoussuture (Figure 4.9). However, certain centershave found the exactly the opposite, and justuse staples.5

The resulting scar is linear, usually with adiameter of 1–2 mm (Figure 4.10). These scarscan be excised at subsequent sessions, leavingonly one final scar. Alternatively, another scarcan be created above or below the previous

Figure 4.9The surgical defect is closed with a continu-ous stitch.

Figure 4.10(a) The scar 6 months after the procedure.(b) A rare complication of the donor area isthe formation of a keloid, which is morecommonly seen in African-Americans orAsians. Keloids can subsequently be treatedwith intralesional corticosteroid. This par-ticular Asian patient did not mind the keloid,as it was well camouflaged by his donor hair.He did not inform our center of this compli-cation, and it was not discovered until hereturned two years later for his subsequentsecond session.


one. All of this is camouflaged nicely by thepatient’s hair, which must have a prerequisitelength of 2 cm.

Complications in the donor are very rare,and include keloid formation (Figure 4.10b)wound dehiscence, and paresthesias.

Graft hair preparationThe strips are placed in saline on ice packs andsubsequently subdivided into grafts with onlyone single hair follicle (micrografts) or one totwo follicular bundles/follicular units contain-ing two to four hairs (minigrafts). This is per-formed by meticulous dissection of the stripswith a #10 Personna blade and fine jewelers’forceps (Figure 4.11). Appropriate magnifica-tion is necessary to perform this. Excessiveamounts of fat, hair without matrices, and anyscar tissue (especially from a previous trans-plant) is removed (Figure 4.12).

During preparation, grafts are grouped ac-cording to size and density on Petri dishes onice (Figures 4.13 and 4.14). It is essential thatduring this whole process strips and grafts arenot permitted to dry out and are well mois-tened with saline.

The most obvious advantage of using thesesmall grafts is the elimination of tufting remi-niscent of the old grafts. Because of the naturalappearance of the small grafts, the patient isnot committed to have to continue throughmany sessions to get that final natural look.

The recipient areaIn the frontal area, facial framing is frequentlywhat the patient wants. Positioning the hair-line is critical, and must be discussed at lengthwith the patient. This is drawn in before thesurgery. Stough has presented guidelines.6 At

Figure 4.11Strips are placed on a tongue depressor andare sectioned with a #10 blade into smallergrafts.

Figure 4.12Much of the fat is trimmed away, leavingonly 1 mm of fat underneath the follicle.


view, the area marked is always parallel to theground and on the flat portion of the scalp (Fig-ure 4.15b).

Figure 4.13Grafts are subdivided into micrografts con-taining single hairs (bottom) or minigraftswith single follicular bundles of 2–3 hairs(top).

Figure 4.14The grafts are grouped on to Petri dishesaccording to the number of hairs per graft.

Figure 4.15(a) and (b). The hairline is drawn onto the recipient area.

the UBC hair clinic we mark an area 8–11 cmmidline above the glabella and create a curved,bell-shaped hairline (Figure 4.15a). On lateral


4.17). They are directed parallel to the direc-tion of the hair. Usually we allow 1.5–2.5 mmbetween the slits laterally and 1 mm anteriorlyor posteriorly (Figure 4.18). The majority of pa-tients get satisfactory cosmetic results with 3sessions of slit grafting in a totally bald area.Those with pre-existing hair may only need 2

Figure 4.16On the vertex of the scalp, the hair directionis planned.

Figure 4.17Slits into the recipient area are made with anEllis 1.5 or 2 mm spear tip.

Figure 4.18(a) and (b). Slits are made into the recipient area.

On the vertex, the area is marked as to hair di-rection prior to the surgery (Figure 4.16).

The recipient area is anesthetized with afield block of 2% lidocaine with a mandatory20-minute waiting period to maximize vaso-constriction. Slits are made with an Ellis 1.5mm or 2.0 mm spear tip on a handle (Figure


of 1100–1400 grafts, and allows the placementof grafts into the anterior portion as well as thevertex of the scalp.

Planting into the slits is done meticulouslywith jewelers’ forceps (Figures 4.19 and 4.20).Special care is taken not to harm any of thegrafts. The hairs in the grafts are aligned with

Figure 4.19Grafts are placed on to the fingers of thenurses.

Figure 4.20Grafts are placed into slits with jewelers’forceps.

Figure 4.21(a) and (b). Scalp after placement of grafts.

sessions. In the frontal area, a zone of approxi-mately 300 pure micrografts is created. Theremaining minigrafts are placed behind thisfrontal zone. For a regular session, 600–900total grafts are transplanted, usually covering30–50% of the anterior portion of the scalp. Amegasession increases coverage, with a total


the appropriate angle and direction fitting di-rectly into the slits. The grafts can be flush orslightly elevated above the surrounding tissue(Figures 4.21a and 4.21b).

A regular session will usually take 5–6hours. A megasession may take 6–8 hours tocomplete. Patients leave the office with a moistdressing covering the donor and recipient ar-eas (Figure 4.22). The dressing is removed thenext day. With appropriate postoperative careand daily shampooing, after one week virtu-ally all crusting will have disappeared. Facialedema beginning 48 hours after the procedureand lasting for 5 days is certainly common, es-pecially with megasessions. Patients arewarned appropriately and are told to expect it.If the facial edema does not then happen, thenthis becomes a bonus for the patient. Foreheadswelling is treated with the frequent applica-tion of ice-packs and upright positioning (at atleast a 45 degree angle) for one week whilesleeping. It is best for patients to take one weekoff work. A full working schedule and exercisecan be resumed 1 week after the procedure.

Patients are warned of a telogen effluviumthat can occur with the transplanted grafts aswell as with pre-existing recipient hair. Pa-tients must wait for up to six months to see thefull benefits of a hair transplant.

We perform repeat sessions after a mini-mum of six months between sessions. This al-lows the transplanted hair to grow in visiblyand allows us to visualize where to put thenew set of grafts.

The average patient with marked hair losswill receive on the average 3 sessions (Figures4.23–4.25).

Finasteride and hairtransplantsWe frequently recommend our male patientswith pre-transplant Norwood-Hamilton StagesIII–V to take finasteride 1 mg daily. Finasteridemay stabilize any further thinning of pre-ex-isting hair in the recipient area. This wouldlogically reduce the number of sessions neces-sary. There also is a possibility of regrowth aswell as in the patient illustrated in Fig. 3.36.(See Figures 3.39a and 3.39b in Chapter 3 onandrogenetic alopecia)

Minoxidil and hairtransplantsThere are reports in the literature that topicalminoxidil solution twice daily may lessen theeffluvium usually seen postoperatively.7 Manyof our female patients continue to use topicalminoxidil 5% solution after transplantation tohelp stabilize any further loss and further re-duce the number of sessions.

Figure 4.22Post-operative dressing covering donor andrecipient area. Graftcyte® dressings areplaced over the recipient area.


Hair transplantation inWomenBecause AGA in women may be more diffuse,the occipital donor area may be affected. It isarea. important to choose the appropriate fe-

male surgical candidate. Atleast 30% (in theauthor’s experience) have significant thinningin the donor area and are not good candidates.Another problem with women is the resultingeffluvium of pre-existing hair in the recipientThis can be somewhat lessened with the useof topical minoxidil solution applied twice

Figure 4.24(a). A 27-year-old male prior to hair transplant, (b). 1 year later, after two regular sessions.

Figure 4.23(a). A 40-year-old male prior to hair transplant, (b). Two years later, after four regular sessions.


daily, but frequently will still occur even then.In such cases the patient will experience efflu-vium of both the transplanted hair and her pre-existing hair, and will feel that her situationhas worsened significantly compared to herpre-transplant state. Our experience is that aslong as the female patient is warned that theremay be significant worsening before improve-ment and that the lag time is 6 months, thenshe will be prepared emotionally. If she is not

able to accept this fact, she is not a candidatefor hair transplant surgery.

ConclusionHair transplant surgery has become very popu-lar, as its results are cosmetically very natural.Micro-grafting, mini-grafting and strip harvest-

Figure 4.25(a). A 43-year-old male prior to hair transplant. (b). Two megasessions and a regular sessionand 3 years later. (c). Side view of the same patient before hair transplant. (d). Side view afterhair transplant.


ing have made the transplant an efficient tech-nique for increasing the number of follicles inspecific areas affected by AGA. Combinationmedical therapy with systemic finasteride ortopical minoxidil solution may certainly addto the cosmetic result.

References

1. Stough D. Hair replacement surgical andmedical, 1st edn. 1996, St Louis, Missouri:Mosby.

2. Unger W. Hair Transplantation, 3rd edn.1995, New York: Marcel Dekker.

3. Klein J. The tumescent technique forliposuction surgery. Am J Cosmet Surg 1987;4:263–7.

4. Coleman W.P.D. and J.A.Klein. Use of thetumescent technique for scalp surgery,dermabrasion, and soft tissue reconstruction.J Dermatol Surg Oncol 1992; 18(2):130–5.

5. Stough D. The donor site. In Hair replace-ment surgical and medical, ed. D.Stough, pp.139–49, 1996: St Louis, Missouri: Mosby.

6. Stough D. Determination of hairline place-ment. In Hair replacement surgical andmedical, ed. D.Stough, pp. 425–9, 1996, StLouis, Missouri: Mosby.

7. Kassimir J.J. Use of topical minoxidil as apossible adjunct to hair transplant surgery. Apilot study. J Am Acad Dermatol 1987; 16(3Pt 2):685–7.

Drugs can affect hair by causing alopecia. Thischapter will review which drugs have been im-plicated in hair loss and explore the mecha-nisms of how pharmaceutical agents can alterhair cycling and structure.

Drugs that cause alopeciaThe true incidence of drug-related alopecia ishard to determine accurately. Practicing der-matologists make the diagnosis infrequently,but it is also true that they rarely see the vastmajority of such patients—those receivingchemotherapy. Drugs are capable of produc-ing a wide spectrum of alopecia, from com-plete baldness to slight, barely noticeableshedding. Subtle cases can be difficult to de-tect, and it is possible that many patients maylose small amounts of hair and never realizeit. Even if they do notice it, the loss of hair isconsidered to be trivial, and so may go unre-ported or may be reported without adequatedocumentation.

The work-up for any patient with hair lossmust include a thorough drug history. Re-peated questioning may be necessary becauseof forgetfulness or ignorance.

Drug-induced alopecia is usually confinedto the scalp, although the eyebrows, the axil-lary and pubic regions and the body may also

be involved. The pattern of hair loss is almostalways diffuse. Female androgenetic alopecia(AGA) poses a real problem, because it is veryprevalent and can co-exist with diffuse alo-pecia. A drug-induced alopecia can certainlyunmask a tendency for androgenetic alopeciaand accelerate the miniaturization process ofAGA. The scalp itself is usually unremarkable,except in rare instances. Some drugs can causea severe drug-induced lichenoid eruption ofthe scalp.

Certain laboratory tests such as scalp biopsyand blood work can be helpful in ruling outother causes of alopecia. A scalp biopsy withobligatory transverse sectioning will give youthe anagen-telogen ratio and the terminal-vellus ratio, and will detect any inflammatoryprocess. This will help rule out AGA and alo-pecia areata, as well as helping to confirm ananagen or telogen effluvium.

One must understand the basic mechanismsof hair growth and cycling in order to under-stand drug-induced hair loss. This is all re-viewed in detail in Chapter 1. Each humanscalp follicle produces hair cyclically and be-haves independently of neighboring follicles.The scalp follicle passes through a growing,metabolically active phase known as anagen,which lasts 4–8 years. Following anagen, abrief transitional catagen phase of two weeksleads to a metabolically inactive restingtelogen phase. The telogen phase lasts for three

5 Drug-induced alopecia


months, after which the club hair is shed asthe hair follicle initiates a new cycle.

There are two mechanisms of drug-inducedalopecia—direct and indirect effects. Direct ef-fects include anagen growth interruption, pre-cipitation of catagen, and disturbedkeratinization, resulting in hair shaft damage.Indirect effects include causing a systemic dis-ease (hypothyroidism or zinc deficiency) or asevere skin disease (lichenoid eruption ortoxic epidermal necrolysis) of which alopeciais a feature.

Scalp follicles are in differing phases of thehair cycle and are randomly scattered over thescalp. Almost 90% of scalp follicles are inanagen, 10% in telogen, and 1% in catagen.Follicles are susceptible to noxious agents, usu-ally when they are actively growing. During theanagen phase, the mitotic activity of the hairmatrix is so high that it can be compared withthe most actively kinetic tissues of the body,namely bone marrow and mucous membranes.For this reason anagen hair matrix is highly sus-ceptible to noxious events, while catagen andtelogen follicles are relatively safe. The dura-tion of anagen and telogen phases, the percent-age of hairs in anagen and telogen phases, andthe density of the follicles will account for thevarying severity of alopecia in different areas ofhair growth. The regions of the body with high-est percentage of anagen hairs, such as the scalpand beard, are more likely to be affected bydrugs than the regions of the body with the low-est percentage of anagen follicles, such as theeyebrows and eyelashes.

Drug-induced alopecia usually involvespharmaceutical alteration of the cycling proc-ess. Hair loss occurring a few days after drugintake indicates an effect on hair matrix cells.Hair loss developing weeks to months after drugintake may be due to hair matrix effects, butmay result from changes in keratin productionor changes in the hair cycle. If one excludes

anti-mitotics, the most common mechanism byfar for drug-induced alopecia is the precipita-tion of catagen. Of course, in the clinical set-ting, there is confusion, because many diseasesfor which drugs are administered also producea precipitation of catagen. An example of sucha dilemma is highlighted by Reeves andMaibach.1 Ahmad2 in reporting a case ofcimetidine-induced alopecia failed to take intoaccount the fact that the stress from a duodenalulcer might have caused the alopecia.

Anagen effluvium (Table 5.1)

Cytostatic drugs

Any drug that affects cell division can alterhair growth. Cytostatic drugs suppress hairmatrix cell mitosis, impede hair cortex forma-tion and cause an anagen effluvium in almost100% of patients.3,4 The resultant hair containsfewer cells per unit length, is thin and breakseasily. Only the actively dividing matrix cellsof anagen hairs are affected by cytostatic drugs.The intensity of damage to the cortex of thehair shaft depends on the drug dosage and theduration of its administration. A small singledose will produce constriction of the hairshaft. A large single dose that strongly sup-presses mitosis produces a sharp point-con-striction. The hair breaks at the point ofconstriction, with hair fall beginning in 7–14days (see Figure 5.1). Continued treatmentwith a smaller constant dose produces a slowdecrease in hair shaft diameter to a taperedpoint. Combined therapy with two or moreanti-mitotic agents has a greater effect than alarger dose of only one agent. A spectrum ofchanges seems to occur, and the predominanteffect may depend on the dose and timing ofthe administration. In some cases, especially

Drug-induced alopecia 137

Table 5.1Drug-induced anagen effluvium46

in-patients subjected to multiple cycles ofchemotherapy, hair loss may be almost com-plete.

Alopecia most commonly occurs with theuse of doxorubicin (adriamycin), cyclophos-phamide, chlormethamine (mechlormetha-

mine), methotrexate, fluorouracil, vincristine,daunorubicin, bleomycin and hydroxy-car-bamide. Drugs that may aggravate alopeciawhen used in combination chemotherapy in-clude chlorambucil, thiotepa, cytarabine, vin-blastine and dactinomycin.

Figure 5.1Anagen effluvium. A 33-year-old female with lymphoma on dacarbazine, bleomycin,doxorubicin and vinblastine. Note the marked hair loss over the entire scalp. (a) posteriorview (b) lateral view


Certain drugs affect specific phases of themitotic process within the actively dividinghair matrix. Those drugs that are S phase-spe-cific include cytosine arabinoside, hydroxyu-rea, 6-mercaptopurine and methotrexate. TheM phase of mitosis is affected greatly by vinc-ristine and vinblastine. Most of the cytotoxicagents are not phase-specific: these includealkylating agents (cyclophosphamide,ifosfamide, melphalan, thiotepa, busulfan,carmustine, dacarbazine), nitrosoureas,antitumor antibiotics, procarbazine, and cis-platin.

Colchicine

Colchicine, used in the treatment of gout, hasanti-mitotic activity operating through failureof spindle formation. Cells with the highestrates of division are affected earliest.5 Colchi-cine can produce diffuse hair loss in 1–10% ofcases. The mode of action is due to metaphasearrest.6 Harms7 reported a case of diffuse alo-pecia that occurred after 2 months of colchi-cine therapy. Hairs were dystrophic andbroken off 1–2 cm above the scalp. Hair loss isdose-dependent. It may persist for 1–3 months,and may be reversible even if the drug is con-tinued.8

Vasopressin

Vasopressin, a vasoconstrictor and anti-diu-retic pituitary hormone, has been reported tocause alopecia by causing an anagen effluviumfrom cutaneous infarcts. All areas affected byanagen effluvium had normal hair growth af-ter the medication was discontinued.9

Telogen effluviumThere are 5 functional types of telogen efflu-vium (TE) as proposed by Headington.10 Three

of these types are related to events in anagenand two related to telogen. The five types areas follows: 1. Immediate anagen release (IAR), character-

ized by a relatively short onset—usually 3–5 weeks. Follicles that would normallycomplete a longer cycle by remaining inanagen prematurely enter telogen. Imme-diate anagen release probably character-izes most drug-related events. IAR isprobably underreported because of report-ing inertia by physicians whose clinicaljudgement is that a probable drug-relatedhair loss is a trivial event with expectedreversal when the drug has been discon-tinued.

2. Delayed anagen release (DAR), character-ized by a prolonged anagen rather thancycling normally into telogen. When folli-cles are finally released from anagen, ifsufficient are involved, the clinical sign ofincreased shedding will be found. DAR isprobably associated with postpartum hairloss and oral contraceptives. Cimetidinehas also been implicated as causing DAR.

3. Shortened anagen (SA) occurs when theanagen phase is significantly decreased intime. If anagen is decreased by 50%, thereis a corresponding doubling of telogenhairs. Etretinate may cause SA.

4. Immediate telogen release (IMR): normaltelogen, which may last 4–12 weeks, isshortened to just a few days. All folliclesin telogen may be susceptible. There issome good evidence that topical minoxidilsolution may effect IMR, as the affectedfollicles are promptly stimulated to cycleinto anagen.

5. Delayed telogen release (DTR) occurswhen telogen is prolonged and there isslightly more synchronous growth and


fallout on the scalp. No drugs have beenimplicated with this mechanism conclu-sively, but reports of delayed-onset shed-ding with drug treatment might be a resultof DTR.

The following list of drugs have been impli-cated as causing telogen effluvium (Tables5.2–5.5)

Anti-coagulants

All forms of anti-coagulants may induce hairloss. These include heparin and coumarins. TE

occurs in more than 10% of patients, appearsto be related to drug dosage, and tends to bemore frequent in women (Figure 5.2).

Anti-thyroid drugs

Reversible alopecia is a constant finding in ia-trogenic hypothyroidism, which occurs duringtreatment of thyrotoxicosis. Telogen effluviumis frequently associated with hair dryness andbrittleness. Anti-thyroid drugs that may pro-duce telogen effluvium include iodine, meth-ylthiouracil, propylthiouracil, andcarbimazole.

Table 5.2 Drug-induced telogen effluvium (incidence less than 1 %)46


Psychopharmacologic medications

Lithium

Hair loss is a possible adverse effect of lithiumcarbonate, and may be noticed within weeksor years after commencing therapy.11

Headington feels it is due to immediate anagenrelease. However, in those patients in whomthe onset of the hair loss may take years, thismechanism is less likely. A correlation be-tween hair loss and lithium blood level and/ordosage is suspected, but not established. Inmost reports, doses ranged from 0.4 to 1.5 g/day, with serum lithium assays between 0.5and 1.4 Meq/L.12–17

A review described 101 cases of lithiumr-elated hair loss in over 25 years of use.18 A 3-year survey of lithium-treated subjectsreported a 12% incidence of alopecia.13 About20% of patients on long-term lithium therapy,who had high lithium levels, reported hairthinning; 23% described their hair as also be-coming straighter.19

Patients on lithium who develop alopeciamust undergo a thyroid function assessment,since this drug is known for its ability to affectthe thyroid gland. Hypothyroidism (com-monly) and thyrotoxicosis (rarely) have beendescribed in patients on lithium therapy, andboth conditions may manifest with hair

Table 5.3Drug-induced telogen effluvium (incidence of 1–5%)46

Table 5.4Drug-induced telogen effluvium (incidence of more than 5%)46


Table 5.5Drug-induced telogen effluvium (exact incidence unreported)46


changes.20,21 There is a case report of alopeciaareata occurring during lithium therapy.22 Thisis probably coincidental.

Valproate

Valproic acid (VPA), once ingested, dissociatesin the gastrointestinal tract into a salt or ionicform, valproate. VPA and divalproex (a stablecombination of valproate sodium and valproicacid) may cause hair changes. A review of theliterature mentions 643 cases of valproatein-duced alopecia,18 with a 0.5%–12.0% reportedfrequency.23,24 Patients on VPA who develophair loss tend to have a high valproate bloodconcentration.25 It is not completely estab-

lished whether alopecia is dose-related, butusually dosage reduction leads to regrowth ofhair in individuals with valproate-associatedalopecia.26

Carbamazepine

There are 177 documented cases ofcarbamazepine-induced alopecia.18 With a re-ported incidence of 1.6% and 6%.27,28 A three-fold dose reduction of 200 mg/day helped onefemale patient.29 Carbamazepine and VPA pos-sibly have different mechanisms of hair loss,despite a documented decrease in serumamounts of zinc and copper caused by bothmedications.30 Some individuals may have an

Figure 5.2Telogen effluvium. A 63-year-old female onwarfarin showing general shedding. Hair lossis not as marked as in anagen effluvium. (a)Top view, with a slightly increased width ofhair-part. (b) Lateral view, illustrating markedthinning on the temporal area. (c) Pathologyof telogen effluvium, showing a dispropor-tionate number of telogen hairs.


increased genetic predisposition to medicinalalopecias.

Tricyclic/tetracyclic antidepressants

A few instances of diffuse hair loss associatedwith tricyclic antidepressants (TCA) have beendocumented. All TCA versions have been im-plicated with alopecia: amitriptyline,amoxapine, despiramine, doxepin, imi-pramine, nortriptyline, and protriptyline.31

The tetracyclic antidepressant drugmaprotiline and trazodone may also result inhair loss.31 However, none of the monoamineoxide inhibitors are known to cause alopecia.

Serotonin reuptake inhibitors

Several serotonin reuptake inhibitors can alsocause hair loss on rare occasions. Fluoxetineis the most frequently prescribed anti-depres-sant, and with this there are 725 documentedcases.18 Sertraline has been reported in 46 in-stances.32,33 and paroxetine in 30 subjects 18

The majority of these have a typical pattern ofreversible diffuse alopecia, with a 2–6 monthlatency period. Sometimes alopecia may de-velop 1.5 years following fluoxetine introduc-tion.34,35 In another case, a fluoxetine-inducedalopecia was still evident 1.5 years after drugdiscontinuation.36

Other anti-psychotics/anxiolytics

Haloperidol, olanzapine and respiridone havebeen documented as causing hair loss.Anxiolytic medicines of the barbiturate andbenzodiazepine classes, as well as zolpidem,generally do not result in alopecia.Clonazepam is one exception.31 Buspirone isalso associated with hair loss on rare occa-sions.31

Oral contraceptives

Telogen hair is lost 2–3 months after discon-tinuation of treatment with oral contracep-tives. Pathogenesis is probably similar to thatin post-partum hair loss.37 This is believed byHeadington to be a delayed anagen release.10

There is prolongation of the anagen phase, ow-ing to the estrogens. The utilization of low-dose estrogen contraceptives is onlyoccasionally associated with this effect.

Antihypertensive agents

Several anti-hypertensive agents are known tocause hair loss. Beta-blockers may have a di-rect toxic effect on the hair follicles. This side-effect is reversible once medication isterminated.

Captopril can also cause hair loss. It mayform a complex with zinc, and thus decreasezinc levels, particularly in those patients withrenal disease.38–40 Low zinc levels can causehair loss.

Topical ophthalmic beta-blockers

Topical ophthalmic beta-blockers can causehair loss. Hair loss is not confined to the scalpalone, but also extends to eyelashes and eye-brows. Females are more commonly affected.It occurs 1–24 months after treatment. Signifi-cant recovery is seen after 4–8 months from thetime use of the solution is discontinued.41

Interferons

Telogen effluvium occurs in 20–30% of pa-tients treated with interferons. There is no re-lationship between dosage and time of onsetor severity of hair loss. In some cases, telogenloss subsides despite continuing treatment.42


Keratin production interference

Thallium

Thallium is no longer used as a drug, but maybe ingested accidentally in rodent poisons orcontaminated foods. Thallium ingestion pro-duces changes in the matrix cells, with subse-quent disturbed keratinization. Intrafollicularthinning, accumulation of air bubbles in thehair shaft, breakage of the hair shaft and theinduction of telogen is seen in thallium alo-pecia. Available evidence indicates that thal-lium inhibits the utilization of cystine in theproduction of the keratin molecule. Acute poi-soning produces hair loss in 10 days, alongwith ataxia, fatigue, joint pains and weakness.Hair losses of several months’ to years’ dura-tion, with muscle aches, have been reported inchronic thallium intoxication.

Retinoids

Soriatane and accutane can produce brittle,dry, unmanageable, loosely anchored hairs.Retinoid-induced alopecia has a later onsetand is almost always reversible. It is due to ashortened anagen release, rather than an im-mediate anagen release, which is what is morecommonly seen with other drugs. However,just like any telogen effluvium, retinoids cancertainly unmask a tendency for androgeneticalopecia. The package insert for accutane men-tions hair loss. Diffuse hair loss is commonlyobserved during soriatane treatment, with evi-dent alopecia occurring in about 20% of pa-tients.31

Cholesterol-lowering agents

Agents that block cholesterol synthesisthrough a variety of mechanisms can disrupt

keratinization. Cholesterol is a component ofcellular lipids, and its synthesis and metabo-lism are essential for the production of normalepidermal structures. Triparanol, which hasbeen withdrawn from the market because ofcataract induction, can cause significant alo-pecia, loss of hair color and ichthyosis. Clofi-brate may occasionally produce hair loss.31

How to managedruginduced alopeciaIn cases where an effective therapeutic agentcauses alopecia and no appropriate alternativecan be found, an informed patient and physi-cian should discuss the risks and benefits ofcontinuing, stopping or changing the dose ormedication. The advantages and disadvan-tages of maintaining the drug must be re-viewed. Such choices are especially difficultwhen the offending agent is otherwise effec-tive. Similarly, the negative implications ofstopping or changing the regimen also need tobe considered. Decisions are based on alterna-tive medications and hair loss severity and itsemotional impact. More research may furtherclarify drug-induced hair-loss issues, and of-fer new therapeutic recommendations.

The use of topical 5% minoxidil solution fordrug-induced telogen effluvium in those caseswhen the offending drug cannot be terminatedor switched is certainly a therapeutic optionwe use at the University of British ColumbiaHair Clinic. Minoxidil tends to maintain hairsin anagen and convert telogen hairs intoanagen hairs more quickly. It certainly can beoffered to the patient. During the early conver-sion of telogen to anagen hairs, there is surgeof ‘telogen release’. Patients may temporarily


(for the first month of minoxidil application)experience more hair loss, shedding telogenhairs and subsequently replacing them withthe more desired anagen hairs. Patients shouldbe warned of this temporary setback.

For drug-induced anagen effluvium, topicalminoxidil 5% solution has been reported towork.43 We rarely need to use it, as the alopeciais usually reversible. The use of cooling scalpdevices is still controversial.44,45

References1. Reeves J. and Maibach H. Drug- and chemi-

cal induced hair loss, pp. 506–17. 1983;Washington DC: Horizon Books.

2. Ahmad S. Cimetidine and alopecia [letter].Ann Intern Med, 1979; 91(6):930.

3. Dunagin W.G. Clinical toxicity of chemo-therapeutic agents: dermatologic toxicity.Semin Oncol, 1982; 9(1): 14–22.

4. Delaunay M. [Cutaneous side effects ofantitumor chemotherapy]. Ann DermatolVenereal, 1989; 116(4):347–61.

5. J Hardman, Limbird L., Molinoff P., et al.Goodman & Gilman’s The PharmacologicalBasis of Therapeutics, 9th edn, 1996; NewYork: McGraw-Hill, Inc. 647–9.

6. Rook A. Some chemical influences on hairgrowth and pigmentation. Br J Dermatol,1965; 77:115–29.

7. Harms M. Alopecia and hair changesfollowing colchicine therapy. Hautarzt,1980; 31(3):161–3.

8. Blankenship M.L. Drugs and alopecia.Australas J Dermatol, 1983; 24(3):100–4.

9. Maceyko R.F., Vidimos A.T. and Steck W.D.Vasopressin-associated cutaneous infarcts,alopecia, and neuropathy. J Am AcadDermatol, 1994; 31(1):111–13.

10. Headington J.T. Telogen effluvium. Newconcepts and review [see comments]. ArchDermatol, 1993; 129(3):356–63.

11. Mortimer P.S. and Dawber R.P. Hair loss andlithium. Int J Dermatol, 1984; 23(9):603–4.

12. Dawber R. and Mortimer P. Hair loss duringlithium treatment [letter]. Br J Dermatol,1982; 107(1):124–5.

13. Orwin A. Hair loss following lithiumtherapy [letter]. Br J Dermatol, 1983;108(4):503–4.

14. Eustace D.P. Lithium-induced reaction[letter]. Br J Psychiatr, 1986; 148:752.

15. Kusumi Y. A cutaneous side effect oflithium: report of two cases. Dis Nerv Syst,1971; 32(12):853–4.

16. Yassa R. and Ananth J. Hair loss in thecourse of lithium treatment: a report of twocases. Can J Psychiatr, 1983; 28(2):132–3.

17. Jefferson J. Lithium and hair loss. Int DrugTher News, 1979; 14:23.

18. Pillans P.I. and Woods D.J. Drug-associatedalopecia. Int J Dermatol, 1995; 34(3): 149–58.

19. McCreadie R.G. and Morrison D.P. Theimpact of lithium in South-west Scotland. I.Demographic and clinical findings. Br JPsychiatr, 1985; 146:70–4.

20. Kirov G. Thyroid disorders in lithium-treated patients. J Affect Disord, 1998;50(1):33–40.

21. Freinkel R.K. and Freinkel N. Hair growthand alopecia in hypothyroidism. ArchDermatol, 1972; 106(3):349–52.

22. Silvestri A., Santonastaso P. and Paggiarin D.Alopecia areata during lithium therapy. Acase report. Gen Hosp Psychiatr, 1988;10(1):46–8.

23. Davis R., Peters D.H. and McTavish D.Valproic acid. A reappraisal of its pharmaco-logical properties and clinical efficacy inepilepsy. Drugs, 1994; 47(2): 332–72.

24. McKinney P.A., Finkenbine R.D. andDeVane C.L. Alopecia and mood stabilizertherapy. Ann Clin Psychiatr, 1996;8(3):183–5.

25. Klotz U. and Schweizer C. Valproic acid inchildhood epilepsy: anticonvulsive efficacyin relation to its plasma levels. Int J ClinPharmacol Ther Toxicol, 1980; 18(10): 461–5.


26. Henriksen O. and Johannessen S.I. Clinicaland pharmacokinetic observations onsodium valproate—a 5-year follow-up studyin 100 children with epilepsy. Acta NeurolScand, 1982; 65(5):504–23.

27. Mattson R.H., Cramer J.A. and Collins J.F. Acomparison of valproate with carbamazepinefor the treatment of complex partial seizuresand secondarily generalized tonic-clonicseizures in adults. The Department ofVeterans Affairs Epilepsy Cooperative StudyNo. 264 Group [see comments]. New Engl JMed, 1992; 327(11):765–71.

28. Verity C.M., Hosking G. and Easter D.J. Amulticentre comparative trial of sodiumvalproate and carbamazepine in paediatricepilepsy. The Paediatric EPITEG Collabora-tive Group. Dev Med Child Neurol, 1995;37(2):97–108.

29. Ikeda M., Maruyama K., Nobuhara Y., et al.Cytoprotective effects of 4,6-bis(1H-pyrazol-1-yl)pyrimidine and related compounds onHCI.ethanol-induced gastric lesions in rats.Chem Pharm Bull (Tokyo), 1997; 45(3):549–51.

30. Suzuki T., Koizumi J., Moroji T., et al. Effectsof long-term anticonvulsant therapy oncopper, zinc, and magnesium in hair andserum of epileptics. Biol Psychiatr, 1992;31(6):571–81.

31. Physician Desk Reference. 1999; Montvale,NJ: Medical Economics.

32. Bourgeois J. Two cases of hair loss aftersertraline use. J Clin Psychopharmacol,1996; 16(1):91–2.

33. McDougle C.J., Brodkin E.S., Naylor S.T., etal. Sertraline in adults with pervasivedevelopmental disorders: a prospectiveopen-label investigation. J ClinPsychopharmacol, 1998; 18(1):62–6.

34. Ogilvie A.D. Hair loss during fluoxetinetreatment [letter]. Lancet, 1993; 342(8884):1423.

35. Jenike M.A. Severe hair loss associated withfluoxetine use [letter]. Am J Psychiatr, 1991;148(3):392.

36. Gupta S. and Major L.F. Hair loss associatedwith fluoxetine [letter]. Br J Psychiatr, 1991;159:737–8.

37. Wong R.C. and Ellis C.N. Physiologic skinchanges in pregnancy. J Am Acad Dermatol,1984; 10(6):929–40.

38. Brodin M.B. Drug-related alopecia. DermatolClin, 1987; 5(3):571–9.

39. Smit A.J., Hoorntje S.J. and Donker A.J. Zincdeficiency during captopril treatment.Nephron, 1983; 34(3):196–7.

40. Leaker B. and Whitworth J.A. Alopeciaassociated with captopril treatment [letter].Aust NZ J Med, 1984; 14(6):866.

41. Fraunfelder F.T., Meyer S.M. and MenackerS.J. Alopecia possibly secondary to topicalophthalmic beta-blockers [letter]. JAMA,1990; 263(11):1493–4.

42. Tosti A., Misciali C., Bardazzi F., et al.Telogen effluvium due to recombinantinterferon alpha-2b. Dermatology, 1992;184(2):124–5.

43. Duvic M., Lemak N.A., Valero V., et al. Arandomized trial of minoxidil in chemo-therapy-induced alopecia. J Am AcadDermatol, 1996; 35(1):74–8.

44. Goldhirsch A., Kiser J., Ross R., et al. [Preven-tion of cytostatic-related hair loss byhypothermia of a hairy scalp using a coolingcap]. Schweiz Med Wochenschr, 1982;112(16):568–71.

45. Katsimbri P., Bamias A. and Pavlidis N.Prevention of chemotherapy-inducedalopecia using an effective scalp coolingsystem. Eur J Cancer, 2000; 36(6):766–71.

46. Litt J. (ed.). Drug eruption reference manual.Millennium edn. 2000; New York: TheParthenon Publishing Group.

Telogen effluvium (TE) is discussed at lengthin Chapter 5 as it relates to medications. How-ever, TE can occur as a result of a systemic dis-turbance. Metabolic imbalances, such as thosedescribed below, may cause an immediateanagen release (IAR) as described byHeadington.1 Follicles that would normallycomplete a longer cycle by remaining inanagen prematurely enter telogen and are sub-sequently shed 2–3 months after the offendinginsult has been instituted.

Acute telogen effluviumsecondary to a knowncause

FeverFever can cause alopecia 8–10 weeks after thebout. It can be quite severe, is not total and isusually reversible. Fever, which augmentsmetabolic demands, would probably impairthe ability of the rapidly multiplying follicularmatrix cells to proliferate normally.2 Endog-enous pyrogens, such as interferons a and ?,may slow down matrix proliferation.2

Interferons a and ? have been shown to de-crease epithelial proliferation and to affectfollicular matrix cells directly.3,4

Postpartum

During pregnancy anagen is prolonged, and, asa result, percentages of anagen hairs increaseduring pregnancy from 84% in the first trimes-ter to 94% in the final trimester.5,6 After partu-rition, there is a delayed anagen release, asdescribed by Headington.1 Follicles entercatagen and then telogen. Increased hair lossmay occur 1–4 months after childbirth, andmay continue for several months.7,8 There maybe aggravating factors, such as psycho-physi-cal trauma, blood loss, and low plasma pro-tein. Full recovery is usual in 4–12 months.8,9

Loss is more marked in the frontal and tempo-ral regions, but may be generalized (see Figure6.1). It is never total. Telogen effluvium tendsto be less severe in subsequent pregnancies.5

Crash dieting/hypo-proteinemia

Acute voluntary starvation in young women isnot uncommon, and must be questioned ontaking history. Obese adolescents sometimesinflict on themselves a diet of salads and fruitslacking in protein. This also can lead to hairloss. Rooth and Carlstrom10 noted hair loss,edemas and weakness in 20 obese patients ona 200 calorie diet or on a total fast; but thesechanges were prevented by the addition of asmall amount of protein.

6 Telogen effluvium: acute and chronic


Thyroid influences

There is no consistent correlation between thedegree and duration of hypothyroidism andthe severity of hair loss.9 Diffuse alopecia maysometimes be the first or only cutaneous signof hypothyroidism. The hair loss is diffuse. Athorough history regarding weight gain, coldtolerance, and energy level is important. Pa-tients usually respond to thyroxine replace-ment11 unless the problem has been of verylong duration and some follicles have atro-phied. Severe thyrotoxicosis can also causediffuse alopecia of the scalp.12

Iron deficiency

Iron deficiency with or without anemia hasbeen reported to be present in as many as 72%

of women with diffuse alopecia13. Iron defi-ciency even in the absence of anemia (lowhemoglobin) has also been reported by Hard.14

Because androgenetic alopecia and iron defi-ciency are both common conditions in women,the two not infrequently occur together. It ispossible that telogen effluvium from iron defi-ciency may unmask an underlying androge-netic alopecia.

Major interventions and pro-

longed anesthesias

Blood loss and surgery with prolongedanesthesia may cause telogen effluvium15,16

(see Figure 6.2). Desai and Roaf17 report telogeneffluvium in a patient after prolonged surgery,with regrowth after 4 months. This is clearlydifferent from the patchy alopecia occurringafter localized pressure from surgery.18

Figure 6.1A 30-year-old female presenting with a one-month history of abrupt diffuse hair sheddingcommencing 6 weeks after the birth of her last child. (a) Side view, showing fronto-temporalthinning. (b) Top view, showing a widening of the central part.

Telogen effluvium: acute and chronic 149

Malignant disease, renal failure,

hepatic disease and malabsorption

Hodgkin’s disease may present with telogen ef-fluvium as its first sign.19 This kind of hair lossis also referred to as ‘toxic telogen effluvium’.15

Scalp hair can become dry, brittle andsparse with chronic renal disease.20,21 Theremay thinning of body hair, including pubic oraxillary hair.

Hepatic disease has been reported to beassociated with diffuse alopecia. Zaun22

studied 53 patients who had either hepati-

tis, cirrhosis or fatty liver. He found in-creased telogen counts in 34 patients andevident hair loss in 11. The liver is the majorsite of amino acid inter-conversion. It hasbeen suggested that disturbed liver metabo-lism of cystine and methionine may be re-lated to alopecia.22

When sparse hair and growth retardationare associated with chronic frequent loosepale and bulky stools, malabsorptionshould be investigated.9 Inflammatorybowel disease has been reported to be asso-ciated with hair loss, particularly withCrohn’s disease.23

Figure 6.235-year-old female with a 6-week history ofabrupt diffuse hair shedding commencing 8weeks after bowel surgery. (a) Side view,showing marked thinning. (b) Top view,showing thinning of the central part. (c)Occipital view, displaying a significantwidening of the parting.


Psychological stress, acute

anxiety, and depression

Acute anxiety or depression may cause atelogen effluvium.15. There is literature thatdoes support the notion of psychogenictelogen effluvium,24,25 but the paucity of re-ports suggests that it is uncommon.2

Medications

These are discussed extensively in Chapter 5.

Chronic telogen efflu-vium of unknown causein the female patient

‘Woman is herself constantly doing somethingto her hair. She even carries a little mirror eve-rywhere with her with the principal object oflooking at her hair to see that it is all right.Obviously, it is a source of anxiety to her.’—CBerg, 195126

Frequently encountered in dermatologicalpractice is the woman who presents withchronic diffuse hair loss of unknown cause.Women who present with this type of hair lossfrequently are upset and want a satisfactoryexplanation for their problem.

Diffuse cyclic hair loss in women was firstdescribed by Guy et al. in 1959.27 They de-scribe a ‘not uncommon condition’ presentingwith transitory episodes of shedding lastingseveral weeks with no apparent cause. Thetypical patient is a ‘vigorous otherwise healthywoman’ who presents with diffuse hair lossthat is cyclic and reversible. They considered

this to be a physiological phenomenon. Amodern term for this condition, coined byWhiting, would be Chronic Telogen Effluvium(CTE).28,29 CTE is not uncommon. It is a form ofdiffuse hair loss affecting the entire scalp forwhich no obvious cause can be found. It usu-ally affects women of 30 to 60 years of age whogenerally have a full head of hair prior to theonset of shedding. The onset is usually abrupt,with or without a recognizable initiating fac-tor. The degree of shedding is usually severein the early stages, and the hair may come outin handfuls. Females present with a diffusethinning, reduction in pony tail diameter, in-creased parting widths over the entire scalpand increased telogen shedding, frequentlywith a positive pull test. CTE contrasts withclassic acute telogen effluvium by its persist-ence and its tendency to fluctuate for a periodof years. Patients are particularly troubled by

Figure 6.3A histological transverse section of chronictelogen effluvium, showing a disproportion-ate number of telogen hairs on transversesection (courtesy of Dr Magdalena Martinka).


the continuing hair loss, and fear total bald-ness. Repeated reassurance that the conditiondoes not cause complete baldness is necessary.CTE does appear to be self-limiting in the longrun. Scalp biopsies show an increase percent-age of telogen hairs (see Figure 6.3). No appar-ent cause can be found.

Trueb et al.30 feel that in approximately 30%of cases of chronic diffuse loss of scalp hairwith a duration of at least 6 months no under-lying abnormality can be found. Typically thisoccurs in women, starting abruptly without arecognizable initiating factor, and involvingthe entire scalp area in increased shedding oftelogen hair. With the exception of bitemporalrecession, hair thinning is usually discretewhich contrasts to the intense emotional over-tones brought about by this situation. This mayinitially lead to the differential diagnosis ofpsychogenic pseudoeffluvium. Owing to thesynchronization of the hair cycle, the amountof shed hair here is greater than that inandrogenetic alopecia, while miniaturizedhairs are not a feature of the disorder. Overlapwith androgenetic alopecia and/or psycho-genic pseudo-effluvium is not uncommon.Scalp dysesthesia or a sensation of pain in thehair (trichodynia) is an accompanying symp-tom in a significant proportion of cases, andcorrelates better with emotional upset thanwith actual hair loss.

In certain cases of CTE, laboratory testingmay often show ferritin levels below the nor-mal male reference range of 25–30 µg/l.31 Thenormal ferritin levels for men and women dif-fer in most laboratories. Usually normal refer-ence levels for women are considerably lower,as a large number of the ‘normal control’ groupare menstruating women. Van Neste andRushton feel that topping ferritin levels to atleast the lower limit for men may correct thisproblem to a certain degree.31 These authorsalso feel that hemoglobin levels should be

above the lower male range (greater than 13 g/dl) to maintain the normal anagen to telogenratio of 9:1. Nutritional supplements (exceptfor iron when indicated) are not recom-mended. Sufficient nutrition is obtained in anormal diet. There is evidence that the takingof excessive and unnecessary supplementscould actually induce telogen effluvium.31 Forexample, large amounts of zinc in supple-ments (> 25 mg/day) may affect iron absorp-tion adversely.31

At the University of British Columbia HairClinic our approach to CTE is: (1) Confirm thediagnosis with a 4 mm scalp biopsy with trans-verse sectioning (see Figure 6.3). (2) Make sureyou have ruled out any underlying cause oftelogen effuvium. (3) Top up ferritin levels togreater than 30 µg/1. The patient should bemonitored every 4–6 months with repeat ferri-tin levels until they have reached this thresh-old level. (4) Topical minoxidil 5% solutiontwice daily. We have found that topicalminoxidil solution is beneficial in maintain-ing hairs in anagen and increasing conversionof hairs from telogen to anagen. Patients mustbe warned that initially there may increasedshedding with topical minoxidil solution, asone must temporarily shed more telogen hairsto increase the eventual percentage of anagenhairs. We feel that it is likely that topping upferritin levels will maximize the hair growthpotential of topical minoxidil in those men-struating women with low ferritins. However,further studies with double-blinded placebocontrols analyzing the single and combina-tional benefits of supplemental iron and topi-cal minoxidil solution for CTE are needed.

CTE is usually reversible. However, in thosewomen who have a genetic predisposition toandrogenetic alopecia (AGA), CTE may un-mask their AGA, and hair will not necessarilygrow back to the same density as before.


References1. Headington J.T. Telogen effluvium. New

concepts and review. Arch Dermatol, 1993;129(3):356–63.

2. Fiedler V. Diffuse alopecia: telogen hair loss.In Disorders of hair growth, ed. E.Olsen, pp.241–252. 1993, McGraw-Hill, Inc.: NewYork.

3. Yaar M., Karassik R.L., Schnipper L.E. andGilchrest B.A. Effects of alpha and betainterferons on cultured humankeratinocytes. J Invest Dermatol, 1985;85(1):70–4.

4. Tabibzadeh, S.S., P.G. Satyaswaroop andP.N.Rao. Antiproliferative effect of inter-feron-gamma in human endometrial epithe-lial cells in vitro: potential local growthmodulatory role in endometrium. J ClinEndocrinol Metab, 1988; 67(1):131–8.

5. Pecoraro V. The normal trichogram ofpregnant women. In Advances of biology ofthe skin, ed. W.Montagna, p. 203. 1969,Pergamon Press: Oxford.

6. Lynfield Y. Effect of pregnancy on thehuman hair cycle. J Invest Dermatol, 1960;35: 323–7.

7. Schiff B. Study of postpartum alopecia. ArchDermatol, 1963; 87:609.

8. Skelton J. Post partum alopecia. J ObstetGynecol, 1966; 94:125.

9. Rook A. Diffuse alopecia: Endocrine,metabolic and chemical influences on thefollicular cycle. In Diseases of the hair andscalp, ed. A.Rook, pp. 136–66. 1991,Blackwell Scientific Publications: Oxford.

10. Rooth G. and S.Carlstrom. Therapeutic fasting.Acta Med Scand 1970; 187(6): 455–63.

11. Freinkel R.K. and N.Freinkel. Hair growthand alopecia in hypothyroidism. ArchDermatol, 1972; 106(3):349–52.

12. Williams R. Thyroid and adrenal interrela-tions with special reference to hypotrichosisand axillairis in thyrotoxicosis. J ClinEndocrinol Metab, 1947; 7:52.

13. Rushton D.H., Ramsay I.D., James K.C., et al.Biochemical and trichological characteriza-tion of diffuse alopecia in women. Br JDermatol, 1990; 123(2):187–97.

14. Hard S. Non-anemic iron deficiency as anetiologic factor in diffuse loss of hair of thescalp in women. Acta Derm Venereol, 1963;43:562–9.

15. Camacho F. Alopecias due to telogeneffluvium. In Trichology: diseases of thepilosebaeous follicle, ed. F.Camacho, pp.403–9. 1997, Aula Medica Group SA:Madrid.

16. Thompson J.S. Alopecia after ileal pouch-anal anastomosis. Dis Colon Rectum, 1989;32(6):457–65.

17. Desai S.P. and E.R.Roaf. Telogen effluviumafter anesthesia and surgery. Anesth Analg,1984; 63(1):83–4.

18. Abel R. Post operative (pressure) alopecia.Arch Dermatol, 1960; 81:34.

19. Klein A.W., R.I.Rudolph and J.J.Leyden.Telogen effluvium as a sign of Hodgkindisease. Arch Dermatol, 1973; 108(5):702–3.

20. Lubach D. [Dermatological changes inpatients receiving long-term hemodialysis].Hautarzt, 1980; 31(2):82–5.

21. Scoggins R. Cutaneous manifestations ofhyperlipidemia and uraemia. Postgrad Med1967; 41:357.

22. Zaun H. Wachstumsstorungen der kopfhaareals folge von hepatopathien. Arch Klin ExpDerm, 1969; 235:386–93.

23. Schattner A. and Y.Shanon. Crohn’s ileocoli-tis presenting as chronic diffuse hair loss. J RSoc Med, 1989; 82(5):303–4.

24. Kligman A. Pathologic dynamics of humanhair loss. Arch Dermatol, 1961; 83:175–98.

25. Dahlin P.A., J.George and J.C.Nerette.Telogen effluvium: hair loss after spinal cordinjury. Arch Phys Med Rehabil, 1984; 65(8):485–6.

26. Berg C. The unconscious significance of hair.1951, London: George Allen & Unwin Ltd.

27. Guy W. Diffuse cyclic hair loss in women.Arch Dermatol, 1959; 81:83–5.


28. Whiting D.A. Chronic telogen effluvium.Dermatol Clin, 1996; 14(4):723–31.

29. Whiting D.A. Chronic telogen effluvium:increased scalp hair shedding in middle-aged women. J Am Acad Dermatol, 1996;35(6): 899–906.

30. Trueb R.M. [Idiopathic chronic telogeneffluvium in the woman]. Hautarzt, 2000;51(12):899–905.

31. Van Neste D.J. and D.H.Rushton. Hairproblems in women. Clin Dermatol, 1997;15(1):113–25.

IntroductionCicatricial (scarring) alopecia represents a di-verse group of diseases characterized by lackof follicular ostia (Figure 7.1) and irreversiblealopecia. The terms cicatricial and scarring areused interchangeably. A basic knowledge offollicular anatomy is important in the under-standing of scarring alopecias, because the lo-cation of the inflammatory infiltrate is crucialin determining irreversibility of alopecia.Follicular stem cells are located in the bulgearea where the arrector pili muscle inserts intothe follicles. These cells migrate down into the

hair follicle, and subsequently differentiateinto the various layers of the hair follicle. Asthe hair cycles through anagen, catagen, andtelogen, there is a permanent upper portion ofthe hair follicle and a non-permanent lowerportion, (see Chapter 1, Figure 1.8). When theinflammation is located deep, in the vicinityof the non-permanent portion, a scarring alo-pecia is unlikely to develop. If the inflamma-tion is located within the permanent portion,particularly around the stem cells of the bulgearea and the infundibulum, then a cicatrizingalopecia is more likely to occur. Follicles canbe saved from irreversible damage if this peri-bulge infiltrate can be controlled. Scarringalopecias are true trichologic emergencies.

ClassificationClassification schemes for cicatrizingalopecias have been based upon clinical, his-tological or proposed pathogenic criteria.1,2

Clinically, scarring alopecias are categorizedas either inflammatory or non-inflammatory.The non-infectious inflammatory scarringalopecias include chronic cutaneous lupuserythematosus (CCLE), lichen planopilaris(LPP) and folliculitis decalvans (FD). CCLEand LPP are characterized by keratoticfollicular papules, while FD presents with pus-

7 Cicatricial (scarring) alopecias

Figure 7.1Lack of follicular ostia is the hallmark sign ofscarring hair loss.


tules. The non-inflammatory scarringalopecias are pseudopelade of Brocq (PP) andfollicular degeneration syndrome, develop-mental abnormalities, genetic disorders, andneoplastic infiltrates. A second scheme, basedupon pathology, classifies the cicatrizingalopecias according to inflammatory infiltratecell type: lymphocyte or neutrophil. The lym-phocytic-mediated disorders include CCLE,LPP, and PP, while the neutrophilic mediatedconditions include FD, dissecting cellulitis,and acne keloidalis. This pathologically basedclassification system assists the clinician bothin therapeutic decision-making and in gaininga better patho-physiological understanding ofthese disorders.

Scarring alopecias can also be classified asprimary or secondary.3 Primary scarring alo-pecia is defined microscopically as preferen-tial destruction of follicular epithelium and /or its associated adventitial dermis with rela-tive sparing of the interfollicular reticular der-mis. In primary scarring alopecias, the hairfollicle is the primary target of destruction.CCLE, LPP, PP, and FD are primary alopecias.Secondary scarring alopecias result fromevents outside the follicular unit that impingeupon and eventually eradicate the follicle. Inthese cases, the hair follicle is simply an ‘in-nocent bystander’. Follicular destruction isnot the primary event. Sarcoidosis andmorphea are examples of secondary scarringalopecias.

Sperling has coined the term central, cen-trifugal scarring alopecia (CCSA).4 This group-ing includes pseudopelade, folliculardegeneration syndrome, and folliculitisdecalvans. These conditions are centered onthe crown or vertex and progress in a roughlysymmetrical pattern, with disease activity lim-ited to the peripheral zone surrounding thealopecic zone.

The biopsy for cicatrizing

alopecias

A scalp biopsy is crucial in the diagnosis of acicatrizing alopecia. First, a biopsy site is se-lected. This site should be representative of ac-tive disease (primary lesion), preferably with apositive pull test and a paucity of follicular ori-fices. A less cosmetically important site, suchas the posterior scalp, is preferable. The area ismarked with a red marker, and lidocane withepinephrine is infiltrated into the area. Tenminutes is then allowed to take advantage ofthe vasoconstrictive effect of the epinephrine.The hair in the biopsy site is clipped. Thepunch is placed parallel to the direction of thehairs and inserted to the depth of the bevel.The biopsy should include the subcutaneousfat, because this is the location of terminalanagen hair bulbs. Two 4 mm punch biopsiesare performed. One is submitted for transversesectioning and the other is divided in half andsubmitted for both direct immunofluorescenceand longitudinal sectioning. Special stains,such as PAS and elastin, may also be re-quested. Pressure is then applied to the biopsysite with a cotton applicator that may be satu-rated with aluminium chloride. The biopsysite is then closed with a blue 4.0 nylon su-ture. The blue suture allows for easier recogni-tion and differentiation from hair duringsuture removal 7 to 10 days later.

Lymphocytic-mediatedcicatricial alopecias

Clinical featuresThe three most common lymphocytic-medi-ated cicatricizing alopecias are CCLE, LPPand PP.

Cicatricial (scarring) alopecias 157

CCLE accounts for 30 to 40% of patientswith scarring alopecias and has a definite fe-male predilection. Very few patients (< 10%)who present with CCLE ever progress to sys-temic LE. However, an ANA is recommendedfor all patients with CCLE. In a series of 86 pa-tients with CCLE of a mean duration of 15.1years, 35 per cent (30/86) had scarring alo-pecia.5 A published report6 of 89 patients withCCLE showed that 34% had scalp involve-

ment. More than half these patients had scalpinvolvement at the onset of the condition. In asmaller study by Callen, 7/17 patients (41%)with CCLE had cicatricial scalp involvement.7

In three out of the seven, the scalp was themost prominent finding.7 This common in-volvement of the scalp is intriguing, becausethe scalp is a relatively light-protected area. In10% of patients with CCLE, scalp involvementmay be the sole manifestation of LE.8 Age of

Figure 7.2Chronic cutaneous lupus erythematosus of the scalp. (a) and (b). A 23-year-old female withpainful erythematous atrophic plaques. (c). A 60-year-old female with frontal scalp involve-ment. (d). Follicular hyperkeratosis occurring centrally within a plaque of lupus erythemato-sus.


onset of scalp CCLE is usually at between 20and 60 years of age. Patients present with ery-thematous plaques of alopecia, atrophy, tel-angiectasia and follicular hyperkeratosis(Figure 7.2). Scalp lesions begin as erythema-tous papules or irregular small scaly plaques.These lesions slowly progress to large ery-thematous, edematous plaques. At this pointpatients may experience loss of hair. This ini-tial alopecia induced by follicular inflamma-tion is potentially reversible. A prominentthickened and adherent scale may develop,which when removed reveals keratinous plugson its under-surface. These keratinous plugsare from the follicular openings, and representfollicular hyperkeratosis. Follicular hyperk-eratosis is more active in the center of a plaque,a clue to help distinguish CCLE from LPP (Fig-ure 7.2d). As the lesion expands, the centralerythema fades and the surface flattens.Hypopigmentation and depigmentation beginto appear. Central atrophy and telangiectasiaeventually become prominent, and scarringdevelops. With continued spread of the dis-ease, large, white atrophic scarred alopecicplaques will predominate over their inflamma-tory precursors. There is also increased curli-ness of hairs in scarred areas, owing totorsional within the hair follicle. In addition,normal anagen hairs can easily be pulled outof the scalp, a characteristic feature of the scar-ring alopecias.

The term lichen planopilaris was first intro-duced in 1895 by Pringle,9 who described theassociation of lichen planus with follicularkeratotic lesions. In 1915, Graham-Little10 de-scribed folliculitis decalvans et atrophicans orfollicular scalp lesions resulting in cicatricialalopecia associated with follicular keratoticlesions at other sites. These two presentationsare now considered variants of lichen planus.A clinical triad of classic plaquetype lichen

planus, spinous or acuminate lesions, and alo-pecia of the scalp or other hairy areas has beendescribed.11 It was felt 40 years ago that onehad to have this triad to make a diagnosis ofLPP. This view is limited, and fails to accountfor the majority of intermediate cases. There isa spectrum of LPP. Mehregan et al.12 showedthat 50% of their series of 45 patients withscalp LPP had strictly scalp involvement only.Seven per cent had either axillary or groin in-volvement, 7% nail involvement, 27% mucousmembrane involvement and 40% glabrousskin involvement. Clearly, patients with scalplichen planus should be followed up to assesswhether lichen planus develops elsewhere(Figures 7.3h, 7.3i and 7.3j). The whole skinsurface, the oral mucosa and the nails must beexamined. Of all patients who have lichen pla-nus, a series of 807 patients showed that only10 (< 1%) had scalp involvement.13

LPP accounts for 30–40% of scarringalopecias. It usually occurs between 30 and 70years of age, and a female predominance (2:1)has been noted. LPP is usually an insidiousprocess evolving over several years, with a pre-dilection for areas of greater hair density, suchas the occipital scalp in men with AGA (Fig-ures 7.3b and 7.3c). Follicular hyperkeratosisis present at the periphery of the plaques,rather than centrally (Figures 7.3a), and ulcera-tions may even develop (Figure 7.3d). Pruritusand tenderness are often a prominent feature,and anagen hairs can be extracted with gentlehair-pulling. Lesions typical of lichen planusdo not occur on the scalp. LPP may be verywidespread, with its extent not clearly appar-ent unless the scalp is shaved (Figures 7.3e,7.3f, 7.3g). Occasionally drugs such as gold14

or mepacrine (atabrine)15 can trigger scalp li-chen planus and cause irreversible hair loss.Tufted folliculitis consisting of several hairshafts emerging from a single ostium can also


Figure 7.3Lichen planopilaris (LPP). (a) Follicularhyperkeratosis at the periphery of erythema-tous alopecic areas. (b) and (c) LPP affectingthe spared areas of male androgenetic alo-pecia. (b) Showing active inflammation. (c)Burnt out LPP. (d) Ulcerative lesion of LPP ofthe scalp. (e) Extensive case of LPP at theback of the scalp.


(f) and (g). Close-up after the head has been shaved, showing marked involvement of much ofthe scalp. (h), (i), (j). LPP in a 45-year-old male with scarring alopecia as well as acuminatelesions on the arms and lichen planus-like lesions in the groin. This fits well with Graham-Little disease. (k). Tufting of hairs in LPP.


Figure 7.4Pseudopelade of Brocq (a). Scarring hair lossaffecting central portion of the scalp. (b) A 5-year-old with pseudopelade (Brocq). (c), (d),(e) An 8-year-old boy with scatteredpseudopelade (Brocq).


(f) and (g) PP progressing over 10 years in a40-year-old male. (h) PP affecting the areaspared by androgenetic alopecia. (i) PPaffecting the area most affected byandrogenetic alopecia and mimickingandrogenetic alopecia. (j) pp affecting tnebeard area.


occur in LPP (Figure 7.3k). Tufting is commonas an endstage phenomenon in many scarringalopecias, and occurs because the infundibu-lar epithelium of damaged follicles often healsso as to cause the formation of a common largeinfundibulum. This is known as polytrichia.16

There is a variant of LPP, post-menopausalfrontal fibrosing alopecia.17–19 Kossard has de-scribed an entity occurring in postmenopau-sal women presenting with perifollicularerythema along the marginal hairline, pro-ducing a frontal fibrosing hair loss extendingto the temporal and parietal hair margins.Eyebrow loss was described in 13/16women.19 Histological findings were indistin-guishable from LPP.

In 1885, Brocq of Paris described what laterbecame known as Pseudopelade19a. Pelade isthe French word for alopecia areata (AA).Pseudopelade refers to ‘like alopecia areata butnot alopecia areata’. In pseudopelade (Brocq),the follicular ostia are not present while in AAthey are most certainly present. Brocq subse-quently admitted that this term does confusethe Iiterature19b,19c. Pseudopelade (Brocq)(which is referred to as PP in this text) is re-garded by most as a condition in which de-struction of follicles leading to permanentpatchy baldness is not accompanied by anyclinically evident inflammatory pathology.End-stage LPP or CCLE may mimic an earlypseudopelade (Brocq) as discussed below.

PP is an idiopathic disorder, usually of adult-hood. However, PP in children has been de-scribed. This author has seen at least 3 cases inchildren under the age of 10 (Figures 7.4b-e).Braun-Falco et al. reported an incidence of 4/142 (4.35%) cases of PP under the age of 11 andnine patients (9.6%) in the age range of 11–20.20

PP presents with small, irregular, asymmetrical,ivory porcelain white patches devoid offollicular units. This has been classically de-scribed as ‘footprints in the snow’. There is

controversy as to whether PP is a distinct entityor is effectively the same as end-stage CCLE orLLP.21 Detailed studies by Braun-Falco et al.20,22

strongly support the idea that pseudopelade canexist as a distinct entity. His group described94/142 (66.2%) patients with PP without anyprevious underlying condition. PP is usuallyasymptomatic and without inflammation. Oc-casionally there may be erythema and mild pru-ritus. The parietal and vertex areas of the scalpare primarily involved (Figures 7.4a and 7.4b).Occasionally PP may affect the beard area andnot just the scalp (Figure 7.4j).23 The course isextremely variable. In the majority of cases, ex-tension of the process takes place only veryslowly (Figures 7.4f and 7.4g). The course is of-ten protracted and prolonged. Indeed, after 15–20 years the patient may still be able to arrangehis/her hair to conceal the patches effectively.However, in some cases, extension occurs morerapidly, and exceptionally there may be almosttotal baldness after 2 to 3 years. Occasionallythe pattern of hair loss of PP can mimicandrogenetic alopecia as described byZinkernagel et al.,24 and the diagnosis of PP maybe missed (Figure 7.4i). As with othercicatrizing alopecias, anagen hairs are easily ex-tracted. A form of central centrifugal scarringalopecia in African-Americans, also known asfollicular degeneration syndrome (FDS), over-laps significantly with PP with marked non-in-flammatory cicatricial alopecia on the top of thescalp in black patients.25,26 Although initiallythought to be a consequence of hair-care prac-tices, it is now believed to represent an idi-opathic disorder unrelated to trauma or haircosmetics. Sperling believes the main etiologyfor FDS is that the inner root sheathdesquamates prematurely far below the level ofthe isthmus not only in alopecic areas but evenin non-inflamed follicles or the clinically nor-mal scalp of affected individuals (Figure 7.5).


Figure 7.5Central centrifugal scarring alopecia (follicular degeneration syndrome) in African-Ameri-cans. (a) Black female with significant alopecia. (b) Close-up showing obliteration of follicularostia. (c) Black male with significant alopecia. (d) Close-up of patient illustrating lack offollicular ostia.


Some clinical pearls can be helpful in es-tablishing a diagnosis (Figure 7.6). First, iffollicular hyperkeratosis is present, a centrallocalization tends to occur in CCLE, while aperipheral distribution is seen in LPP. Second,the most likely diagnosis is PP if the scarringalopecia is non-inflammatory. Finally, if pus-tules are present, then FD is the most likelydiagnosis.

Pathology

The histopathology of CCLE reveals follicularvacuolar interface changes, a superficial anddeep perivascular and periadnexal lym-phocytic infiltrate, loss of sebaceous epithe-lium, and fibrosis (Figure 7.7). Perifollicularinflammation is most severe at the level of theinfundibulum, and inflammatory cells mayinvade the follicular epithelium. The presenceof a focally thinned epidermis, a thickenedbasement membrane zone and an increaseddermal mucin helps support the diagnosis ofCCLE. Pigment incontinence is present. Directimmunofluorescence demonstrates granulardeposits of C3 of IgG distributed along the der-mal-epidermal junction.1

The lymphocytic infiltrate of LPP islichenoid, with a characteristic perifollicularinterface dermatitis (Figure 7.8). Other featuresinclude loss of sebaceous epithelium andmarked perifollicular lamellar fibrosis. Inflam-mation affects the upper portion of the folli-cle, but may extend down the length of thefollicle. Pigment incontinence is present.

Figure 7.6Algorithm for diagnosis ofmajor non-infectiousscarring alopecias.

Figure 7.7Pathology of lupus erythematosus showingperi-adnexal and perivascular lymphocyticinfiltration with follicular hyperkeratosis.


Perivascular and peri-eccrine infiltrates areusually not present, as in LE. There may alsobe tufted folliculitis in the upper portion of theepidermis (Figure 7.9). Direct immunofluores-cence may demonstrate grouped globular IgMcytoid bodies in follicular epithelium.

The pathology of PP depends on disease du-ration. In the early stages, a peri-infundibularlymphocytic infiltrate is present beneath a nor-mal epidermis. As PP progresses, the epider-mis becomes atrophic, rete ridges vanish, andsebaceous glands and hair follicles are obliter-ated. Pigment incontinence is less evidentthan in LE or LPP. The end stage of PP is char-acterized by marked scarring and the absenceof an inflammatory infiltrate. Directimmunofluoresence is negative.

Special staining techniques may help in es-tablishing a diagnosis of a scarring alopecia.Elastin staining demonstrated normal or abun-dant elastic tissue in PP, while in LE and LPPthe quantity of elastin is significantly dimin-

Figure 7.9Numerous hairs exiting from one infundibu-lum which clinically appears as polytrichiaor tufted folliculitis. (Courtesy of DrMagdalena Martinka.)

Figure 7.8(a), (b) and (c). Pathology of lichenplanopilaris displaying the characteristicfollicular lymphocytic interface dermatitis.(Courtesy of Dr Magdalena Martinka.)


7.10 dividing entities into lymphocytic- versusneutrophilic-mediated. Folliculitis decalvansis neutrophilic-mediated (Figure 7.11), andwill be described below.

Differential diagnosis

Scalp psoriasis has the presence of follicularostia and the lack of follicular plugging andatrophy. However, there are reported cases ofscarring alopecia in severe scalp psoriasis.28 In-flammatory changes in the infundibular areaof the follicle in psoriasis may disruptfollicular stem cells and result in scarring alo-pecia. Tinea capitis can be scarring, but againthere is no follicular plugging or atrophy. Apotassium hydroxide preparation and/or cul-ture will help confirm the diagnosis.Keratoacanthomas and squamous cell carcino-mas can mimic hypertrophic lupus erythema-tosus.

The lymphocytic scarring alopecias can cer-tainly be difficult to tell apart from each other.Early CCLE and LLP can look quite similar. Inaddition, the co-existence of LPP and CCLE

Figure 7.10Algorithm for pathologicalassessment of major non-infectious scarringalopecias.

Figure 7.11Neutrophilic infiltrate in folliculitisdecalvans. (Courtesy of Dr MagdalenaMartinka.)

ished.27 Periodic acid Schiff staining in LE willdemonstrate a thickened basement membranezone and alcian blue stain or colloidal ironstains will show increased dermal acidmucopolysaccharides.

An algorithmic approach to the pathologyof scarring alopecias is presented in Figure


has been reported.29 Differentiating clinicaland histopathological features of lymphocyticscarring alopecias are discussed above and aresummarized in Figures 7.6 and 7.10.

Treatment

The treatment of scarring alopecia depends onthree variables: diagnosis, patient age, and dis-ease severity. The severity is determined by therapidity of the progression of the condition, thedegree of inflammation, the severity of symp-toms, and the extent of scalp involvement. Thegoals of treatment are to arrest the cicatrizingprocess, decrease follicular inflammation andprevent further fibrosis.

At the University of British Columbia HairClinic the therapeutic strategy for patientswith lymphocytic-mediated scarring alopeciasis based upon the extent of the alopecia:groups with less than 10% scalp involvementand those with more than 10% scalp involve-ment are treated differently. This is summa-rized in algorithmic form in Figure 7.12.

Figure 7.12Algorithmic approach totreatment of lym-phocytic-mediatedscarring alopecias.

Figure 7.13Injecting intralesional cortisone into thesurrounding hairy areas of scarring alopecia.Triamcinolone 10 mg/ml, injected with avolume of 0.1 ml/injection for 20 injections,can halt further spread of the condition andreduce symptoms of itch and burning.Injections are performed once monthly.


If there is less than 10% scalp involvement,double therapy with topical and intralesionalcorticosteriods is initiated. Intralesional cor-ticosteroid, 2 ml of 10 mg per ml, is adminis-tered to scarring areas once every four weeks(Figure 7.13), and an ultra-potent topical cor-ticosteroid is applied twice daily. If the pa-tient is not responding within eight weeks tothis double therapy, then hydroxychl-oroquine, 200 mg twice a day,30 is added for aminimum of six months (Figures 7.14 and7.15). If the alopecia is very severe, rapidlyprogressive, inflamed, and symptomatic, thenprednisone is added at 1 mg per kilogram perday and tapered over two months. The pred-nisone provides bridge therapy, because of adelay in the therapeutic effects of hydroxy-chloroquine.

If there is more than 10% scalp involve-ment, triple therapy is immediately initiatedwith intralesional steroid, ultra-potent topical

corticosteroid and hydroxychloroquine. If thealopecia is rapidly progressive, very inflamedand symptomatic, then a systemic steroid isalso administered for eight to twelve weeks.

If improvement is not noted after sixmonths, than other treatments can be at-tempted. Isotretinoin,31–33 at doses of 1 mg perkg per day, can be initiated and then taperedonce improvement is detected. Dapsone (100mg/day)34–37 and thalidomide (100 mg/day)38–40

are other alternatives. Again, therapy is ta-pered once improvement is acheived. A pulltest is conducted with each visit, and therapyis continued for six to twenty-four months un-til the pull test is negative. When a pull test isnegative for over two years and alopecia isclinically stable, then scalp reduction and/orhair transplantation are further options. Pre-mature transplantation may actually aggravatethe condition. Increasing the number of hairs,which can serve as a primary target in scarring

Figure 7.14Lupus erythematosus: the patient from Figure7.2c, showing marked improvement after 1year of hydroxychloroquine 200 mg twicedaily, monthly intralesional corticosteroidinjections and topical superpotent corticos-teroid ointment twice daily.

Figure 7.15Lichen planopilaris: the patient from Figure7.3d with previous ulcerative LPP improvedmarkedly with hydroxychloroquine,intralesional corticosteroid and topicalcorticosteroid.


topical minoxidil solution for scarringalopecias, many clinicians feel that topicalminoxidil, by retaining unaffected hairs inanagen for a longer period of time, enables theoverall density to be better than that of un-treated individuals.41

Figure 7.16Folliculitis decalvans in a 30-year-old male. (a) Marked erythema and folliculitis. (b) After 6months of isotretinoin 1 mg/kg/day, showing much improvement.

Figure 7.17Folliculitis decalvans in a 17-year-old female,showing hair shafts embedded within theskin.

Figure 7.18Tufted folliculitis in dissecting cellulitis,most evident after the scalp has been shaved.

alopecias, may cause the patient to becomemore symptomatic with increased inflamma-tion, pruritus or burning if the condition is re-motely still active.

The use of topical minoxidil is controver-sial. Although there are no controlled trials for


Neutrophil-mediatedcicatricial alopeciasThe neutrophil-mediated cicatricial alopecias,such as FD, are considered an abnormal im-mune response to the normal scalp flora. Pa-tients present with round patches of alopeciawith overlying erosion, scale or crust.Follicular-based pustules develop in succes-sive crops (Figure 7.16). Hair shafts are occa-sionally embedded within the scalp (Figure7.17) Tufted folliculitis is a feature frequentlyseen in FD (Figure 7.18).42 In the early stages,the pathology demonstrates a neutrophilic fol-liculitis (Figure 7.11); however, as the diseaseprogresses, fibrosis is prominent.43,44 Dissect-ing cellulitis can present as a boggy cystic in-flammatory process (Figure 7.19).

The therapeutic strategy for the neutrophil-mediated cicatrizing alopecias is targeted atanti-staphylococcal therapy with systemicerythromycin, cephalosporins, cloxacillin,rifampin and fusidic acid. There is some evi-dence that a combination of rifampin 300 mgtwice daily and clindamycin 300 mg twicedaily for twelve weeks affords more benefitthan single-agent therapy.43 Systemic fusidicacid may also have some benefit.44 Topicaltherapy can also be added, such as topicalfusidic acid.44 For severe dissecting folliculi-tis, high-dose isotretinoin for a prolongedcourse is recommended.45–49

Patients may be so symptomatic with dis-comfort, itch and burning, that controlling theinflammation for these individuals is more im-portant than salvaging the hair. Laser-assistedhair removal50 may help for this subset of pa-tients.

Figure 7.19(a). Dissecting cellulitis of the scalp withcharacteristic boggy cysts. (b). Close-up ofboggy cysts.


ConclusionThe scarring alopecias are trichological emer-gencies. An accurate diagnosis is arrived atthrough a careful clinical and histo-pathologi-cal assessment. An aggressivemultiplemodality therapeutic approach is of-ten necessary to gain disease control.

References1. Newton R.C., Hebert A.A., Freese T.W. and

Solomon A.R. Scarring alopecia. DermatolClin, 1987; 5(3):603–18.

2. Headington J.T. Cicatricial alopecia.Dermatol Clin, 1996; 14(4):773–82.

3. Templeton S.F. and A.R.Solomon. Scarringalopecia: a classification based on micro-scopic criteria. J Cutan Pathol, 1994;21(2):97–109.

4. Sperling L.C., A.R.Solomon and D.A.Whiting. A new look at scarring alopecia[editorial; comment]. Arch Dermatol, 2000;136(2):235–42.

5. de Berker D., M.Dissaneyeka and S.Burge.The sequelae of chronic cutaneous lupuserythematosus. Lupus, 1992; 1(3):181–6.

6. Wilson C.L., Burge S.M., Dean D. andDawber, R.P. Scarring alopecia in discoidlupus erythematosus. Br J Dermatol, 1992;126(4):307–14.

7. Callen J.P. Systemic lupus erythematosus inpatients with chronic cutaneous (discoid)lupus erythematosus. Clinical and laboratoryfindings in seventeen patients. J Am AcadDermatol, 1985; 12(2 Pt 1):278–88.

8. Callen J.P. Chronic cutaneous lupus ery-thematosus. Clinical, laboratory, therapeutic,and prognostic examination of 62 patients.Arch Dermatol, 1982; 118(6):412–6.

9. Pringle J. Lichen pilaris spinulosus. Br JDermatol, 1905; 17:77–102.

10. Little E. Folliculitis decalvans etatrophicans: Report of a case. Br J Dermatol,1915; 27: 183–5.

11. Silver H. Follicular lichen planus (lichenplanopilaris). Arch Dermatol Syph, 1953; 67:346–54.

12. Mehregan D.A., H.M.Van Hale, and S.A.Muller. Lichen planopilaris: clinical andpathologic study of forty-five patients. J AmAcad Dermatol, 1992; 27(6 Pt 1):935–42.

13. Altman J. The variations and course oflichen planus. Arch Dermatol, 1961; 84:179.

14. Woods B. Lichen post-aurique. In Transac-tions of the St John’s Hospital Dermatologi-cal Society. 1968, London: The Society.

15. Feder A. Clinical observations of atypicallichen planus and related dermatoses due toatabrine toxicity. Ann Int Med, 1949; 31: 1078.

16. LoPresti P., C.M.Papa and A.M.Kligman. Hotcomb alopecia. Arch Dermatol, 1968;98(3):234–8.

17. Lee W.S., S.M.Hwang and S.K.Ahn. Frontalfibrosing alopecia in a postmenopausalwoman. Cutis, 1997; 60(6):299–300.

18. Kossard S. Postmenopausal frontal fibrosingalopecia. Scarring alopecia in a patterndistribution [published erratum appears inArch Dermatol 1994 Nov.; 130(11):1407].Arch Dermatol, 1994; 130(6):770–4.

19. Kossard S., M.S.Lee and B.Wilkinson.Postmenopausal frontal fibrosing alopecia: afrontal variant of lichen planopilaris. J AmAcad Dermatol, 1997; 36(1):59–66.

19a. Brocq L.Alopecia, Journal of Cutaneous andVenereal Diseases 1885. 3:49.

19b. Brocq L. et al. Réchèrches sur 1’alopecieatrophiante, varieté psuedopelade. Annalesde Dermatologie et de Syphiligraphie, 6, 1,97, 209.

19c. Brocq L. Pseudopelade in Traite elementairede dermatolgie Practique, Doin, Paris Vol. 2.P648.

20. Braun-Falco O., T.Bergner and G.P.Heilgemeir. [The Brocq pseudopelade—adisease picture or disease entity]. Hautarzt,1989; 40(2):77–83.


21. Dawber R. What is pseudopelade? Clin ExpDermatol, 1992; 17(5):305–6.

22. Braun-Falco O., Imai S. and Schmoeckel C.,et al. Pseudopelade of Brocq. Dermatologica1986; 172(1):18–23.

23. Madani S., M.J.Trotter and J.Shapiro.Pseudopelade of Brocq in beard area. J AmAcad Dermatol, 2000; 42(5 Pt 2):895–6.

24. Zinkernagel M.S. and R.M.Trueb. Fibrosingalopecia in a pattern distribution: patternedlichen planopilaris or androgenetic alopeciawith a lichenoid tissue reaction pattern? [seecomments]. Arch Dermatol, 2000; 136(2):205–11.

25. Sperling L.C. and P.Sau. The folliculardegeneration syndrome in black patients.‘Hot comb alopecia’ revisited and revised.Arch Dermatol, 1992; 128(1):68–74.

26. Sperling L.C., Skelton H.G. 3rd and SmithK.J., et al. Follicular degeneration syndromein men. Arch Dermatol, 1994; 130(6):763–9.

27. Elston D.M., McCollough M.L., WarschawK.E. and Bergfeld W.F. Elastic tissue in scarsand alopecia. J Cutan Pathol, 2000;27(3):147–52.

28. Wright A.L. and A.G. Messenger. Scarringalopecia in psoriasis. Acta Derm Venereol,1990; 70(2):156–9.

29. Vanderhorst J. Mixed lichen planus-lupuserythematosus disease: A distinict entity:Clinical, histopathological and immun-opathological studies in six patients. ClinExp Dermatol, 1983; 8:631–40.

30. Bulengo-Ransby S.M. and J.T.Headington.Pseudopelade of Brocq in a child [seecomments]. J Am Acad Dermatol, 1990; 23(5Pt 1):944–5.

31. Shornick J.K., N.Formica and A.L.Parke.Isotretinoin for refractory lupus erythemato-sus. J Am Acad Dermatol, 1991; 24(1):49–52.

32. Vena G.A., C.Coviello and G.Angelini. [Useof oral isotretinoin in the treatment ofcutaneous lupus erythematosus]. G ItalDermatol Venereol, 1989; 124(6):311–15.

33. Green S.G. and W.W.Piette. Successfultreatment of hypertrophic lupus erythemato-sus with isotretinoin. J Am Acad Dermatol,1987; 17(2 Pt 2):364–8.

34. Singh Y.N., Adya C.M., Verma K.K., et al.Dapsone in cutaneous lesions of SLE: anopen study. J Assoc Physicians India, 1992;40(11): 735–6.

35. Lindskov R. and F.Reymann. Dapsone in thetreatment of cutaneous lupus erythematosus.Dermatologica, 1986; 172(4):214–7.

36. Rothe M.J. and F.A.Kerdel. Treatment ofcutaneous lupus erythematosus. Lupus,1992; 1(6):351–6.

37. Duna G.F. and J.M.Cash. Treatment ofrefractory cutaneous lupus erythematosus.Rheum Dis Clin North Am, 1995; 21(1): 99–115.

38. Holm A.L., Bowers K.E., McMeekin T.O. andGaspari A.A. Chronic cutaneous lupuserythematosus treated with thalidomide.Arch Dermatol, 1993; 129(12):1548–50.

39. Knop J., Bonsmann G., Happle R., et al.Thalidomide in the treatment of sixty casesof chronic discoid lupus erythematosus. Br JDermatol, 1983; 108(4):461–6.

40. Hasper M.F. and A.H.Klokke. Thalidomidein the treatment of chronic discoid lupuserythematosus. Acta Derm Venereol, 1982;62(4):321–4.

41. Dawber R. Update of minoxidil treatment ofhair loss. In Hair and its disorders, biology,pathology, and management, ed. F.Camacho,pp. 167–76. 2000, London: Martin Dunitz Ltd.

42. Annessi G. Tufted folliculitis of the scalp: adistinctive clinicohistological variant offolliculitis decalvans [see comments]. Br JDermatol, 1998; 138(5):799–805.

43. Powell J.J., R.P.Dawber and K.Gatter.Folliculitis decalvans including tuftedfolliculitis: clinical, histological and thera-peutic findings. Br J Dermatol, 1999;140(2):328–33.

44. Abeck D., H.C.Korting and O.Braun-Falco.Folliculitis decalvans. Long-lasting re-sponse to combined therapy with fusidic


acid and zinc. Acta Derm Venereal, 1992;72(2): 143–5.

45. Scerri L., H.C.Williams, and B.R.Allen.Dissecting cellulitis of the scalp: response toisotretinoin. Br J Dermatol, 1996; 134(6):1105–8.

46. Plewig G., J.Nikolowski and H.H.Wolff.Action of isotretinoin in acne rosacea andgram-negative folliculitis. J Am AcadDermatol, 1982; 6(4 Pt 2 Suppl): 766–85.

47. Shaffer N., R.C.Billick and H.Srolovitz.Perifolliculitis capitis abscedens etsuffodiens. Resolution with combinationtherapy. Arch Dermatol, 1992;128(10):1329–31.

48. Bachynsky T., O.M.Antonyshyn and J.B.Ross. Dissecting folliculitis of the scalp. Acase report of combined treatment usingtissue expansion, radical excision, andisotretinoin. J Dermatol Surg Oncol, 1992;18(10):877–80.

49. Dubost-Brama A., Delaporte E., Alfandari S.,et al. [Perifolliculitis capitis abscedens andsuffidiens. Efficacy of isotretinoin]. AnnDermatol Venereal, 1994; 121(4):328–30.

50. Chui C.T., Berger T.G., Price V.H. andZachary C.B. Recalcitrant scarring folliculardisorders treated by laser-assisted hairremoval: a preliminary report. DermatolSurg, 1999; 25(1):34–7.

AA see alopecia areata acne 16, 47, 156adrenoleukodystrophy, premature male AGA and 85adriamycin (doxorubicin), alopecia and 137AGA see androgenetic alopeciaalkylating agents 138alopecia

assessment of patient with 1–18causes of 10tDPCP treatment of 57fdrug-induced 134–46irreversible 155reversible 139, 143see also hair loss

alopecia areata (AA) 9, 10, 16, 19–81, 163AGA and 96–7autoimmune disorders and 21of beard 34, 36fclinical features of 28–36cyclosporin in 66fcytokines and 24differential diagnosis of 38–42, 40–1fDown’s syndrome and 20f, 21emotional stress and 24etiology of 19extent of hair loss 30, 34fextracranial 35fgenetic factors and 19–21histopathology of 29fimmunological factors and 21–4intralesional corticosteroid injections for 44fnail changes and 39fnail dystrophy and 34, 39fneurological factors and 25pathogenesis 23fpathology of 27–8pattern of hair loss 30prognosis of 36–7systemic steroids and 46–7telogen effluvium and 95–6topical immunotherapy for 54–5ftreatment of children with systemic steroids 47treatment of 42–66

treatment plan 66–70white hairs, vitiligo and 37f

alopecia areata circumscripta 31–2fAlopecia Areata Investigational Assessment

Guidelines 43alopecia masking lotion 68alopecia totalis (AT) 30, 34f, 42alopecia universalis (AU) 30, 34f, 42amitriptyline 143amoxapine 143ANA see antinuclear antibodies examinationanagen effluvium 134, 136–8, 137f

drug-induced 137tanagen (growing) hairs 6, 155anagen phase, alkaline phosphatase activity and 3anagen-telogen hair ratio 12, 27, 134androgen blockade 102–4, 114androgen receptor blockers (ARP inhibitors) 104–5androgen receptor proteins (ARP) 85androgenetic alopecia (AGA) 10t, 16, 83–119, 151,

158differential diagnosis 38history 9iron deficiency and 148miniaturization of hairs 27surgical management of 121–33treatment in men 109–12treatment in women 108–9vellus hairs in 6–8in women 16, 88, 89f, 91f, 134

anemia, iron deficiency 16anesthesias, telogen effluvium and prolonged 148angiogenesis, tretinoin and 108animal models, AA and non-AA 25–7anthralin 43, 48, 49–51, 68, 69anti-coagulants, hair loss and 139anti-psychotics/anxiolytics 143anti-thyroid drugs, telogen effluvium and 139antidepressants, tricyclic/tetracyclic 143antihypertensive agents 143antinuclear antibodies (ANA) examination 16, 157antitumor antibiotics 138anxiety, telogen effluvium and acute 150

Index

Note: References to figures are indicated by ‘f’ and references to tables by ‘t’.

176 Index

arrector pili muscle 5, 98, 155atherogenesis 88autoeczematization 64autoimmune diseases 21, 23autoimmune polyglandular syndrome 21, 22autoimmunity, clues for 21–4

baldnesscoronary heart disease and 87drugs and 134patterns in population 85prostate cancer and 88

beard, alopecia areata of 34, 36fBeau’s lines 34beta-blockers 143betamethasone dipropionate 43, 48biologic response modifiers 101, 105–8, 114bitemporal recession 91, 151bleomycin 137body, alopecia areata of 34body hair, thinning of 149bulge area, stem cells of 5, 155buspirone 143busulfan 138

C3H/HeJ mice 25, 26calcitonin gene-related peptide 25captopril 143carbamazepine, alopecia and 142–3carbimazole 139cardiovascular disease 87carmustine 138castling, DPCP and 52catagen 134, 136, 155catagen hairs 6, 27, 98catagen-telogen hair ratio 101cell-mediated immunity 22–4cellulitis 156central centrifugal scarring alopecia (CCSA) 156, 164fcephalosporins 171chemotherapy 134children

anthralin and 49hair loss in 9systemic steroid treatment in 47therapeutic modality choices for 69topical therapies for 67

chlorambucil 137chlormethamine 137cholesterol-lowering agents 144

chondroitin sulfate 3chromosome 8p 12 26chronic cutaneous lupus erythematosus (CCLE)

155, 156, 157histopathology of 165vs LPP 158, 167

chronic telogen effluvium (CTE) 150, 151cicatricial (scarring) alopecias 10t, 16, 17, 155–72

algorithm for diagnosis for 165finflammatory 155lymphocytic 167pathology algorithm 167f

cimetidine, alopecia induced by 136circumscript alopecia 32fcircumscript alopecia areata 38clindamycin 171clobetasol propionate 68clofibrate 144clonazepam 143cloxacillin 171colchicine 138corticosteroids 43–7, 69cortisone, injection of intralesional 168fcoumarins 139Cox proportional hazards model 87Crohn’s disease 149cyclophosphamide 137, 138cyclosporin 65–6cyproterone acetate (CPA) 101, 104–5, 108cysts, boggy 171fcytarabine 137cytochrome P450 aromatase enzyme 86cytokines, alopecia areata and 24cytomegalovirus (CMV) infection 24cytosine arabinoside 138cytostatic drugs 136–8 dacarbazine 138dactinomycin 137dapsone 169daunorubicin 137dehydroepiandrosterone sulfate (DHEAS) test 16,

98, 108delayed anagen release (DAR) 138delayed telogen release (DTR) 138depression 9, 150dermal acid mucopolysaccharides 167dermographism, severe 64despiramine 143dexamethasone 43

Index 177

diabetes mellitus 22dibromoketone 53diffuse alopecia 16, 143, 148diffuse alopecia areata 30, 33fdiffuse cyclic hair loss, in women 150dihydrotestosterone 85dinitrochlorobenzene (DNCB) 51–2diphenylcyclopropenone (DPCP) 26, 51, 52–64,

delayed response 59feczematous eruptions from 60–1 fpigmentary changes with 62ftreatment of eyebrows with 60funilateral treatment with 59f

discoid lupus erythematosus (DLE) 10t, 16, 17divalproex 142dopaquinone 6Down’s syndrome, alopecia areata and 20f, 21doxepin 143doxorubicin (adriamycin), alopecia and 137drug-induced

alopecia 134–46anagen effluvium 137f, 145lichenoid eruption of scalp 134telogen effluvium 139t, 140t, 141t

Dundee experimental bald rat (DEBR) 25dyslipidemia 88dysmorphobia 9dystrophic anagen hairs, positive pull test 96dystrophic hairs, counts of 12dystrophy, checking for presence of 15 eczema, DPCP and 64elastin staining 156, 166eosinophils 27epidermal growth factors (EGF) 105erythema 163, 170ferythema multiforme 64estrogen, AGA and 105eumelanin 6exclamation point hairs 32feyebrows

dermatography of 69injection with triamcinolone 45floss of 163treatment with DPCP 64

facial edema 130facial hypertrichosis 107ferritin, levels of 98, 151fever, alopecia and 147

finasteride 101, 102–4, 109, 133hair transplants and 130and minoxidil combination therapy 110

fluocinolone 43fluorouracil 137fluoxetine 143follicular bundles, with miniaturized hairs 99ffollicular degeneration syndrome (FDS) 156, 163,

164ffollicular hyperkeratosis 58, 158, 165follicular ostia 10, 88, 155follicular scalp lesions 158follicular stem-cell gene therapy 114follicular stem-cells 155folliculitis, tufted 166, 170f, 171folliculitis decalvans (FD) 155, 156, 167, 170f, 171fronto-parietal/fronto-temporal recession 90fusidic acid 171 gastric parietal cell antibodies 22gene replacement therapy 70gold, hair loss and 158graft hair preparation 126Graham-Little disease 160f hair

density and distribution of 10dryness of 139thinning of 86

hair anatomy 1–8hair color, loss of 144hair cortex 4, 5, 136hair counts 13, 103hair cycling, on human scalp 6hair follicles 1–2

cellular components of 24growth inhibitors 24layers of 3fnon-permanent and permanent segments 7

hair grafts, planting of 129hair loss 9, 158

pattern in a family 95fprevention of 101, 113severity of 148see also alopecia

hair matrix cell mitosis 136hair removal, laser-assisted 171hair shafts 2, 6

abnormalities of 15quality of 10, 11f

178 Index

hair shedding 9, 12abrupt diffuse 148f, 149fphysiological 6

hair thinning 9, 89, 151hair transplants 101, 108, 110, 121–2f, 169

complication of donor area 126finasteride and 130male 113f, 132fminoxidil and 130multiple-bladed knife for 123fpositioning of hairline 126–8recipient area 126–30removal of donor strips 124f

hair weights, study of 103hair-growth promoters 101hair-specific antibodies 23hairpieces 69, 101hairs

light-microscopic examination of 13–16miniaturization of 27, 83

halcinonide 43haloperidol 143Henle’s layer 2, 4, 5hen’s egg test 53heparin 139hepatic disease 149hirsutism 16, 87, 108Hodgkin’s disease 149hormone modifiers 101, 102–5Hox genes 26–7human leukocyte antigens (HLA) 19–21Huxley’s layer 2, 4, 5hyaluronic acid 3hydroxycarbamide 137hydroxychloroquine 169hydroxyurea 138hyper-androgenism 16, 87, 98, 108hyper-insulinemia 88hyperpigmentation 64hypertension 47, 88hyperthryoidism 9hypertrichosis 108hypertrophic lupus erythematosus 167hypo-proteinemia 147hypopigmentation 64, 158hypopituitarism 85hypothyroidism 9, 136, 140, 148 iatrogenic hypothyroidism 139ICAM-1 27

ichthyosis 144ifosfamide 138imipramine 143immediate anagen release 138, 147immediate telogen release 138immunosuppressive therapy, responsiveness to 21inflammatory bowel disease 149infundibulum 1, 5, 155, 163inner root sheath (IRS) 2, 4, 5insulin-resistance-associated disorders 88interferons 143intracellular androgen metabolism, AGA and 85intralesional corticosteroids 67, 69, 169intramuscular corticosteroid therapy 47iodine, telogen effluvium and 139iron deficiency 16, 148isotretinoin 169, 171isthmus 1, 5 Kaplan-Meier survival analysis 53keloids 125keratin 4keratinization, disturbed 136, 144keratinocytes, abnormal 24keratoacanthomas 167keratotic follicular papules 155 leflunomide 26lichen planopilaris (LPP) 155, 156, 158–63, 159–

60f, 169fcicatricial alopecia 10tpathology of 166fperipheral distribution 165

lichen planus 17, 22, 158lichenoid eruption 136lithium 140–2Ludwig pattern, stages of 89Ludwig Stage I pattern, in teenagers 95fLudwig Stage III, women with 108Ludwig Stages I–III 90flupus erythematosus 22, 158, 169f

chronic cutaneous scalp 157fluteinizing hormone-releasing hormone (LH-RH)

105lymphadenopathy 62f, 64lymphocytic-mediated cicatricial (scarring) alopecias

156–70treatment algorithm 168f

M phase drugs 138

Index 179

McKusick Mendelian Inheritance in Man (MIM) 83Major Histocompatibility Complex (MHC) 19malignant diseases 149maprotiline 143mechlormethamine 137medulla 2, 4melanin 3, 6melanocytes 6, 24–5melphalan 18, 138men

AGA treatment options 101frontal hairline recession 89vertex balding in 87

mepacrine (atabrine), hair loss and 1586-mercaptopurine 138mesenchymal-derived dermal papilla 86methotrexate 137, 138methylprednisolone 47methylthiouracil 139mice, hairless 26micro-grafting 132Microsporum canis 42mini-grafting 132miniaturized hairs 88, 93minoxidil (Rogaine) 43, 47–8, 101, 105–8, 109

and hair transplants 130hypertrichosis of the face and 107ftopical 133, 170use of betamethasone dipropionate and 48f

monoamine oxide inhibitors 143morphea 156mouse teratogenicity test 53myasthenia gravis 22 nail dystrophy, alopecia areata and 34, 37National Alopecia Areata Foundation (NAAF) 19,

70National Institute of Arthritis and Musculoskeletal

and Skin Diseases (NIAMS) 19neutrophil-mediated cicatricial alopecias 171nitrosoureas 138non-cicatricial (non-scarring) alopecias 10f, 16, 17fnon-inflammatory cicatrizing alopecias 155nortriptyline 143Norwood-Hamilton classification 92, 109Norwood-Hamilton pattern 90, 94fNorwood-Hamilton Stage III 92fNorwood-Hamilton Stage III and IV 103Norwood-Hamilton Stage VII 94fNorwood-Hamilton Stages IV–VI 93f

obesity 47, 88olanzapine 143onychorrhexis 34ophiasis 33f, 37, 58fophiasis inversus (sisapho) 30, 33foral contraceptives 143oral cyclosporine 22outer root sheath (ORS) 2, 5 papular atrichia 85paroxetine 143PAS stain 156patchy alopecia areata 30, 33f, 42patient, history of 9patient expectations, therapy and 113–14peri-infundibular lymphocytic infiltrate 166perifollicular interface dermatitis 165pernicious anemia 22pheomelanin 6photochemotherapy (PUVA) 64–5, 70

squaric acid dibutyl ester and 52phototrichogram method 103pigment incontinence 165cis-platin 138polymyalgia rheumatica 22polytrichia 163polytrichia folliculitis 166fpost-menopausal frontal fibrosing alopecia 163postpartum hair loss 138, 147prednisolone, pulsed oral 47pressure-induced alopecia (PIA) 38, 42procarbazine 138Propecia 102, 104propylthiouracil 139prostate cancer, AGA and incidents of 88protriptyline 143pruritus 158, 163pseudopelade (PP) 38, 156, 161f, 163, 166psycho-physical trauma 147psychogenic pseudoeffluvium 151psychopharmacologic medications 140–3pull-tests 10, 11f, 93, 156, 169pulse therapy, intravenous methylprednisolone 47pustules 156PUVA therapy see photochemotherapypyrogens, endogenous 147 quail-chick model 86 5α-reductase 85

180 Index

renal failure 149respiridone 143reticular alopecia areata 30, 33fRetin-A 108rifampin 171Rogaine see Minoxidil S phase-specific drugs 138SAHA (seborrhea, alopecia, hirsutism, acne)

syndrome 87Salmonella typhimurium 51sarcoidosis 156scalp

cellulitis of 171fphysiology of 1–8

scalp biopsies 14–15f, 16, 134, 151, 156scalp irritation, minoxidil and 10scalp lesions 158scalp prostheses 68fscalp psoriasis 167scalp reduction 169scarring alopecia see cicatricial alopeciasebaceous epithelium, loss of 165seborrheic dermatitis 100serotonin reuptake inhibitors 143sertraline 143serum ferritin, evaluation of 16sex hormone binding globulin (SHBG) 105short-contact therapy 49shortened anagen (SA) 138sisapho 30, 33fskin diseases, alopecia and severe 136Smyth chicken model 25soriatane 144spironolactone 101, 105, 108squamous cell carcinomas 167squaric acid dibutyl ester (SADBE) 26, 51, 52steroid-metabolizing enzymes 85steroids

systemic 22, 46–7topical, intralesional and systemic 43

stressalopecia areata and emotional 24telogen effluvium and psychological 150

striae, systemic steroids and 47substance P (SP) expression 24, 25support groups 69suprabulbar area 1, 4fsyphilitic alopecia 27, 28systemic diseases 136

systemic erythromycin 171 targeted follicular gene therapy 114telangiectasia 158telogen effluvium 9, 10t, 16, 96f, 142f

acute and chronic 147–53alopecia areata and 27, 28, 95differential diagnosis 38, 134drug-induced 139–44pathology of 28types of 138–9in women 86

telogen hairs 6, 27, 98, 155cross-section of 8fpositive pull test 96

temporal triangular alopecia (TTA) 42terminal-vellus hair ratio 27, 134testosterone 85thalidomide 169thallium, hair loss and 144thiotepa 137, 138thyroid dysfunction 16thyroid function assessment 140thyroid influences 21, 148thyroid screening 9thyroid stimulating hormone test (TSH) 98thyrotoxicosis 139, 140tinea capitis 9, 10t, 38, 167topical immunotherapy 43, 51–64, 69topical ophthalmic beta-blockers 143trachyonychia 34traction alopecia 10t, 38trazodone 143tretinoin (all-trans-retinoic acid) 108triamcinolone acetonide 45triamcinolone hexacetonide 45triangular temporal alopecia 38trichodynia 151trichogram/pluck test 12trichologic anatomy 1–8trichomalacia 28trichotillomania 9, 27, 28, 38triparanol 144tufting, cicatricial alopecias and 163tyrosine 6 ulcerative colitis 22 valproic acid (VPA) 142vasopressin 138

Index 181

vellus hairs 6, 98, 99fvellus-like hairs 7fvertex pattern balding 87vertex thinning 90vinblastine 137, 138vincristine 137, 138vitiligo 63f, 64

womenAGA in 88, 89f, 91ffinasteride and 104hair loss in 86hair transplantation in 131–2treatment of AGA in 101, 108–9

Woods light examination 42 zolpidem 143

Date post:	24-Nov-2014
Category:	Documents
Upload:	michael-tamburello
View:	488 times
Download:	7 times

Hair Loss

Documents