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Diseases of the Hair and Scalp dad Peet eer | ey Pere | rider Pr |Diseases of the Hair and Scalp EDITED BY RODNEY DAWBER MA, MB, ChB, FRCP Consultant Dermatologist, Department of Dermatology, Churchill Hospital, Oxford THIRD EDITION b Blackwell Science© 1982, 1991, 1997 by Blackwell Science Ltd Editorial Offices: Osney Mead, Oxford OX2 oEL 25 John Street, London WC1N 2BL 23 Ainslie Place, Edinburgh EH3 6AJ 350 Main Street, Malden MA 02148 5018, USA 54 University Street, Carlton Victoria 3053, Australia Other Editorial Offices: Blackwell Wissenschafts-Verlag GmbH Kurfiirstendamm 57 10707 Berlin, Germany Blackwell Science KK MG Kodenmacho Building 7-10 Kodenmacho Nihombashi Chuo-ku, Tokyo 104, Japan 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, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the copyright owner. First published 1982 Second edition 1991 Third edition 1997 Set by Excel Typesetters Co., Hong Kong Printed and bound in Italy , by G. Canale & C, SpA, Turin The Blackwell Science logo is a trade mark of Blackwell Science Ltd, registered at the United Kingdom Trade Marks Registry DISTRIBUTORS Marston Book Services Ltd PO Box 269 Abingdon Oxon OX14 4YN (Orders: Tel: 01235 465500 Fax: 01235 465555) USA Blackwell Science, Inc. Commerce Place 350 Main Street Malden, MA 02148 5018 (Orders: Tel: 800 759 6102 617.388 8250 Fax: 617 388 8255) Canada Copp Clark Professional 200 Adelaide St West, 3rd Floor Toronto, Ontario MsH 1W7 (Orders: Tel: 416 597-1616 800 815-9417 Fax: 416 597-1617) Australia Blackwell Science Pty Ltd 54 University Street Carlton, Victoria 3053 (Orders: Tel: 3 9347 0300 Fax: 3 9347 5001) A catalogue record for this title is available from the British Library ISBN 0-865 42-866-2 Library of Congress Cataloging-in-publication Data Diseases of the hair and scalp/ edited by Rodney Dawber.—3rd ed. . cm. Includes bibliographical references and index. ISBN 0-865 42-866-2 1. Hair—Diseases. 2. Scalp— Diseases. I. Dawber, R.P.R. © (Rodney P. R.) [DNLM: 1. Hair Diseases. 2. Scalp Dermatoses. WR 450 D611 1997] RL151.D56 1997 616.5/46—dce21 DNLM/DLC for Library of Congress 96-45303 CIPContents List of contributors, vi Preface to the third edition, vii Preface to the first edition, viii The physiology and embryology of hair growth, 1 A.G. Messenger & R.P.R. Dawber Hair follicle structure, keratinization and the physical properties of hair, 23 R.P.R. Dawber & A.G. Messenger The hair in infancy and childhood, 51 ].H. Barth Hair patterns: hirsuties and androgenetic alopecia, 67 N.B. Simpson @& J.H. Barth Diffuse alopecia: endocrine, metabolic and chemical influences on the follicular cycle, 123 R.P.R. Dawber, N.B. Simpson & J.H. Barth Hereditary and congenital alopecia and hypotrichosis, 151 R. Sinclair & D. de Berker Defects of the hair shaft, 239 D. de Berker & R. Sinclair Hypertrichosis, 299 J... Barth Io II Iz 13 14 TS 16 17 18 19 Traumatic alopecia, 328 R.P.R. Dawber & C.L. Gummer Alopecia areata, 338 A.G. Messenger & N.B. Simpson Cicatrical alopecia, 370 R.P.R. Dawber & D.A. Fenton The colour of the hair, 397 R.P.R. Dawber @& C.L. Gummer Infections and infestations, 418 R.P.R. Dawber & D.A. Fenton Psychological factors and disorders of the hair, 461 R.P.R. Dawber Hair cosmetics, 466 C.L. Gummer & R.P.R. Dawber Hair and scalp in systemic diseases, 483 R.P.R. Dawber & N.B. Simpson Diseases of the scalp and skin diseases involving the scalp, 494 R.P.R. Dawber & D. de Berker Naevi, tumours and cysts of the scalp, 528 R.P.R. Dawber Measurement of hair growth and investigation of hair disease, 564 J.H. Barth @ A.G. Messenger Index, 581List of contributors J.H. BARTH Department of Chemical Pathology and Immunology, Institute of Pathology, The General Infirmary at Leeds, Leeds LSt 3EX D. de BERKER Department of Dermatology, Bristol Royal Infirmary, Bristol BS2 8HW R.P.R. DAWBER Department of Dermatology, Churchill Hospital, Oxford OX3 7L] D.A. FENTON Department of Dermatology, St Jobn’s Institute of Dermatology, St Thomas’ Hospital, London SE1 7EH vi C.L. GUMMER Procter and Gamble (H & BC) Europe, Egham TW20 9NW A.G. MESSENGER Department of Dermatology, Royal Hallamshire Hospital, Sheffield Sto 2JF N.B. SIMPSON Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NExz 4LP R. SINCLAIR Department of Dermatology, St Vincent's Hospital, Melbourne, AustraliaPreface to the third edition Since the last edition our knowledge of many aspects of hair biology, pathology and therapeutics has expanded almost exponentially! Because of this several sections of this edition have been almost totally reorganized. Rod Sinclair, David de Berker and Andrew Messenger have joined the writing team, adding much to the areas of hair structure in health and disease, hair growth control mechanisms and alopecia areata — fields in which they are world authorities. However, as none of the writers are hair surgeons it was decided once more not to expand the book to accommodate this topic as it is covered expertly and comprehensively in every major textbook of dermatological surgery. - Those in dermatology will be aware that since the last edition was in preparation, my co-editor, Dr Arthur Rook, has died. His immense scholarship during the writing of the first edition was massively educational for me and those who knew of his editorial, academic and historical skills will recognize that he lives on in this edition, mainly in the detailed clinical historical areas. However, this book is not meant solely as a prag- matic guide for practising dermatologists; it is hoped that our collective experience will also make this volume of use to hair scientists, paediatricians, tricho- logists and cosmeticians and in particular geneticists. These are exciting times for molecular genetics and this is reflected in Chapters 6 and 7 on hereditary follicular and hair shaft abnormalities. There is also much more information on genetic mechanisms, but as yet no treatments! We also hope that now that all the clinical figures are in colour it will prove more useful as a diag- nostic manual than previous editions. We should again point out that this edition is not meant to be ‘everything on hair’; it thus reflects our particular interests to some degree. Rodney Dawber vilPreface to the first edition With a few notable exceptions most physicians, including most dermatologists, took little interest in disorders of the hair, apart from ringworm and alopecia areata and certain rare hereditary disorders of the hair shaft, until the development of scientific endocrinology in the present century provided some understanding of the mechanisms underlying certain common disturbances of hair growth. Recent research has greatly increased our knowledge of the complex endocrine influences on the hair, and has also established that a wide range of other metabolic and nutritional disturbances, and some psychiatric states, may first be clinically manifest as, or be accompanied by, changes in the density, pattern, colour or texture of the hair. Apart from those abnormalities of the hair which result from direct external infection, or from chemical or physical trauma, almost all are caused by or are related to systemic processes. The patient who complains of loss of hair, or of the growth of hair which she considers abnormal or excessive, is presenting her physician with a symptom which is as worthy of careful study and investigation as is abdominal pain or cough or any other symptom. viii Research by anthropologists and zoologists has thrown much light on the origin and significance of certain common changes in hair pattern, which have in the past wrongly been regarded as abnormal. They have also made it clear that there is no scientific justifi- cation for the study of the scalp hair in isolation from the reduced but far from vestigial hair coat in other regions of the body. This book attempts to present a practical clinical account of the hair and its disorders. It is hoped that it will be of value not only to the dermatologist, but also to other physicians who wish to understand the significance of changes in their patients’ hair. The comparative physiology of hair growth is described because it throws light on clinical situations in man. The history of each disorder is discussed briefly, where it explains international inconsistencies in nomenclature, and at greater length where it explains how discredited ‘scientific’ theories of the past have taken a prominent and sometimes a misleading place in contemporary folklore. Diseases of the scalp are included because they are so often associated with some disturbance of hair growth. Arthur Rook Rodney DawberChapter 1 / The physiology and embryology of hair growth A.G. MESSENGER & R.P.R. DAWBER Introduction, 1 Embryology, 2 Types of hair, 5 The hair cycle, 5 Introduction Hair is a characteristic feature of mammals. The factors which control hair growth and replacement in some mammals other than man have been extensively studied for a variety of motives. Economic pressures have certainly provided a stimulus for research into hair growth in the sheep and other species which directly or indirectly serve man’s needs. In addition, numerous experimental investigations have been carried out on the common laboratory animals. These studies in other mammals are of great importance in clinical practice for they throw light on the origin and significance of the complex mechanisms by which the growth and replacement of human hair are regulated. Although a striking feature of hair in man is its relative sparcity, where it is present it is often long and plentiful and by no means vestigial (Goodhart 1960). Man has largely lost the general covering of body hair which protects the skin of other primates. Ashley Montagu (1964) suggests that this reduction in body hair may have followed the hunting way of life which necessi- tated the development of a mechanism for the rapid loss of body heat. The eccrine glands were evolved and selection pressures then favoured the partial loss of the covering of hair which impaired their function. The head hair and beard are adornments directly concerned with sexual display (Patzer 1985); many authors writing in the fields of ethnology, anthropology, soci- ology and psychology have suggested more profound Systemic control of the hair cycle, 8 Hormonal control factors of human hair growth, 9 Intrinsic control of the hair cycle, 12 The dynamics of hair growth, 19 The trichogram, 20 The rate of hair growth, 20 functions for adult body hair — even mystical and magical significance (Leach 1958). Pubic hair is in general much better developed in man than in other species and axillary hair is an almost exclusive huaman characteristic. It is probable that the hair in both sites is concerned with the wider dissemination of the odour of the apocrine glands, which become functional at the age at which this hair develops. The general covering of body hair in many mammals has an important function in conserving heat, and in some the colour or pattern of colours serves as camouflage. In mammals living in geographical regions in which there are marked seasonal changes in temperature, a heavy coat which made survival possible could well be a handicap in warmer weather. Moulting probably evolved under such conditions to allow the necessary seasonal adjustment of the weight (and in some species also of the colour) of the coat. REFERENCES Goodhart, C.B. (1960) The evolutionary signification of human hair patterns and skin colouring. Advances in Science, 17, 53. Leach, E.R. (1958) Magical hair. Anthropological Institute of Great Britain and Ireland, 88, 147. Montagu, A. (1964) Natural selection and man’s relative hair- lessness. Journal of the American Academy of Dermato- logy, 187, 357. Patzer, G.L. (1985) The Physical Attractiveness Phenomena. Plenum Publications, New York.Chapter 1 (i) (b) Fig. r.x Early stages of hair follicle development in human foetal skin (a) from Olsen, E.A. (1994) Disorders of Hair Growth, McGraw-Hill Inc, New York, USA. Part (b) shows the formation of the epidermal hair peg; (i) oblique growth of the peg; (ii) the tip of the peg has become concave and encloses the dermal papilla. The upper bulge represents the Embryology (References, p. 4) A knowledge of the embryology of hair is valuable for the dermatologist, not only because it may eventually lead to an understanding of many of the genetic disorders of hair growth, but also because the sequence of events by which the hair follicle is formed in fetal life is partly recapitulated in each adult cycle of follicular activity suggesting that similar regulatory mechanisms are operating (Fig. 1.1a and b). The early work on the embryology of hair was carried out in Germany. Alber von Kolliker (1817-1905), Swiss by birth, became Pro- fessor of Anatomy in Wurzburg in 1847, and was a pioneer in the application of the cell theory in comparative anatomy and embryology. In 1850 he published an important article on the embryology of the skin in the journal of which he was co-founder (Kolliker 1850). P.G. Unna (1850-1929) of Hamburg was the first dermatologist to give serious attention to this subject (Unna 1876). The few English-language texts (iii) (ii) Developing sebaceous gland __— — Epidermis Hair peg Developing fs ae arrector pili f Sa muscle - Dermal papilla (iv) Sebaceous gland Hair 7 Arrector Internal '.” pili muscle root sheath Hair cone —~ Dermal papiila future sebaceous gland; the lower bulge, the site of attachment of the arrector muscles. In (iii) the sebaceous gland has formed. The cone of the internal root sheath is evident; (iv) the tip of the hair emerges from the protection of the internal root sheath. that did not ignore completely the embryology of the hair quoted Stohr’s Histology, which also appeared in English translation in 1896. The German work became still more widely known with the publication in 1910 of the Manual of Human Embryology, edited by Keith and Moll, to which F. Pinkus (1910) contributed an important chapter. The scientific approach in the United States to disease of the hair, based on studies of the embryology and physiology of the hair follicle, was given great impetus by Martin Engman, Professor of Dermatology, Washington University, St Louis, who had worked for a year in Unna’s clinic. Engman initiated a long-term research programme, in which C.H. Danforth, Mildred Trotter, L.D. Cady and others took part. The publications of this group (Danforth 1925) laid the foundations for much subsequent work on the hair. This account of the embryology of the human hair follicle is based largely on the writings of Pinkus (1958), Sengel (1976) and Spearman (1977). The first signs of hair follicle development occurbetween 9 and 12 weeks of gestational age in the eyebrow region and on the upper lip and the chin (Fig. 1.1a). These are the sites at which vibrissae are present in mammals other than man. This pre-germ stage of development is seen as a crowding of cells in the basal layer of the fetal epidermis. Electron microscopic studies (Breathnach & Smith 1968) showed that the initial crowding of epithelial cells in the pre-germ stage is not at first associated with other significant changes in the cells concerned. More or less simultaneously, mesenchymal cells begin to aggregate directly beneath the developing epithelial component. Cells in the basal layer elongate to form the hair germ which, as it enlarges, becomes asymmetrical and grows obliquely downwards. This solid column of cells, now known as the hair peg, the broad tip of which becomes slightly concave, carries before it the aggregation of mesenchymal cells which will form the dermal papilla and dermal sheath in the developed follicle. The cellular population of the dermal papilla is established at an early stage in development and thereafter is thought to remain stable throughout successive adult hair cycles (Wessels & Roessner 1965; Pierard & de la Brassinne 1975). As the follicle elongates the lower end becomes bulbous (the bulbous hair peg), and the cavity at the tip deepens to enclose the dermal papilla. Hair follicle development proceeds in a cephalocaudal direction and is completed by about 22 weeks. During the hair peg stage two swellings appear at the posterior side of the follicle. The upper swelling is the precursor of the sebaceous gland; the lower swelling (bulge or ‘Wulst’) is the impending site of attachment of the arrector muscle. In many follicles a third swelling appears above the sebaceous gland bud. In some areas of the skin, notably in the axillae, groins, genital skin, areolae and face, this third swelling will form the apocrine gland. Elsewhere it involutes. Between the epithelial cells melanocytes can be seen, and at first these are scattered throughout the lower part of the bulb and in the epithelial column. As hair follicle development proceeds, functionally active melanocytes are found only in that portion of the bulbous hair germ which will form the hair bulb matrix. The mesenchymal cells surrounding the bulb begin to form the dermal sheath. Above the matrix a cone of cells differentiates from The physiology/embryology of hair growth the matrix; these will form the hair. A second concentric cone surrounding the first is the future inner root sheath. The outer of the three components of the inner root sheath differentiates first as Henle’s layer; inside this Huxley’s layer and then the cuticle of the inner root sheath, the overlapping tile-like cells of which project downwards towards the base of the follicle. The differentiation of Henle’s and Huxley’s layers reaches an advanced stage before presumptive cuticular cells can be detected (Robins & Breathnach 1970). The inner cone gives rise to the cortex and cuticle of the hair shaft; there is no medulla in fetal hair. The cone of the inner root sheath extends upwards over the developing hair. However, upward growth of the hair and inner root sheath probably do not occur until the follicle has reached its full size. Lumen formation below the level of the sebaceous gland bud occurs by a process of cellular necrosis. Above this level, lumen formation in the future infundibulum occurs by a combination of necrosis and keratinization. The first hair coat of fine lanugo hair is shed in utero at about one month before birth at full term (Kligman 1961; Pecoraro & Astore 1990). The second coat of shorter lanugo, in all areas except the scalp where the hair may be both longer and of larger calibre, is shed during the first three or four months of life, almost imperceptibly, or as a wave terminating in almost complete alopecia. These first and second coats are synchronized in growth and in the sequence of shedding. The more or less unsyn- chronized mosaic pattern of hair growth then becomes established. Tissue recombination experiments have shown that development of skin appendages depends on a series of interactive messages passing between the dermis and the overlying epidermis (Kollar 1970; Sengel 1976; Hardy 1992). The initial message is derived from the dermis and instructs the epidermis ‘to form an appendage. This signal is common to all classes of vertebrate; thus, mouse dermis is able to instruct chick epidermis to initiate development of a feather follicle and chick dermis will initiate hair follicle development in mouse epidermis. This is followed by a less well- defined but class-specific signal from the epidermis which instructs the dermis to form a dermal papilla. Finally, a second dermal message stimulates the epider-Chapter 1 mal germ to form the class-specific appendage. The aggregation of mesenchymal cells is a key developmental event and hair follicles will not form in its absence. The molecular basis for follicular embryo-genesis is complex and is not yet well understood. A wide variety of molecules has been implicated including basement membrane and extracellular matrix components (Westgate et al. 1984; Couchman ef al. 1990), growth factors (Moore et al. 1983; Green & Couch- man 1984; Tam 1985; Nanney et al. 1990; Lyons et al. 1990; Jones et al. 1991; Du Cros et al. 1992), cell adhesion molecules (Hirai et al. 1989; Chuong et al. 1991; Hirai et al. 1992) and retinoids (Hardy e¢ al. 1983; Chuong et al. 1992). Much of our knowledge is based on observational studies of gene and molecular expression but an increasing number of experimental models, using various culture techniques and transgenic animals, are being devised to examine the function of specific molecules in the developmental process. REFERENCES Breathnach, A.S. & Smith, J. (1968) Fine structure of the early hair germ and dermal papilla in the human foetus. Jounal of Anatomy, 102, 511. Chuong, C.-M., Ting, $.A., Widelitz, R.B. & Lee, Y.-S. (1992) Mechanism of skin morphogenesis: II. Retinoic acid modu- lates axis orientation and phenotypes of skin appendages. Development, 115, 839. Couchman, J.R., King, J.L. & McCarthy, K.J. (1990) Distrib- ution of two basement membrane proteoglycans through hair follicle development and the hair growth cycle in the rat. Journal of Investigative Dermatology, 94, 65. Danforth, C.H. (1925) Hair with special reference to hypertrichosis. Archives of Dermatology, 11, 494. Du Cros, D.L., Isaacs, K. & Moore, G.P.M. (1992) Localiza- tion of epidermal growth factor immunoreactivity in sheep skin during wool follicle development. Journal of Investiga- tive Dermatology, 98, 109. Green, M.R. & Couchman, J.R. (1984) Distribution of epidermal growth factor receptors in rat tissues during embryonic skin development, hair formation, and the adult hair growth cycle. Journal of Investigative Dermatology, 83, rr8. Hardy, M.H. (1992) The secret life of the hair follicle. Trends in Genetics, 8, 55. Hardy, M.H., Van Exan, R.J., Sonstergard, K.S. & Sweeny, P.R. (1983) Basal lamina changes during tissue interactions in hair follicles—an in vitro study of normal dermal papillae and vitamin A-induced glandular morphogenesis. Journal of Investigative Dermatology, 80, 27. Hirai, Y., Nose, A., Kobayashi, $. & Takeichi, M. (1989) Expression and role E- and P-cadherin adhesion molecules in embryonic histogenesis II. Skin morphogenesis. Develop- ment, 105, 271. Hirai, Y., Takebe, K., Takashina, M., Kobayashi, S. & Take- ichi, M. (1992) Epimorphin: a mesenchymal protein essential for epithelial morphogenesis. Cell, 69, 471. Jones, C.M., Lyons, K.M. & Hogan, B.L.M. (1991) Involve- ment of Bone Morphogenetic Protein-4 (BMP-4) and Vgr-1 in morphogenesis and neurogenesis in the mouse. Develop- ment, III, $31. Kligman, A.M. (1961) Pathologic dynamics of human hair loss. Archives of Dermatology, 83, 175. Kollar, E.J. (1970) The induction of hair follicles by embryonic dermal papillae. Journal of Investigative Dermatology, 553 374- Kolliker, A. (1850) Zur entwicklungsgeschichte der aussern Haut. Zeitschrift fiir wissenschaftlicher Zoologie, 2, 67. Lyons, K.M., Pelton, R.W. & Hogan, B.L.M. (1990) Organo- genesis and pattern formation in the mouse: RNA distribution patterns suggest a role for Bone Morphogenetic Protein-2A (BMP-2A). Development, tog, 833. Moore, G.P., Panaretto, B.A. & Robertson, D. (1983) Epider- mal growth factor delays the development of the epidermis and hair follicles of mice during growth of the first coat. Anatomical Record, 205, 47. Nanney, L.B., Stoscheck, C.M., King, L.E., Underwood, R.A. & Holbrook, K.A. (1990) Immunolocalization of epidermal growth factor receptors in normal developing human skin. Journal of Investigative Dermatology, 94, 742- Pecoraro, V. & Astore, I.P.L. (1990) Measurements of hair growth under physiological conditions. In: Hair and Hair Diseases (eds C.E. Orfanos & R. Happle), pp. 237-254. Springer-Verlag, Berlin. Pierard, G.E. & de la Brassinne, M. (1975) Modulation of dermal cell activity during hair growth in the rat. Journal of Cutaneous Pathology, 2, 35. Pinkus, H. (1910) The development of the integument. In: Manual of Human Embryology, vol. 1, (eds H. Kubel & F. Mall), Lippincott, Philadelphia, p. 243. Pinkus, H. (1958) Embryology of hair. In: The Biology of Hair Growth (eds W. Montagna, R.A. Ellis), pp. 1-32. Academic Press, New York. Robins, E.J. & Breathnach, A.S. (1970) Fine structure of bulbar end of human foetal hair follicle at stage of differentiation on inner root sheath. Journal of Anatomy, 107, 131. Sengel, P. (1976) The Morphogenesis of Skin, Cambridge Uni- versity Press, Cambridge.Spearman, R.LC. (1977) Hair follicle development, cyclical changes and hair form. In: The Hair Follicle (ed. A. Jarrett), p. 1268. Academic Press, London. Tam, J.P. (1985) Physiological effects of transforming growth factor in the newborn mouse. Science, 229, 673. Unna, P.G. (1876) Beitrage zur Histologie und Entwicklungs- geschichte der menschlichen Oberhaut und ihrer Anhangs- gebilde. Archiv fiir microascopisch Anatomie und Entwicklungsmach, 12, 665. Wessells, N.K. & Roessner, K.D. (1965) Nonproliferation in dermal condensations of mouse vibrissae and pelage hairs. Developmental Biology, 12, 419. Westgate, G.E., Shaw, D.A., Harrap, G.E & Couchman, J.R. (1984) Immunohistochemical localization of basement membrane components during hair follicle morphogenesis. Journal of Investigative Dermatology, 82, 259. Types of hair There are several different types of hair. Most animals characteristically have an overcoat of thick long guard hairs and an undercoat of fine, more densely packed underhairs. Many species also have vibrissae which are large specialized sensory hairs. Vibrissa follicles are enclosed in a blood sinus and are richly innervated. Other specialized hairs include the quills of the hedgehog. In man three types of hair are recognized although all may arise from the same follicle at different times during life. The first coat of hair in man, which develops in utero, is known as lanugo. Lanugo hair is fine and non-medullated and is usually shed between the eighth and ninth month of gestational age. Postnatal hair is classified into two groups—vellus and terminal. Vellus hair is short, of fine calibre, non-medullated and generally non- or lightly pigmented. Terminal hair is thicker, longer, pigmented and often medullated. In prepubertal children terminal hair occurs on the scalp, eyebrows and eyelashes. The hair elsewhere on the face and trunk is usually vellus in nature although it is not uncommon to see terminal hairs on the limbs in children. After puberty, vellus follicles in many regions of the skin enlarge to become terminal follicles under the influence of androgens. Studies on postpubertal pilosebaceous follicles suggest that sebaceous gland activity may influence vellus follicle growth (Blume et al. 1993). Conversely, terminal follicles on the scalp may The physiology/embryology of hair growth convert to vellus status. The distinction between vellus and terminal hairs is easy at the two extremes but inter- mediate forms are common and the definitions are somewhat arbitrary. Rushton and colleagues (1983) classify hairs less than 30 mm in length and less than 40m in diameter as vellus. Histologically, a vellus hair has been defined as having a shaft diameter of 30 um or less and not exceeding the thickness of its surrounding inner root sheath (Headington 1984). REFERENCES Blume, U., Verschoore, M., Poncet, M., Czernielewski, J., Orfanos, C.E. & Schaefer, H. (1993) The vellus hair follicle in acne: hair growth and sebum excretion. British Journal of Dermatology, 129, 23. Headington, J.T. (1984) Transverse microscopic anatomy of the human scalp. Archives of Dermatology, 120, 499. Rushton, D.H., James, K.C. & Mortimer, C.H. (1983) The unit area trichogram in the assessment of androgen- dependent alopecia. British Journal of Dermatology, 109, 429. The hair cycle (References, p. 16) From the time that it is formed each hair follicle undergoes a repetitive sequence of growth and rest known as the hair cycle (Paus 1996). The growth phase is known as anagen, and the involutional and resting phases are termed catagen and telogen respectively (Dry 1926). The relative duration of the phases of the cycle varies with the age of the individual and the region of the body and can be modified by a variety of factors, both local and systemic. There are also wide variations in the dynamics of the hair cycle between different species. The structural changes that occur during the hair cycle are essentially the same whatever the species or follicle type and although this account is based on descriptions of the human hair cycle it is largely applicable to other mammals as well. Anagen (Fig. 1.2) The sequence of events in anagen development to some extent recapitulates those of the original morphogenesis of the follicle in fetal skin (Spearman 1977). TheChapter 5 Telogen Anagen 4 5 Fig. 1.2 In stage x of anagen cells at the base of the epithelial sac—the secondary germ—begin to show mitotic activity, In stage 2 the lower part of the follicle grows down, partly enclosing the dermal papilla. The inner root sheath appears as a keratinized plate-like structure overlying the matrix. At the same time cells in the dermal papilla enlarge and begin to become separated by an extracellular matrix. As the follicle enters anagen 3 the keratinizing inner root sheath assumes a conical shape and the cortex starts to differentiate beneath it. 6 6 Catagen Tyrosinase activity and melanogenesis becomes apparent in | melanocytes in the matrix. In anagen 4 the cortex is keratinizing but has not yet penetrated the inner root sheath. Pigment donation to cortical cells is evident at this stage. In anagen 5 the developing hair shaft finally penetrates the inner root sheath at the level of the sebaceous duct and anagen 6 represents the fully developed follicle. Stages 1-5 of anagen are sometimes known collectively as proanagen and stage 6 as metanagen.stages of anagen development were first defined by Chase and colleagues (1951) in the mouse but are equally applicable to human follicles (Fig. 1.2). Catagen Mitosis in the matrix decreases and then stops and the follicle enters catagen (Parakkal 1970). Keratinization of the hair shaft continues and the terminal portion of the hair becomes club-shaped. Melanization ceases just prior to entry into catagen and the club is therefore unpigmented. In most follicle types (vibrissae are an exception) the lower part of the outer root sheath Fig. 1.3 Catagen follicle showing apoptotic cells in the epithelial column. The physiology/embryology of bair growth Fig. 1.4 Catagen follicle showing the epithelial column with prominent thickening of the basement membrane. The dermal papilla is undergoing condensation as the extracellular matrix is lost. undergoes apoptotic degeneration (Fig. 1.3) (Weedon & Strutton 1981) and the base of the follicle, together with the club hair, moves upwards eventually to lie at the level of the arrector insertion. The inner root sheath disintegrates and disappears. The hair club is surrounded by a capsule of epithelial cells to which it is attached by keratinized fibres. The basement membrane of the outer root sheath, otherwise known as the ‘vitreous’ or ‘glassy’ membrane, becomes greatly thickened and corrugated. The dermal papilla remains closely associated with the base of the follicle (Fig. 1.4).Chapter 1 Telogen Telogen is the resting phase of the hair cycle. The club is held in the epithelial sac and may be retained until the next anagen is well advanced and occasionally for more than one subsequent hair generation. The dermal papilla, still closely applied to the base of the follicular epithelium, loses its blood supply and its extracellular matrix during catagen to appear as a tightly packed ball of cells in the telogen follicle. The follicle re-enters anagen spontaneously at the end of telogen or may be induced to do so if the resting hair is plucked. Systemic control of the hair cycle All hair follicles show an inherent rhythmic behaviour. In all mammals this intrinsic cycling may be modulated by systemic factors although the importance of these factors shows wide inter-species variation. In some species, the hair cycle is accompanied by changes in the water and collagen content of the dermis and in the thickness of the dermis and the epidermis (Chase et al. 1953; Ebling & Hale 1966; Hansen et al. 1984). The interplay between local and systemic factors in controlling the hair cycle has been shown experimentally in studies on the rat. Flaps raised on the flanks of rats, rotated through 90-180° and then replaced, continue to moult in their original direction for a prolonged period (Durward & Rudall 1949; Ebling 1990). Homografts between isogenic animals of different ages also retain the moult pattern of the donor whereas autografts retain that of the recipient. However, hair cycles in rotated skin and in autografts eventually come into phase with the surrounding skin (Ebling 1990). The moult waves in rats of different ages joined para- biotically also eventually come into phase. Synchrony between hair growth cycles is seen in many animals in the neonatal period, including man (Pecoraro e¢ al. 1964a). In many mammals, moult waves continue into adult life. In man, follicular activity rapidly becomes asynchronous although hair follicles in man and other animals are often arranged in groups of three (Meijéres trio group) and hair cycles within the group are synchronized (Saitoh et al. 1970). Moult waves in laboratory animals occur spontaneously and become less well defined with increasing age. In wild animals, the moult becomes adapted to environmental stimuli, particularly day length (the photoperiod), resulting in seasonal changes in the coat (Bissonnette 1935; Bissonnette & Wilson 1939; Duby & Travis 1972) (Fig. 1.5). Moulting may occur once, twice or even three times a year. The summer and winter coats often differ in thickness and sometimes in colour allowing adaptation to different environmental conditions (Johnson 1981). In the domesticated merino sheep selection has resulted in wool follicles which remain permanently in anagen. The effects of the photoperiod on hair growth are mediated in part by the pineal and pituitary glands. Pinealectomy prevents seasonal moulting (Smale et al. 1988; Badura & Goldman 1992) whereas administration of the pineal hormone melatonin advances onset of the growth of the winter coat and prevents growth of the summer coat (Allain & Rougeot 1980; Rose et al. 1987), Prolactin production by the pituitary correlates inversely with melatonin levels; prolactin levels are high during the summer, fall as the day length shortens in the autumn and remain low during the winter. In mink the autumn moult coin- cides with the fall in prolactin (Martinet et al. 1984) and serum prolactin is also reduced in animals kept in short day length conditions or treated with melatonin (Rose et al. 1985). Pinealectomy abolishes the fall in prolactin in animals kept in short day length conditions and prevents the development of the winter coat Fig. 1.5 Shedding of the fleece during the spring moult in the goat.(Badura & Goldman 1992). The selective inhibition of prolactin secretion with bromocryptine advances the onset of the winter coat (Rose et al. 1987) whereas treatment with the dopaminergic agonist pimozide, which enhances prolactin levels, has the opposite effect (Badura & Goldman 1992). However, not all hair follicle types respond in the same way; in voles pinealectomy blocks the growth of long winter guard hairs in animals kept in short day length conditions but does not prevent the increase in length of underhairs (Smale et al, 1988). The passage of moult waves is also influenced by a number of peripheral hormones (Maurel ez al. 1987; Ebling 1990). In rats and other animals, oestradiol, testosterone and adrenal steroids delay the onset of anagen and gonadectomy and adrenalectomy have the opposite effect. Conversely, thyroid hormones acceler- ate the onset of follicular activity whereas thyroidec- tomy or treatment with propylthiouracil delay it. Effects of hormones on the anagen phase of hair growth have also been demonstrated (Ebling 1990). Oestradiol and thyroxine both reduce the duration of anagen in rats but oestradiol decreases the rate of hair growth whereas thyroxine has the opposite effect suggesting these hormones have different points of action. Seasonal variation in hair growth also occurs in man (Orentreich 1969; Randall & Ebling 1991). The mag- nitude is seldom sufficient to be clinically detectable although some people comment that their hair ‘grows better’ during the summer months and, occasionally, alopecia areata shows seasonal variation in activity. The most striking example of a systemic influence on the human hair growth cycle is the increase in telogen shedding which occurs following pregnancy. During pregnancy there is an increase in the proportion of follicles in anagen (Lynfield 1960) and an increase in the proportion of thick hairs although there is also a small reduction in the rate of hair growth (Pecoraro et al. 1969). Post-partum there is a rapid increase in telogen hairs followed by excessive shedding starting 2-3 months later. These changes are presumably related to the hormonal changes of pregnancy although the mechanism has not been studied. Telogen shedding may also be caused by a number of drugs and by febrile and other catabolic illnesses (Kligman 1961). Evidence The physiology/embryology of hair growth for the popular notion that psychological stress causes hair loss is anecdotal but there is one convincing report of telogen effluvium following conviction in a prisoner who underwent a series of trials for murder (Kligman 1961r). In general, the longer scalp hair attainable by women is thought to relate to a longer anagen phase. Hormonal control factors of human hair growth Androgens Androgens are the most important systemic modula- tors of human hair growth. They are necessary for conversion of vellus hair on the body and the beard region to terminal hair, a process which starts at puberty and continues for several decades. The response of hair follicles to androgens varies with body site; the growth of pubic and axillary hair occurs earliest, reaches a peak during the third decade and, in the case of axillary hair, then declines. Beard growth is maximal during the fourth decade and remains much the same thereafter. Growth of chest hair peaks even later and that of terminal hairs in the nares and the external auditory meatus is a feature of late middle age. The growth of hair on the scalp is not androgen dependent but, paradoxically, androgens are necessary for the development of balding. Man is not the only mammal to show androgen-induced changes in hair growth; the mane in lions and in red deer is presumably stimulated by male hormones and several other primates, such as the macaque and the uacari, show balding on the scalp. The importance of androgens in beard growth and balding was first recognized by Hamilton (1942, 1958). He observed that men castrated before the age of puberty neither grew beards nor went bald unless they were treated with testosterone. Castration of older men prevented the progression of balding but did not reverse it. Beard growth was partially reversed by castration, the reversibility being greatest in those who had been castrated at an early age. In order to respond to androgens, hair follicles must possess androgen receptors. Genetic males who lack androgen receptors (testicular feminization) have testes and normal! or high levels of circulating testosterone.Chapter 1 However, they have female externa! genitalia and, in the complete form of the syndrome, fail to develop pubic and axillary hair, do not grow beards and do not go bald. Some pubic and axillary hair may be present in incomplete forms of testicular feminization. Pharma- cological blockade of androgen receptors with cyproterone acetate will partly reverse hirsutes (Ebling et al. 1977) and induce some recovery of hair growth in women with androgenetic hair loss (Mortimer et al. 1984) although, as would be predicted from Hamil- ton’s observations, anti-androgen treatment does not completely reverse hair growth to a prepubertal state. There is a pronounced genetic influence on androgen- dependent hair growth, particularly in respect of balding which tends to run in families. However, genetic factors are also important in the growth of beard and body hair. This is most evident in racial differences— for example, beard growth in Caucasian men is greater than that in Japanese men (Hamilton 1958). These genetic differences are presumably determined at the level of the hair follicle as they do not reflect differences in circulating androgen levels. Mechanism of action of androgens. The wide range of responses to androgens depending on body site suggests the specificity of the response is determined locally in the skin. This is well illustrated by the success of hair transplantation where follicles from relatively non-responsive occipital skin retain the behaviour of the donor site when transplanted into bald scalp. Moreover, the development of micrografting, in which individual follicles are transplanted, indicates that androgen responsiveness is at the level of the follicle itself. 3 Androgens circulate in the blood either free or bound to proteins, especially sex-hormone-binding globulins. Free steroid diffuses into the cell where it binds to a specific nuclear receptor (King 1987). Interaction between the receptor hormone complex and nuclear DNA activates the relevant genes to regulate the appropriate RNA. Understanding how androgens affect hair growth is complicated by the fact that they may undergo extensive intracellular conversion in the target tissue (Strauss & Pochi 1976) (Fig. 1.6). The weak androgen dehydro-epiandrosterone can be converted to androstenedione which itself can be reversibly converted to testosterone. The metabolism of testosterone to the more potent androgen dihydrotestosterone (DHT) by the enzyme sa-reductase appears to be an important step in many androgen-responsive tissues including the hair follicle. Men who are deficient in sa-reductase (Type II pseudo-hermaphroditism) have testes and normal or high levels of testosterone production but have ambiguous external genitalia. Following puberty they show a male pattern of skeletal muscle development and a female distribution of pubic and axillary hair growth. However, beard growth is sparse and the frontal hair line does not recede (Imperato- McGinley 1983). Thus, the response of pubic and axillary follicles to androgens does not require the formation of DHT. However, 50-reductase activity does appear to be necessary for the full expression of secondary sexual hair characteristics on the body, beard and scalp. This conclusion is supported by animal studies of 5a-reductase inhibitors. In the macaque, topical treatment with a 5a-reductase inhibitor, 4MA, prevents the development of balding (Rittmaster et al. 1987) and the oral administration of Oestrone «—_____*_—____» Oestradiol 1 3 1 Dehydroepiandrosterone -——» Androstenedione «———_>—_——. Testosterone 2 3 1 Aromatase 2 5a-reductase 3 1728-hydroxysteroid dehydrogenase Androsterone Epiandrosterone Io 5a -androstane-3, 17-diol 5a -androstane-3a, 17(-diol 2 5a-androstanedione «—>—+» 5a -dihydrotestosterone Fig. 1.6 Pathways of androgen metabolism.finasteride, another 5a-reductase inhibitor, increases scalp hair growth in balding macaques (Diani et al. 1992). Several studies, most using plucked hairs as a source of tissue, have looked at the ability of human hair follicles to metabolize androgens (Takayasu & Adachi 1972; Schweikert & Wilson 1981). These have shown that hair roots have both hydroxysteroid dehydrogenase and 50-reductase activity. In studies where testosterone was the starting material the major metabolite was androstenedione and, although testosterone was also metabolized to DHT, the level of 5a- reductase activity did not correlate well with the site-dependent secondary sex characteristics of the hair. The picture is further complicated by the fact that there are at least two isoforms of 50-reductase encoded by different genes (Jenkins ef al. 1992). The type 1 isoform is found in many tissues, including the scalp, but type 2 5a-reductase has a more limited distribution. Men with 50-reductase deficiency have a mutation in the type 2 gene—their production of type 1 5a-reductase is normal. Type 2 5a-reductase activity has been demonstrated in cultured dermal papilla cells from beard hair follicles (Itami e¢ al. 1991) but not in scalp dermal papilla cells; neither has the type 2 isoform been identified in normal scalp tissue (Harris 1992). These observations are consistent with the sparse beard growth in men with 5oa-reductase deficiency but the absence of balding is more difficult to explain. It is possible that the level of type 2 activity in the scalp is too low to be detected; alternatively, if DHT is necessary for the development of balding it may derive from the circula- tion rather than from a local source. Site of androgen action in the hair follicle. Androgens alter the size of the hair follicle and the diameter of the hair fibre. They also modify the duration of the hair growth cycle. Treatment of hirsute women with cyproterone acetate reduces the final length of thigh hairs and this is due to a shortening of the anagen phase of the hair cycle rather than a reduction in linear growth rate (Ebling et al. 1977). On the basis of morphometric data, Van Scott and Ekel suggested that hair follicle size was dependent on the volume of the dermal papilla (1958), an idea which has some experimental support. Using the rat vibrissa model, Ibrahim and Wright The physiologylembryology of hair growth (1982) confirmed Oliver’s observation (see below) that a new dermal papilla was reconstituted from the dermal sheath when the hair bulb was amputated. They also found that the volume of hair fibre growing from such a follicle, after regeneration of the hair matrix, correlated with the volume of the reconstituted dermal papilla. Taken together, these observations suggest that androgens could act on hair growth by a primary effect on the dermal papilla. This idea is not without precedent as androgen action in some other tissues is via a primary effect on the mesenchyme (Cuhna & Lung 1978; Lasnitzki & Mizuno 1980). Androgen receptors have been demonstrated in the nuclei of dermal papilla cells by imnmunohistochemical staining of tissue sections (Choudry et al. 1992; Itami et al. 1995a). Im-munoreactive androgen receptors were also identified in interfollicular keratinocytes and dermal fibroblasts, in sweat glands, sebaceous glands and in the hair follicle infundibulum. However, there was no staining in epithelial cells in the lower part of the hair follicle. Androgen receptors have been identified in cultured human dermal papilla cells by classical binding studies using the synthetic non-metabolizable androgen, mibolerone (Randall et al. 1992). Dermal papilla cells from all the body sites so far studied contain saturable androgen receptors and the receptor concentration is higher in cells from beard and pubic follicles than in those from occipital scalp follicles. Cul- tured human dermal papilla cells also express 5a- reductase activity and the levels are higher in beard than in scalp cells (Itami et al. 1990; Thornton et al. 1993). Beard dermal papilla cells express the type 2 isoform of the enzyme whereas in scalp cells only type x 5a-reductase has been identified (Itami et al. 1991). If the dermal papilla is the primary target of androgen action, how does it respond to androgens in order to communicate a growth regulatory effect on the follicular epithelium? Androgens might act simply by changing the volume of the dermal papilla to alter the area over which matrix cells interact with the papilla. Such changes in papilla volume undoubtedly take place although we do not know if this reflects a change in cell number, in the volume of the extracellular matrix or both. A second possibility is that the dermal papilla secretes growth promoting factors which act directly IIChapter 1 on the matrix epithelium. Culture media conditioned by beard papilla cells grown in the presence of testosterone stimulate the growth of cultured outer root sheath keratinocytes (Itami et al. 1995a). This effect is due, at least in part, to insulin-like growth factor-1 (IGF-1) (Itami et al. 1995b). Thyroid hormone Thinning of scalp and body hair is a well-known feature of thyroid deficiency. Freinkel and Freinkel (1972) plucked hairs from the occipital and parietal scalp of hypothyroid subjects and found that there was an abnormally high level of telogen hairs. After 8 weeks of thyroid replacement therapy anagen : telogen ratios were restored to normal. Hair diameter is also reduced in hypothyroidism in a pattern similar to that seen in female androgenetic alopecia (Jackson et al. 1972). Growth hormone The normal pubertal growth spurt depends on testosterone and growth hormone. There is some evidence that the androgenic effects of testosterone in the skin also require both hormones. In combined gonadotrophin and growth hormone deficiency a much higher total dose of testosterone is needed to induce the growth of axillary hair than in isolated gonadotrophin deficiency (Zachmann et al. 1976). Synergism between androgens and pituitary hormones is well recognized in the regulation of sebaceous activity (Ebling & Cunliffe 1992) and it is possible that similar mechanisms operate in the hair follicle. Intrinsic control of the hair cycle In man, local mechanisms predominate in controlling the hair cycle and systemic factors are relatively unim- portant. Understanding the intrinsic regulation of the cycle is a major goal of hair biology but one that has yet to be realized. However, several ideas have been proposed and recent advances have begun to provide insight into some of the factors involved. I2 Growth factors It has been known for many years that plucking of resting hairs from telogen follicles advances the onset of anagen. This led to the idea that the hair cycle is con- trolled by a locally active inhibitor, or chalone, which accumulates during anagen causing entry into catagen when present in sufficient concentration (Chase & Eaton 1959; Bullough 1975). It was proposed that the inhibitor disperses during telogen and that this could be accelerated by plucking resting hairs. This idea has been disputed because the plucking of resting hairs from follicles which have already entered anagen does not prolong the anagen in progress although it does advance the onset of the next anagen cycle (Ebling 1990}. In support of the chalone hypothesis, Paus et al. (1990) extracted a factor from murine skin which inhibited hair growth in vivo and in vitro. This inhi- bitory factor appeared to derive from the epidermis and was present in telogen skin but not in anagen skin. It has not been characterized further although, in a previous study, a lectin-like hair growth inhibitor was isolated from rat skin (Frater 1983). Whereas the identity and nature of putative hair follicle chalones are unknown a large number of specific growth factors and their receptors have been identified in the hair follicle and some show changing expression during the hair cycle (Stenn et al. 1996; Peus & Pit- telkow 1996) although information on function is available for only a few. Epidermal growth factor. Epidermal growth factor (EGF) was the first growth factor to be implicated in hair growth as its administration to newborn mice delays the eruption of the coat (Moore e al. 1983) whereas EGF antibody has the opposite effect (Zshi- esche & Eckert 1988). Transforming growth factor alpha (TGFa), which also binds to the EGF receptor, has a similar effect (Tam 1985). When given in large doses to sheep, EGF has a defleecing action (Moore et al. 1985; Hollis & Chapman 1987). EGF receptors have been identified in the hair follicle, mainly distributed in the outer root sheath and the hair bulb but not in the dermal papilla (Green & Couchman 1984;Moore et al. 1991). Further evidence of the role of EGF/TGFa in hair growth comes from observations on two mouse mutants, waved-1 (wa-r) and waved-2 (wa- 2), both of which have a pronounced waviness of the coat and the whiskers with malalignment of hair follicles. Wa-1 mice have TGFa deficiency due to a mutation in the TGFa gene (Mann et al. 1993; Luettke ez al. 1993). In wa-2 mice there is a mutation in the EGF receptor tyrosine kinase; EGF binds to the receptor but signal transduction is defective (Luettke et al. 1994). However, there does not appear to be a significant alteration in hair cycling in these animals. Insulin-like growth factor-t. Isolated human follicles continue to grow hair for up to 10 days in serum-free culture in the presence of supra-physiological concentrations of insulin. Follicles cultured in the absence of insulin enter a catagen-like state. Insulin can be substituted by a much lower concentration of insulin- like growth factor-1 (IGF-1) suggesting that IGF-1 is the physiological ligand (Philpott et al. 1994). Hair follicles are presumably exposed to a relatively constant level of IGF-1 in vivo but its biological effect on hair growth may vary depending on the level of expression of IGF-1 receptors or IGF binding proteins. Fibroblast growth factor-5. There are at least nine members of the heparin-binding Fibroblast Growth Factor (FGF) family. Several have been identified in the hair follicle although a functional role has so far only been shown for FGF-5. Transgenic mice homozygous for a null mutation in the FGF-5 gene grow abnormally long hair. The angora mouse, a spontaneous mutant which also has long hair, has been shown to have a mutation in the FGF-5 gene. The gene is expressed in the outer root sheath in the later stages of anagen suggesting that FGF-5 is involved in terminating anagen (Hebert e al. 1994). It has been suggested from whole follicle organ culture that protein kinase C may be a negative regulator of hair growth: using similar in vitro methods they have also implicated potassium channel openers as hair growth stimulants. The physiology/embryology of hair growth Role of the dermal papilla The dermal papilla invaginates the base of the hair bulb and is continuous at its base with the dermal sheath which surrounds the hair follicle. Both the dermal papilla and the lower part of the dermal sheath develop from the embryonic aggregate of mesenchymal cells. Recombinant experiments, mainly using the rat vibrissa follicle, have shown that, as in fetal development, the dermal papilla plays an essential role in the induction and maintenance of hair growth. The vibrissa follicle is a specialized sensory follicle surrounded by a collagenous capsule enclosing a blood sinus; its large size, accessibility and constant spatial arrangement have made it an ideal model for hair biology, a purpose for which it was first used by Cohen (1961). Ina series of experiments Oliver showed (1966, 1967, 1970) (Fig. 1.7): 1 Removing the dermal papilla from the vibrissa follicle caused a temporary cessation of hair growth. The papilla was then reconstituted by cells migrating from the dermal sheath and hair growth resumed. 2 Amputation of the hair bulb including dermal papilla, bulbar epithelium and the lower part of the dermal sheath also caused cessation of hair growth. If less than one-third of the total length of the follicle was removed the dermal papilla reformed from the dermal sheath, an epithelial matrix developed from the outer root sheath and gave rise to growth of a new hair fibre. 3 If more than one-third of the follicle was amputated the dermal papilla did not regenerate and the epithelial matrix did not develop. However, when an isolated dermal papilla was associated with the lower cut end of such a follicle this induced epithelial matrix formation from the outer root sheath and renewed hair growth. 4 Isolated dermal papillae induced the formation of hair follicles when implanted into the skin in association with afollicular scrotal epidermis (Young & Oliver 1996). These experiments showed that, as in fetal skin, the dermal papilla is responsible for inducing differentiation of the hair matrix epithelium. The lower part of the dermal sheath also has specialized properties and can reconstitute a dermal papilla in vivo. Jahoda and 13Chapter 1 Dermal papilla —@ —_—— (a) Amputation lines (b) Dermal papilla (c) (d) Pee Ee Ey colleagues (1984) have shown that cultured vibrissa dermal papilla cells, like intact isolated dermal papillae, are able to induce hair growth in amputated rat vibrissa follicles, a property not shared by non- - follicular dermal fibroblasts. Subsequently it has been shown that cultured vibrissa papilla cells induce follicle formation when implanted directly into rat ear skin, providing the cells are in contact with the epidermis (Jahoda et al. 1993). Follicles induced by implants of 14 Fig. 1.7 Diagrammatic representation of the recombinant experiments on the rat vibrissa follicle (the collagenous capsule is also illustrated). (a) The dermal papilla is reconstituted from the dermal sheath when the former is removed. (b) If the hair bulb is amputated below the level of the dashed line the dermal papilla is reconstituted from the dermal sheath and a smaller follicle regrows. (c} The follicle will not regrow if the hair bulb is amputated above this level unless an isolated dermal papilla is implanted at its lower pole. (d) Hair follicles develop froma follicular epidermis when implanted into the skin in association with dermal papillae. (From Olsen, E.A. (1994) Disorders of Hair Growth. McGraw- Hill Inc, New York, USA.) vibrissa cells grow vibrissa-like hairs indicating that the hair type specificity resides in the dermal papilla. Reynolds and Jahoda (1992) have also shown that cultured rat pelage dermal papilla cells can induce follicular neogenesis in rat footpad epidermis which unlike ear skin is normally devoid of hair follicles. Although dermal papilla function is fundamental to hair growth it should be emphasized that epithelial-mesenchymal interaction in the hair follicleis bi-directional and the epithelium is not simply a passive participant. Epithelial cells derived from the hair bulb matrix of rat vibrissa follicles proliferate in vitro only when co-cultured with dermal papilla cells (Reynolds & Jahoda r991a). Matrix cells implanted into rat ear skin fail to form hair follicles. Cells cultured from the vibrissa dermal sheath also fail to induce hair growth in this model although these cells are able to reconstitute a dermal papilla ix vivo when hair follicle epithelium is present. However, large hair follicles are formed when matrix cells and dermal sheath cells are implanted together suggesting that dermal sheath cells need to be ‘conditioned’ by signals from the epithelial cells before they are able to form a dermal papilla (Reynolds & Jahoda 1991b). The relationships and respective roles of the adult dermal papilla and the hair bulb matrix epithelium are very similar to those of their embryonic precursors. The dermal component plays a dominant role in both settings but must be primed by the epidermis before it is able to fulfil its inductive potential. As the dermal papilla provides the inductive stimuli for anagen differentiation of the follicular epithelium it seems likely that interactions between the dermal papilla and neighbouring epithelial cells are also involved in regulating the hair growth cycle. Once established during embryonic development the cellular population of the dermal papilla is thought to remain little changed throughout successive hair growth cycles in the adult animal. However, there are major changes in cell morphology, vascularization and in the composition and volume of the extracellular matrix in the dermal papilla during the hair growth cycle (Montagna et al. 1952; Young & Oliver 1976; Couchman & Gibson 1985; Westgate et al. 199rb). During anagen, dermal papilla cells contain prominent golgi apparatus and endoplasmic reticulum and show vigorous pinocytic activity indicative of protein synthesis. There is an extensive extracellular matrix which is rich in basement membrane proteins and proteoglycans. The extracellular matrix diminishes in volume during catagen to become barely discernible in telogen where the dermal papilla appears as a tightly packed ball of cells immediately below the lower pole of the follicular epithelium. As the follicle enters telogen the dermal The pbysiology/embryology of hair growth papilla cells become more compact and their cytoplasm contains few organelles. The capillary loops, present in larger dermal papillae during anagen, are also lost. Thus, during anagen the papilla appears to be an active vascularized synthetic structure whereas in telogen it is non-vascularized and quiescent. However, the molecular basis of dermal papilla function is not yet understood. Hair follicle stem cells All self-renewing tissues are believed to contain stem cells. Stem cells are normally slow cycling but, following certain stimuli, they can be induced to enter the proliferative pool where they undergo cell division giving rise to daughter ‘transient amplifying cells’. Transient amplifying cells have a limited mitotic potential before they become terminally differentiated. Cot- sarelis and colleagues (1990) showed that murine hair follicles contain a discrete cluster of slow cycling cells in the bulge region close to the insertion of the arrector muscle (the “Wulst’). They proposed that these slow cycling cells formed the stem cell population in the follicle. Stem cells would be activated at the onset of anagen by growth stimuli from the dermal papilla which, at this stage of the hair cycle, is in close association with the bulge region. Daughter cells give rise to the lower part of the follicle including the proliferative cells of the hair bulb matrix. As transient amplifying cells the matrix would have a limited mitotic potential which when exhausted would cause the follicle to enter catagen. Cells with the in vitro properties of stem cells have been cultured from human hair follicles (Rochat et al. 1994). These cells were located in the outer root sheath below the mid-point of the follicle deep to the arrector insertion but above the hair bulb. The ‘bulge activation hypothesis’ has not been uni- versally accepted (Holocek & Ackerman 1993) and may not be applicable to all types of hair follicles. However, the concept that stem cells reside in the bulge region is able to explain certain aspects of hair follicle pathology. In alopecia areata, a disease in which follicles are not destroyed, the inflammatory infiltrate is concentrated in and around the hair bulb. In the scar- ring alopecias, on the other hand, the inflammatory I5Chapter 1 infiltrate affects the upper part of the follicle extending down to the arrector insertion, thus including the putative stem cell region. Immune mechanisms in cycle control The expression of class I major histocompatibility complex antigens in the hair follicle is not uniform. Epithelial cells of the outer root sheath in the upper permanent region of the follicle show strong expression of class I antigens, similar to that in the epidermis. However, in anagen follicles in man (Harrist e¢ al. 1983), rats (Westgate et al. 1991a) and mice (Paus et al. 1994), class I expression below the level of the arrector insertion is reduced or absent. Westgate and colleagues (1991a) suggested that the absence of class I expression in the lower follicle would make these cells susceptible to attack by natural cytotoxic cells but that this is prevented by the proteoglycan-rich connective tissue sheath and dermal papilla acting as an immunoprotec- tive barrier. Catagen is associated with a reduction in the proteoglycan content of hair follicle mesenchyme and an increase in class I expression by cells in the degenerating epithelial column. At the same time there is an influx of activated macrophages around the follicle. It is not known whether these infiltrating macrophages have a primary role in driving follicular regression or if they are simply involved in a ‘mopping- up’ operation. Nevertheless, the idea that immune mechanisms play a part in regulating the hair cycle is attractive and is supported by the observation that the immunosuppressive agent, cyclosporin A, has a stimu- latory effect on hair growth (Harper et al. 1984). 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(1987) The effects of N,N-diethyl-4-methy]- 3-0x0-4-aza-5 alpha-androstane-17 beta-carboxamide, a 5 alpha-reductase inhibitor and anti-androgen, on the development of baldness in the stumptail macaque. Journal of Endocrinology and Metabolism, 65, 188. Rochat, A., Kobayashi, K. & Barrandon, Y. (1994) Location of stem cells of human hair follicles by clonal analysis. Ceil, 76, 1063. Rose, J., Oldfield, J. 8¢ Stormshak, F. (1987) Apparent role of melatonin and prolactin in initiating winter fur growth in mink. General and Comparative Endocrinology, 65, 212. Rose, J., Stormshak, F., Oldfield, J. & Adair, J. (1985) The effects of photoperiod and melatonin on serum prolactin levels of mink during the autumn molt. Journal of Pineal Research, 2, 13. Saitoh, M., Uzaka, M. & Sakamoto, M. (1970) Human hair cycle. Journal of Investigative Dermatology, 54, 65. Schweikert, H.U. & Wilson, J.D. (1981) Androgen metabolism in isolated human hair roots. In: Hair Research (eds C.E. Orfanos, W. Montagna & G. Stuttgen), pp. 210-214. Springer-Verlag, Berlin. Smale, L., Dark, J. & Zucker, I. (1988) Pineal and photoperiodic influences on fat deposition, pelage, and testicular activity in male meadow voles. Journal of Biological Rhythms, 3, 349. Spearman, R.LC. (1977) Hair follicle development, cyclical changes and hair form. In: The Hair Follicle (ed. A. Jarrett), p. 1268. Academic Press, London. Stauss, J.S. & Pochi, P.E. (1976) The hormonal control of the pilosebaceous unit. In: Biology and Disease of the Hair (eds K. Toda, Y. Ishibashi, Y. Yori & F. Morikawa), pp. 231-245. University Park Press, Baltimore. Stenn, K.S., Combates, N.J. & Eilertsen, K.J. et al. (1996) Hair follicle growth controls. Dermatologic Clinics, 14, 543. Takayasu, S. & Adachi, K. (1972) The conversion of testosterone to 17 beta-hydroxy-5 alpha-androstan-3-one (dihydrotestosterone) by human hair follicles. Journal of Clinical Endocrinology and Metabolism, 34, 1098. Tam, J.P. (1985) Physiological effects of transforming growth factor in the newborn mouse. Science, 229, 673. Thornton, M.J., Laing, ., Hamada, K. & Messenger, A.G. (1993) Differences in testosterone metabolism by beard and scalp hair follicle dermal papilla cells. Clinical Endocrino- logy, 39, 633- Van Scott, E. & Ekel, T.M. (1958) Geometric relationships between the matrix of the hair bulb and its dermal papilla in The physiology/embryology of hair growth normal and alopecic scalp. Journal of Investigative Derma- tology, 31, 281. Weedon, D. & Strutton, G. (1981) Apoptosis as the mechanism of the involution of hair follicles in catagen trans- formation. Acta Dermato-venereologica (Stockholm), 61, 335- Westgate, G.E., Craggs, R.I. & Gibson, W.T. (1991a) Immune privilege in hair growth. Journal of Investigative Dermato- logy, 975 417. Westgate, G.E., Messenger, A.G., Watson, L.P. & Gibson, W.T. (r991b) Distribution of proteoglycans during the hair growth cycle in human skin. Journal of Investigative Der- matology, 96, 191. Young, R.D. & Oliver, R.E (1976) Morphological changes associated with the growth cycle of vibrissal follicles in the rat. Journal of Embryology and Experimental Mor- phology, 36, 597. Zachmann, M., Aynsley-Green, G. & Prader, A. (1976) Inter- relations of the effects of growth hormone and testosterone in hypopituitarism. In: Growth Hormone and Related Pep- tides {eds A. Pecile & E.E. Muller), pp. 286-296. Excerpta Medica, Amsterdam. Zshiesche, W. & Eckert, K. (1988) Effects of anti-EGF serum on newborn mice. Experientia, 44, 249. The dynamics of hair growth (References, p. 21) The duration of anagen (Fig. 1.8) in human scalp hairs is highly variable. The figure of 1000 days is frequently quoted but this is a very rough approximation (Oren- treich 1969). Courtois and colleagues (1995) found that the mean anagen period in four non-balding adult men varied between 550 and 930 days and that the duration of anagen correlated with hair diameter. The resting hair is retained for 2-3 months and this is followed by a latent period, which may last several months, before the next anagen hair emerges. Ageing causes a progressive alteration in the scalp hair cycle (Barman ez al. 1965; Courtois et al. 1995). The duration of retention of the telogen hair is little affected but there is a gradual shortening of the anagen phase and a lengthening of the latent period. Ageing is also associated with an overall reduction in hair diameter. These changes are more pronounced in balding scalp. The density of hair follicles in normal adult scalp is around 200-300/cm2 (Barman et al. 1965; Rushton et al. 1993; Courtois et al. 1995) and the total population I9Chapter 1 Fig. 1.8 Differences in hair length depend on the duration of anagen, a genetically determined characteristic. Neither of these subjects had had a haircut for over 18 months; length was initially the same. is estimated at 100 000-150 000. Assuming that 80% of follicles are in anagen, each scalp therefore produces about 9km of hair each year. The average rate of normal hair shedding can be calculated at 1oo/day. Although there is wide inter-individual variation this is over twice the observed figure (Kligman 1961; Berth- Jones & Hutchinson 1995), a discrepancy which has yet to be explained. The trichogram Many studies of the hair cycle have depended on the trichogram, the ratio of anagen to telogen hairs (A/T ratio), as established by the microscopic examination of plucked hairs (Braun-Falco & Fischer 1966; Meiers 1967). This technique involves plucking at least 50 hairs with a rapid tug using an instrument such as an artery clip. There are differences in the trichogram with age, with region of the scalp and between individuals. The highest anagen: telogen ratio — over 90% — is found in children. In adults the normal range is between 80 and 95% —telogen counts above 25% are probably abnormal (Kligman 1961). Witzel and Braun-Falco (1963) examined scalp hairs from 146 clinically normal subjects; they found an average in all sites in women of 85% in anagen, and 83% in men. Catagen hairs accounted for 2.1% of the total in 20 women and 3.2% in men but were demonstrable in only 48% of women and 46% of men. In adult men, even in those not clinically bald, the proportion of hairs in telogen is highest in the fronto-vertical region. Barman and colleagues (1965) also found a higher proportion of telogen hairs in the frontal scalp in women. In a German study there were no marked regional differences in the trichogram in non-bald women (Braun- Falco & Fischer 1966) but differences were present in women with androgenetic alopecia. Although the conventional trichogram is still used in clinical practice in some parts of the world, mainly to monitor the response to treatment in female androgenetic alopecia, for the purposes of clinical research it has been superseded by other methods. The unit area trichogram is a more sensitive but time consuming method in which all the hairs within a defined area are plucked and categorized individually (Rushton et al. 1983). As well as providing an anagen: telogen ratio the unit area trichogram also allows measurement of hair density and shaft diameters, key variables in androgenetic alopecia. Most clinical researchers now use the phototrichogram (Saitoh et al. 1969, 1970; Van Neste et al. 1989; Hayashi et al. 1991). Hair in the target site is clipped short, photographed at high mag- nification and re-photographed a few days later. The total number of hairs per unit area, the number of growing hairs (anagen) and of non-growing hairs (telogen) can be determined with reasonable accuracy. The phototrichogram is not as sensitive as the unit area trichogram, particularly in light coloured or grey hair (Rushton et al. 1993), but it is non-invasive and allows repeated sampling of the same site. The rate of hair growth Several different techniques have been employed to measure the rate of hair growth in man (Barth 1986, 1987). Myers and Hamilton (1951) observed the length of time required for the regrowth of the hair after plucking. The time interval ranged from 129 days on the vertex of the scalp and 117 days on the temples, to 92 days on the chin. Plucking the hair damages the follicle and observations based on regrowth after plucking are not necessarily applicable to spontaneousregrowth (Silver et al. 1969). Observations of individual uninjured follicles (Saitoh et al. 1970) showed that new hairs took 3 weeks to reach the scalp surface. By direct measurement of the regenerated hairs, Myers and Hamilton (1951) found the growth rate to be 0.35 mm/day on the vertex and on the temple, and slightly greater in these sites in women than in men. Barman et al. (1965) measured hair growth using a shaving technique and obtained essentially the same figures. However, in this study the growth rate was slightly greater in men than in women (0.349 mm/day and 0.339 mm/day respectively) and this difference was more marked in children (boys 0.34 mm/day, girls 0.302 mm/day) (Pecoraro et al. 1964). Using the intra- dermal injection of 35S cystine to measure linear growth of scalp hair gave a daily average of 0.37 mm (range 0.31-0.41 mm) (Munro 1966). Saitoh and his colleagues in Japan (1969) used a capillary tube technique for measuring the rate of hair growth. They recorded an average daily growth rate of 0.44 mm on the vertex and on the chest, 0.29 mm at the temples and 0.27 mm in the beard. In regions of the body other than the scalp anagen is relatively short and telogen relatively long. There is some disagreement between the figures given by different authors, most of whom reported wide variations in each site (Saitoh et al. 1970). Pinkus (1947) observed a single follicle on the dorsum of one hand daily for 6 years, during which time 12 hairs were formed. The average lifespan of each hair was 180 days (107-195 days). The hairless intervals lasted in six instances 27-52 days, and in the other six 76-92 days. Pecoraro and colleagues (1970) studied the density and rate of growth of axillary hair in 126 subjects aged 10-74 years. The axilla was divided into three subregions, central, brachial and thoracic. There were no significant sex differences in hair density. Hair density and growth rate were highest in the central area. The hairs in the three subregions showed different qualitative responses to pregnancy. In all three subregions the hair density decreased with age. In contrast the pubic hair (Astore et al. 1979) showed a trichogram little influenced by ageing or pregnancy. The physiology/embryology of hair growth REFERENCES Astore, I.P.L., Pecoraro, V. & Pecoraro, E.G. (1979) The normal trichogram of pubic hair. British Journal of Derma- tology, 101, 441. Barman, J.M., Astore, I. & Pecoraro, V. (1965) The normal trichogram of the adult. Journal of Investigative Dermato- logy, 44, 233. Barth, J.H. (1986) Measurement of hair growth. Clinical and Experimental Dermatology, 11, 127. Barth, J.H. (1987) Normal hair growth in children. Pediatric Dermatology, 4, 173. Berth-Jones, J. & Hutchinson, PE. (1995) Novel cycle changes in scalp hair are caused by etretinate therapy. British Journal of Dermatology, 132, 367. Braun-Falco, O. & Fischer, C. (1966) Dynamik des normalen und pathologischen Harrwachstum. Archiv fiir klinische und experimentelle Dermatologie, 226, 136. Chuong, C.-M., Chen, H.-M., Jiang, T.-X. & Chia, J. (r99z) Adhesion molecules in skin development: morphogenesis of feather and hair. Annals of the New York Academy of Sci- ences, 642, 263. Courtois, M., Loussouarn, G., Hourseau, C. & Grollier, J.E (1995) Ageing and hair cycles. British Journal of Dermato- logy, 132, 86. Du Cros, D.L., Isaacs, K. & Moore, G.P. (1991) Distribution of fibroblast growth factor immunoreactivity in skin during wool follicle development. Annals of the New York Academy of Sciences, 638, 489. Hayashi, S., Miyamoto, I. & Takeda, K. (1991) Measurement of human hair growth by optical microscopy and image analysis. British Journal of Dermatology, 125, 123. Jahoda, C.A. & Oliver, R.E (1984} Vibrissa dermal papilla cell aggregative behaviour in vivo and in vitro. Journal of Embryology and Experimental Morphology, 79, 211. Jarrett, A. (1977) In: The Hair Follicle. London, Academic Press. Kligman, A.M. (1961) Pathologic dynamics of human hair loss. Archives of Dermatology, 83, 175. Meiers, H.G. (1967) Die Methode des Trichogrammes. Arzliche Kosmetologie, 6, 22. Munro D.D. (1966) Hair growth measurement using intra- dermal sulphur 35 cystine. Archives of Dermatology, 93, II9. Myers, R.J. & Hamilton, J.B. (1951) Regeneration and rate of growth of hair in man. Annals of the New York Academy of Sciences, 53, 862. Orentreich, N. (1969) Scalp hair replacement in man. In: Advances in Biology of Skin. vol. IX, Hair Growth (eds W. Montagna & R.L. Dobson), pp. 99-108. Pergamon Press, Oxford. 21Chapter 1 Pecoraro, V., Astore, I. & Barman, J.N. (1970) Growth rate and hair density of the human axillae. Journal of Investiga- tive Dermatology, 56, 362. Pecoraro, V., Astore, LP.L., Barman, J.M. & Aruajo, C. (1964) The normal trichogram in the child before the age of puberty. Journal of Investigative Dermatology, 42, 427. Pinkus, F. (1947) The story of a hair root. Journal of Inves- tigative Dermatology, 9, 91. Rushton, D.H., de Brouwer, B., de Coster, W. & Van Neste, D.J. (1993) Comparative evaluation of scalp hair by phototrichogram and unit area trichogram analysis within the same subjects. Acta Dermato-Venereologica (Stockh), 73, Igo. ; Rushton, D.H., James, K.C. & Mortimer, C.H. (1983) The unit area trichogram in the assessment of androgen- dependent alopecia. British Journal of Dermatology, 109, 429. Saitoh, M., Uzaka, M. & Sakamoto, M. (1970) Human hair cycle. Journal of Investigative Dermatology, 54, 65. Saitoh, M., Uzuka, M., Sakamoto, M. & Kobori, T. (1969) 22 Rate of hair growth. In: Advances in Biology of Skin, vol. IX Hair Growth (eds W. Montagna & R.L. Dobson), pp. 183-201. Pergamon Press, Oxford. Silver, A.F., Chase, H.B. & Arsenault, C.T. (1969) Early anagen initiated by plucking compared with early spontaneous anagen. In: Advances in Biology of Skin, vol. [IX Hair Growth (eds W. Montagna & R.L. Dobson), pp. 265-286. Pergamon Press, Oxford. Van Neste, D.J.J., Dumortier, M. & De Coster, W. (1989) Pho- totrichogram analysis: technical aspects and problems in relation with automated quantitative evaluation of hair growth to computer assisted image analysis. In: Trends in Human Hair Growth and Alopecia Research (eds D. Van Neste, J.M. Lachapelle & J.L. Antoine), pp. 155-165. Kluwer, Dordrecht. Witzel, M. & Braun-Falco, O. (1963) Uber den Haarwurzel- status am menschilden Capillitium unter physiologischen Bedingungen. Archiv fir klinsche und experimentelle Der- matologie, 216, 221.Chapter 2 / Hair follicle structure, keratinization and the physical properties of hair R.P.R. DAWBER & A.G. MESSENGER Physiology and biochemistry, 23 Histochemistry, 30 Hair structure, 35 Physical properties of hair, 45 Physiology and biochemistry (References, p. 33) All the cell layers within the outer root sheath are products of the hair matrix in the bulb (Fig. 2.1a,b). The area of active cell division is in the lower bulb and in the upper bulb adjacent to the dermal papilla. From the upper bulb to the zone of complete keratinization cells stream upwards and undergo successively the phases of orientation into layers, hardening and keratinization. The outer root sheath is not a product of the hair matrix but consists of a sleeve of cells continuous with, and similar in structure to, the surface epidermis. It is, however, an intimate part of the hair follicle which pos- sesses many ‘subsections’ which are anatomically and functionally separate (Hashimoto 1988; Hashimoto & Ito 1989). Hair bulb The hair matrix is made up of rapidly dividing cells in the lower bulb and the upper bulb surrounding the dermal papilla (Bertolino 1994, Whiting & Howsden 1996). These cells are several layers deep and have a very rapid turnover; it has been suggested that each matrix cell divides every 23-72 hours (Van Scott et al. 1963). Unlike the epidermal basal layer, there appears to be no diurnal variation in mitotic rate or chalone inhibition in the matrix (Bullough & Lawrence 1958; Kligman 1959; Epstein & Maibach 1969); these cells appear to be working ‘full-out’ during the anagen phase (Wright & Alison 1984; Dover 1988), this being Elastic properties, 45 Hair bending and stiffness, 47 Density of human hair, 48 Variations in hair fibre dimensions, 48 Mechanical properties of hair cuticle, 48 Electrical (static) charge of hair, 49 the suggested reason for psoriatic hair bulb matrix cell kinetics being normal (Shahrad & Marks 1976). At the end of the anagen phase of the follicular cycle continuous cell division slows down and finally ceases in catagen. Matrix cells possess a characteristic ultrastructure (Fig. 2.2). Most of the cell is occupied by the large spherical nucleus; within the scanty cytoplasm are many ribosomes and some mitochondria. Rough surface endoplasmic reticulum, a compact Golgi zone adjacent to the nucleus and arrays of cisternae and vesicles compose the rest of the cytoplasm. The cells are rich in RNA (Fraser et al. 1972). Desmosomal attach- ments and gap junctions are present between adjacent cells and, as in epidermal keratinocytes, filaments extend from the desmosomes into the cell cytoplasm. There are considerably fewer attachment sites between matrix cells than are found in the epidermal basal layer; this may facilitate easier movement of cells from the matrix to the upper bulb and suprabulbar area. The cells surrounding the dermal papilla are precursors of the hair fibre and the more peripheral matrix cells give rise to the inner root sheath. In the suprabulbar part of the follicle these cells become relatively long and thin, with distinct cell boundaries (Auber 19 52). The overall size of the cells and the relative amount of cytoplasm noticeably increase (Montagna & Van Scott 1958). These changes may relate to greater water content and protein synthesis. Ribosomes are mostly strung together as polysomes and a few bound ribosomes are evident. Golgi bodies are poorly developed in this 23Chapter 2 Epidermis Follicular canal Sebaceous duct Keratinized hair Outer root sheath Medulla Layers of Layers of Cuticle cortex presumptive inner root Huxley Cuticle hair sheath Matrix (germinal) zone of bulb {b) Fig. 2.1 A mature anagen hair follicle: (a) light micrograph; (b) line diagram with follicular components labelled. region and consist of a few vesicles adjacent to the nucleus; the endoplasmic reticulum is poorly developed (Parakkal & Maltoltsy 1964). Both nuclei and nucleoli remain prominent in suprabasal cells. The various layers ascending the follicle first become noticeable as cells of different shapes. Medullary cells remain relatively large and spherical whilst presumptive hair cortex cells become spindle-shaped. The structure of each layer will be considered separately, from its development from the appropriate bulbar matrix cells, through differentiation and cell death associated with keratinization higher up the follicle. 24 Medullary cells These differentiate from matrix cells adjacent to the apex of the dermal papilla. Distinctive microscopic changes can be observed before other cell layers are dis- tinguishable. Irregular dense granules develop from the Golgi apparatus (Auber 1952) and these enlarge by coalescing. By cytological and histochemical methods the granules can be differentiated from epidermal keratohyalin, though as will be seen later, the granules have some biochemical similarities to the inner root sheath protein (Harding & Rogers 1971). Medullary cells do not produce these proteins in significant amounts and harden by a different biochemical process than the keratin-forming cells of the cortex and cuticle (Powell & Rogers 1986). The function of medullary granules in man is not known. Medullary cells produce some filaments which are aggregated into bundles and are ran- domly distributed in the cytoplasm. As differentiation proceeds glycogen granules become evident, particularly near the nucleus and other cytoplasmic organelles begin to disintegrate. Mito- chondria begin to swell, the cristae lose orientation and the density of the matrix decreases. Finally the mitochondria become vacuolated like empty vessels. Fully formed medullary cells are wedged between pro- jections of cortical cells and in the fully developed hair, mature cells are arranged along the core of the hair with spaces between them. In vellus and lanugo hair, no medullary cells form and even terminal hair follicles may reveal complete absence or only infrequent medullary cells (Fig. 2.3a,b). Cortical cells These become visible microscopically, at a higher level in the follicle than presumptive medullary cells, as spindle-shaped cells which produce increasing amounts of cytoplasmic filaments parallel both to the long axis of the cell and the hair follicle (Figs 2.4, 2.5). The filaments grade into dense alpha-keratin fibrils but have no clear connection with tonofibrils. This zone of keratinization shows evidence of intense protein synthesis (Parakkal 1969), many polysomes being seenFig. 2.2 Electron micrograph at the junction of the dermal papilla (DP) and hair bulb. A melanocyte (Mn) containing mature melanosomes (M) is seen adjacent to a hair bulb matrix cell (Ma). together with strong nucleolar and cytoplasmic staining for RNA. The higher keratogenous zone shows increasing evidence of cytolysis; hydrolases are released from lysosomes (acid phosphatase stain) and the phospholipid reaction increases (Braun-Falco 1958a). At the same stage, nuclear degradation occurs. Ribosomes are the final organelle to disappear. Stable sulphydryl groups (cysteine reaction) are increasingly found towards the upper keratogenous zone. The fully keratinized ‘dead’ cortical cells retain a membranous nuclear outline (nuclear ‘ghost’) which persists into the hair shaft. Cuticle cells Presumptive cuticular cells elongate in the suprabulbar region and become flattened; during differentiation the cells increasingly overlap (Fig. 2.5). Tonofibrils and desmosomes are present but no alpha-keratin fibrils are produced. Increasing protein synthesis occurs during hardening and keratinization and dense cytoplasmic granules are visible. Reactive phospholipids and cysteine sulphydryl groups are detectable, contributing to the formation of a matrix rather than fibrillar, protein structure (Birkbeck 8& Mercer 1957). The physical properties of hair Hardening (keratin bonding) zone (Fig. 2.1b) During this phase before complete cell death and keratinization, the hair first acquires its strength and flexi- bility in the cuticle and cortex (Auber 1952). The hair fibre decreases in diameter by about 25%, probably due to a combination of water loss due to plasma membrane permeability changes, and contraction of keratin complexes from cytoplasmic water loss. In the final stages of keratin bonding, bound sulphydryl is oxi- dized to cystine and the cysteine reaction of the keratinized area decreases to negligible amounts. Inner root sheath (Figs 2.3b and 2.5) The inner root sheath consists of three layers, from within outwards, the cuticle, Huxley’s and Henle’s layers; the cuticle is one cell thick whilst Huxley’s layer is several cells deep. The cuticle interlocks with the cells of the hair cuticle and is intimately associated with it. All three layers are formed from the peripheral mass of matrix cells in the hair bulb. There is no evidence in man to support the idea that the basal cells of the outer root sheath cells overlying the hair bulb contribute to the formation of the Henle layer. 25Chapter 2 Outer root sheath Henle layer Huxley layer Inner root sheath Sa BUNGIE oo ee areata se Cuticle — Cortex . ; — Medulla Presumptive hair ib) 26 Fig. 2.3. (a) Concentric layers of the hair follicle (resin embedded section). Within the cortex (Co) only occasional medullary cells are present (M). Within the outer root sheath (ORS), all layers show keratinization, which in the Huxley layer (Hu) is only evident in the upper area. (b) Concentric cell layers of the suprabulbar portion of an anagen hair follicle.Fig. 2.4 Hair follicle (longitudinal section), showing the central cortex (Co) surrounded by the root sheaths. The Henle layer (at H) is keratinized. All three layers undergo differentiation in the same sequence but at different rates; firstly, the Henle layer, then the Huxley layer and finally, the cuticle. The late stages of hardening and cell death further up the follicle The physical properties of hair begin in the Henle layer (Fig. 2.4), then the cuticle and finally, Huxley’s layer. It is important to note that complete hardening and differentiation of the inner root sheath occurs before the layers of the developing hair 27Chapter 2 within it. Keratinization proceeds by the secretion of increasing amounts of trichohyalin and flattening of the cells. The trichohyalin granules (Fig. 2.5) are mostly attached to tonofilaments. The final stage of differentiation involves the disintegration of the nucleus,other organelles and the trichohyalin which becomes diffusely visible as electron-dense material between keratin filaments. This is particularly evident in the inner root sheath cuticle. In the lower follicle the junction between the outer root sheath and the Henle layer is maintained by desmosomes and gap junctions; higher up the follicle, after inner root sheath differentiation is complete, the relation with the outer root sheath is maintained by intercellular cement and by interdigitation between cells. The Huxley and Henle layers possess similar intimate methods of contact. With maturation, inner root sheath cells demonstrate thickening of plasma membranes and the deposition of amorphous intercellular material; cells shrink during keratinization, the mature inner root sheath thus becoming a rigid cylindrical tube surrounding the softer ascending hair structures within it (Fig. 2.3a). The fully formed inner root sheath shows detectable amounts of cystine, RNA and phospholipid, probably released from the degradation of hydrolysed organelle 28 Fig. 2.5 Hair follicle (electron micrograph). The inner root sheath cuticle (I.Cu) is visible adjacent to the hair cuticle (Cu). The Huxley layer (Hu) shows numerous (black) trichohyalin granules. membranes and trichohyalin (Jarrett 1958; O’Keefe et al. 1991). Trichohyalin can be purified as a soluble protein and has an extended rod-shaped structure ‘in native conformation. At the level of the follicular canal, desmosomal contacts between adjacent cells begin to be broken down and the cells, singly or in groups, are shed into the follicular canal. This desquamation is probably facilitated by hydrolases of lysosomal origin. The exact source of these enzymes is not known but they may be from the inner or outer root sheath (Straile 1962) or from sebaceous secretion. The prime function of the inner root sheath is probably to mould the hair within it. It effects this by hardening in advance of the hair; since the cuticles of the hair and inner root sheath are closely apposed, in health, the fully keratinized fibre takes the shape of the root sheath (Straile 1962; Swift 1977) and evidently of the layers outside this, including the connective tissue sheaths. Outer root sheath (Figs 2.3a and 2.6) This layer surrounds the hair follicle as a sleeve of cells several layers thick that is continuous with the epidermis (Hashimoto & Ito 1989). It is divisible into twoThe physical properties of hair Fig, 2.6 Outer root sheath. The nucleus (N) is surrounded by cytoplasmic glycogen (g). Adjacent to the cell is the perifollicular connective tissue membrane (coll.). parts: a short lower part surrounding the outer part of the bulb, and the upper part from the neck of the bulb to the level of the sebaceous duct. The area surrounding the follicular opening has the same structure and biochemical characteristics as the surface epidermis and will not be considered further. The part surrounding the hair bulb is one or two cells thick, the outer layer being elongated and the inner layer markedly flattened. In the suprabulbar area it is usually three cells thick and only becomes multilay- ered approximately half way along the follicle. The outer cell layer is the germinative layer continuous with the epidermal basal cells (Parakkal 1969); differentiation occurs in a centripetal direction towards the inner root sheath, the cells enlarging, flattening and becoming vacuolated. The exact fate of the cells adjacent to the Henle layer is not known though it seems likely that movement towards the surface occurs; this certainly occurs in some sheep and mice in which keratinized cells from the upper part of the outer root sheath are shed into the follicular canal along with the inner root sheath. It is possible that some keratinization occurs in the differentiating cells next to the inner root sheath (Jarrett 1958). The outer root sheath differs from the follicular canal in containing prominent Golgi vesicles associated with well-developed rough endoplasmic reticulum; the 29Chapter 2 amorphous cytoplasmic granules produced during differentiation probably develop from this organelle. The granules are not membrane bound. Membrane-limited vesicles are also present together with glycogen par- ticles (Parakkal 1969). The outer root sheath does not produce keratohyalin. The epidermis of the follicular canal differs from the surface epidermis only in degree. Ribosomes are arranged as polysomes lying free in the cytoplasm with only small Golgi vesicles and very little endoplasmic reticulum. The keratohyalin granules are smaller and rounder and more membrane-coating granules are seen than in the surface epidermis. Towards the sebaceous duct the membrane-coating granules decrease both in size and number. The exact function of the outer root sheath is not known. During the early stages of the anagen phase of the hair cycle it elongates rapidly because of a high rate of mitotic activity which ceases when the follicle reaches its full length; subsequent mitotic activity only continues at a rate equal to cell death or cytoplasmic obliteration (Bullough & Lawrence 1958; Montagna & Van Scott 1958) though some investigators have detected higher rates than this (Straile 1962). In general, the outer root sheath is considered a relatively static region displaying little indication of cell movement. However, the observation that partial keratinization occurs in the inner- most cells adjacent to the Henle layer suggests that the moving cylinder of inner root sheath plus hair may pull along the inner cells of the outer root sheath; these cells may also have a role in the differentiation and breakdown of the Henle layer. The outward migra- tion of outer root sheath cells in facilitating the movement of the cell layers within it during the anagen 6 phase, may account for the final outward movement of the terminal part of the hair during the last half of catagen after hair growth has ceased (Straile et al. 1961). Histochemistry (Swift 1977; Lane et al. 1991) Knowledge of the chemical nature of the various morphological components of the hair follicle has accu- mulated by four major methods: histochemistry, immunohistochemistry, electron _ histochemistry, autoradiography and analysis of material extracted 30 from different parts of the follicle (Gillespie 1983; Lane et al. 1991; Jones & Steinert, 1996). As in the epidermis and nail plate, the major protein structures are keratins in nature — filamentous (inter- mediate filament proteins; IF) or matrix (IF associated protein; IFAP) types in different sites. Keratins are highly differentiated, insoluble and resistant proteins in the horny cells of vertebrate animals; but of course most constituents of the keratin filaments already exist in the keratinocytes giving rise to the horny cells in the epidermis, hair and nail (Ogawa & Yoshike 1984). In hair follicle terms, keratinization, the differentiation of keratinocytes, is very complex since there are several specific concentric rings of keratinocytes with differing keratinization characteristics; the major zone of keratinization takes place in mid-follicle and is particularly obvious in the cells, giving rise to the hair cortex above this zone. The studies of Lane et al. (1991) have shown the sen- sitivity of a well-characterized panel of monoclonal antibodies to keratins. Within the hair follicle keratin (K) 7 is expressed deep in the follicle in the Huxley and Henle layers of the inner root sheath. Krg positivity is seen in the Wulsh area of the outer root sheath — thought to represent the site of pluripotential (progeni- tor) cells. K14 is exhibited in the outer root sheath epithelium only. K16 is seen predominantly in the upper follicle with K17 being more extensive in the deep follicle. Note that the latter shows prominently in basal cell carcinoma. The significance of this research will become more obvious as keratin studies move into hair shaft genetic defects particularly as new information appears almost by the day in the field of keratin gene expression in the hair follicle (Powell e¢ al. r991, 1992). For example, Stevens et al. (1996) have shown that monilothrix (autosomal dominant beading of hair) is linked to the trichocyte gene cluster r2g13. The hair follicle is such a complex structure with very many moving individual cell layers, all interrelated, that it will be some time before this very important genetic information becomes practically or therapeutically applicable (Bertolino & O’Guin 1993). Other, more detailed texts, describe the probable ix vivo chemical processes of keratinization in the different cell layers (Gillespie 1983; Ogawa & Yoshike1984; Baden 1988; Goldsmith 1986; Moll et al. 1988). It is of general interest that much of the ‘hardening’ and keratinization within differentiating matrix keratinocytes ascending the follicle involves transglutami- nase mediated cross-linkages as well as the more well-known —-S==S—~ (Cu2+ dependent) type. This is particularly well seen in the internal root sheath and hair medulla (Martinet ef al. 1988; Lichti 1991). Cystine and cysteine In the hair follicle the presumptive cuticle and cortex contain cysteine sulphydryl groups followed by cystine disulphide cross-links (hard keratin) in the fully keratinized hair: only small amounts are to be found in root sheaths, particularly the Henle layer. Stabilization and hardening in the follicle are accompanied by an increase in birefringence of the cortical zone. An alpha- keratin pattern without orientation has been found in the lower bulb using X-ray diffraction studies; keratinization is associated with the development of orientated alpha-keratin as seen in the hair cortex. This G-pattern precedes the formation of disulphide-rich proteins and corresponds to the development of fibrillar bundles in the cortical zone which subsequently acquire cystine-rich proteins (Rudall 1964). Autoradiographic studies have suggested that alpha- keratin-like, low sulphur fibrils (microfibrils) are formed first, and at a later stage an amorphous sulphur-rich matrix protein (interfibrillar) is deposited. Nucleic acids The dividing cells of the hair follicle matrix stain densely for DNA; through the suprabulbar region the intensity fades and the nuclei lose this stain during keratinization. Dermal papillary cell nuclei are strongly positive for DNA. The basal cells of the follicle show the greatest concentration of RNA. Differentiating cortical cells also contain large amounts of RNA associated with great numbers of ribosomes between cytoplasmic fibrillar bundles. As the cortical cells kera- tinize, RNA staining stops abruptly. The physical properties of hair Carbohydrates Glycogen is the main carbohydrate reserve store. Dermal papillary vascular endothelial cells contain glycogen but this is absent from follicular matrix cells; all the differentiated cell layers in the follicle contain glycogen but as cells harden, the amount decreases pro- gressively. Glycogen staining disappears as catagen succeeds the various phases of anagen. Acid mucopolysaccharides are detectable in the follicle connective tissue sheath and the dermal papilla; metachromatic stains are also positive in the peripheral layers of the outer root sheath. Very little acid mucopolysaccharide is detectable in the presumptive hair. Using electron histochemical methods a polysaccharide-rich layer is detectable around matrix cells of the hair bulb, particularly near desmosomes; this coat vanishes from differentiating hair cells but is retained in the inner root sheath—the retention of this coat may be important in the breakdown of the inner root sheath higher up in the follicle. Lipids Very little histochemical work has been carried out to detect lipids in hair follicles. Typically only undifferen- tiated matrix cells show lipid staining and only in small amounts. Prior to trichohyalin deposition early inner root sheath cells contain lipid granules. Phospholipid is evident in matrix cells and in the inner root sheath; these decrease as hardening proceeds. Arginine and citrulline Intensive staining for arginine is found in association with trichohyalin droplets in the developing medulla and inner root sheath. This decreases as cells undergo hardening. The structure of trichohyalin has been investigated extensively (Rogers 1964a,b; Fraser et al. 1972). Both the inner root sheath and medullary proteins are rich in acidic and basic amino acids, contain citrulline and are virtually devoid of cystine. Rogers (1964a,b) proposes that the medullary and inner root sheath trichohyalin globules contain 31Chapter 2 arginine-rich protein (arginine trichohyalin) which by desimidation of the arginine is transferred into citrulline. In biological terms, it seems likely that this method of inner root sheath and medullary hardening has evolved to limit the use of disulphide bond keratinization, which requires considerable amounts of sulphur-containing amino acids, to the cuticle and cortex. This is of great importance in coat formation in animals but whether it is of significance in man is not known. Enzymes (Braun-Falco 1958b) Optical histochemical techniques have demonstrated the presence of many enzymes within the hair follicle, in particular phosphorylase, aldolase, succinic dehydrogenase, cytochrome oxidase, alkaline phosphatase, acid phosphatase, glucose-6-phosphatase, esterases, carbonic anhydrase, aminopeptidase, B- glucuronidase and arginase. Alkaline phosphatase activity is present along the basement membrane and around the periphery of dermal papillary cells. Acid phosphatase activity is associated with preme- lanosomes, Golgi apparatus and endoplasmic reticulum of melanocytes. 32 Dermal papilla The connective tissue contained within the hair bulb is the dermal papilla. The size of the papilla and surrounding bulb are directly related to the size of the hair produced (Durward & Rudall 1958; Schinckel 1961). In anagen follicles the dermal papilla is attached to a basal plate of connective tissue by a narrow stalk. In small follicles there may be no visible vasculature but terminal hair follicles show variable numbers of papillary blood vessels. Papillary cells in the anagen follicle (Fig. 2.7) have prominent Golgi complexes and rough endoplasmic reticulum with bound ribosomes; even in the telogen phase appreciable cytoplasmic volume is still evident. At the beginning of anagen papillary cells show a marked increase in RNA content (Roth 1965). There is a close relationship between the mitotic activity of dermal papillary cells and hair bulb matrix cells (Straile 1965). The fact that papillary cell activity does not predate that in matrix cells is against the idea of the papilla initiating the anagen phase, but it seems probable that the dermal papilla determines the cyclical rhythm of the follicle (Cohen 1965). In rat vibrissae follicles, dermal-epidermal recombination and transplantation techniques have suggested a crucial role for Fig. 2.7 Dermal papillary cells. The cytoplasm shows endoplasmic reticulum (er). Collagen fibres (coll) are present between the cells.the dermal papilla in follicle development, the maintenance of follicles and the control of hair growth (Young & Oliver 1976; Oliver 1980). Early in vitro studies on cultured human dermal papillae cells suggest similar properties to rat vibrissae but shorter survival time (Messenger et al. 1986). Papillary capillary endothelial cells undergo mitotic activity during anagen (Helwig 1958) but these changes occur secondary to those in bulb matrix cells. In human anagen follicles the ratio of papillary cells to matrix cells is approximately 1: 9. Perifollicular structures A hyaline membrane surrounds the follicle; it is thin in the upper part and thick in the lower third. Two layers of collagen fibres surround the lower part, the inner one orientated parallel to the long axis and the outer one perpendicular. These layers are in continuity with the areolar tissue around the sebaceous gland and the papillary layer of the dermis; they also connect to the dermal papilla via the stalk. The blood supply to the follicle arises from the sub- dermal arterial plexus supplying the capillary tuft in the dermal papilla; connected to this are numerous shunts forming a rich plexus around the lower third of the follicle. No cross-shunts are detectable in the parallel vessels that run from about this zone to the higher region at the level of the sebaceous gland where a plexus is again present. Above this, the parallel longitudinal vessels terminate in capillaries surrounding the follicular opening. The whole length of the follicle is surrounded by many sensory nerves (Lynn 1988; Winkelmann 1988); many of these end in blunt terminals. This rich nerve supply reflects the clinical fact that hair fibres act as subtle organs of touch; this is clearly obvious to those subjects who lose all their body hair from disease or drugs. As well as the sensory follicular nerve supply efferent autonomic fibres supply the arrector pilorum muscle. All follicles appear to be innervated, usually by several myelinated fibres. The responses evoked by hair movement are mainly rapidly adapting. Ultrastructural studies have revealed a unique association between nerve terminals and pairs of Schwann cell processes in some hair follicles (Winkelmann 1988). In the hairy The physical properties of hair skin of many mammals, including man, small elevated areas are found often associated with large Tylotrich hairs. These contain the terminals of a single large myelinated axon located in close contact with Merkel cells deep in the epidermis. These are called Pinkus cor- puscles (Haarscheibe); they react to light pressure (Sin- clair 1981). A considerable amount of work has been carried out in recent years on a variety of peptides in cutaneous and hair follicle nerves; their exact physiological and pathological significance is yet to be clari- fied (Weihe & Hartschuh 1988). The arrector pilorum muscle is attached to the follicle well below the site of the ‘entry’ of the sebaceous duct. It has generally been considered to attach to one side of the follicle at the so-called bulge (? stem cell) zone. It has recently been shown that its follicular attachment surrounds the follicle in association with the perifollicular connective tissue sheath (Narisawa 8 Kohda 1993). REFERENCES Auber, L. (1952) The anatomy of follicles producing wool fibres with special reference to keratinisation. Transactions of the Royal Society of Edinburgh, 62, 191. Baden, H.P. (1988) Keratin. In: Pharmacology of the Skin, vol. I (eds M.W. Greaves & S. Shuster), p. 31. Springer- Verlag, Berlin. Bertolino, A.P. & O’Guin, W.M. (1993) Differentiation of the hair shaft. In: Disorders of Hair Growth (ed. E.A. Olsen), pp. 21-38. McGraw-Hill, New York. , Birkbeck, M.S.C. & Mercer, E.H. (1957) The electron microscopy of the human hair follicle. Il. The hair cuticle. Journal of Biophysical and Biochemical Cytology, 3, 215. Braun-Falco, O. (1958a) The fine structure of the anagen hair follicle of the mouse. In: Advances in the Biology of the Skin, vol. IX, Hair Growth, ch. 29 {eds W. Montagna & R.L. Dobson). Pergamon Press, Oxford. - Braun-Falco, O. {1958b) Histochemistry of the hair follicle. In: The Biology of Hair Growth, ch. 4 (eds W. Montagna & R.A. Ellis). Academic Press, New York. , Bullough, W.S. & Lawrence, E.B. (1958) The mitotic activity of the follicles. In: The Biology of Hair Growth (eds W. Montagna & R.A. Ellis), p. 171. Academic Press, New York. Cohen, J. (1965) The dermal papilla. In: Biology of the Skin and Hair Growth, ch. 12 (eds A.G. Lyne & BF. Short). Angus and Robertson, Sydney. 33Chapter 2. Dover, R. (1988) Cell kinetics of the human hair follicle. Clinics in Dermatology, 6(4), 32. Durward, A. & Rudall, K.M. (1958) The vascularity and patterns of growth of hair follicles. In: The Biology of Hair Growth (eds W. Montagna & R.A. Ellis), p. 189. Academic Press, New York. Epstein, W.L. & Maibach, H.I. (1969) Cell proliferation and movement in human hair bulbs. In: Advances in Biology of the Skin, vol. IX, Hair Growth (eds W. Montagna & R.L. Dobson), p. 83. Pergamon Press, Oxford. Fraser, R.D.B., MacRae, T.P. & Rogers, G.E. (1972) Keratins: Their Composition, Structure and Biosynthesis. Thomas, Springfield. Gillespie, J.M. (1983) The structural proteins of hair: isolation, characterization and regulation of biosynthesis. In: Biochemistry and Physiology of the Skin, vol. 1 (ed. L.A. Goldsmith), p. 475. Oxford University Press, Oxford. Goldsmith, L.A. (1986) Cytokeratins — promiscuous molecules. Archives of Dermatology, 122, 594. Harding, H.W.J. & Rogers, G.E. (1971) The E-lysine cross- linkage in citrulline-containing protein fractions from hair. Biochemistry, 10, 624. Hashimoto, K. (1988) The structure of human hair. Clinics in Dermatology, 6, 7. Hashimoto, K. & Ito, M. (1989) Keratinization of outer root sheath of human hair. In: Acne and Related Disorders, 1st edn (eds R. Marks & G. Plewig), p. 3. Martin Dunitz, London. Helwig, E.B. (1958) Pathology of psoriasis. Annals of the New York Academy of Science, 73, 924. Jarrett, A. (1958) The chemistry of inner root sheath and keratins. British Journal of Dermatology, 70, 271. Jones, L.N. & Steinert, P.M. (1996) Hair Keratinization in Health and Disease. Dermatologic Clinics (Update on Hair Disorders), 14(4), 633. Kligman, A.M. (1959) The human hair cycle. Journal of Investigative Dermatology, 33, 307. Lane, E.B., Wilson, C.A., Hughes, B.R. & Leigh, IM. (1991) Stem cells in hair follicles. In: The Molecular and Structural Biology of Hair (eds K.S. Stern, A.G. Messenger & H.P. Baden), pp. 197-213. New York Academy of Sciences, New York. Lichti, U. (1991) Hair follicle transglutaminases. In: The Mol- ecular Structure and Biology of Hair (eds K.S. Stern, A.G. Messenger & H.P. Baden), pp. 82-91. New York Academy of Sciences, New York. Lynn, B. (1988) Structure, function, and control: afferent ’ nerve endings in the skin. In: Pharmacology of the Skin, vol. I (eds M.W. Greaves & S. Shuster), p. 175. Springer-Verlag, Berlin. 34 Martinet, N., Kim, H.C., Girard, J.E., Nigra, T.P., Strong, D.H., Chung, S.I. & Folk, J.E. (1988) Epidermal and hair follicle transglutaminases. Journal of Biological Chemistry, 263, 4236. Messenger, A.G., Senior, H.J. & Bleehen, S.S, (1986) The i vitro properties of dermal papilla cell lines established from human hair follicles. British Journal of Dermatology, 114, 425. Moll, I., Heid, H.W., Franke, W.W. & Moll, R. (1988) Pat- terns of expression of trichocytic and epithelial cytokeratins in mammalian tissue. Differentiation, 39, 167. Montagna, W. & Van Scott, E.J. (1958) The anatomy of the hair follicle. In: The Biology of Hair Growth (eds W. Mon- tagna & R.A. Ellis), p. rx. Academic Press, New York. Narisawa, Y. & Kohda, H. (1993) Arrector pili muscles surround human facial vellus hair follicles. British Journal of Dermatology, 129, 138. Ogawa, H. & Yoshike, T. (1984) Keratin, keratinisation and biochemical aspects of dyskeratosis. International Journal of Dermatology, 23, 507. O'Keefe, E.J., Hamilton, E.H. 8 Payne, R.E. (1991) In: The Molecular and Structural Biology of Hair (eds K.S. Stern, A.G, Messenger & H.P. Baden). New York Academy of Sci- ences, New York. Oliver, R.E (1980) Local interactions in mammalian hair growth, In: The Skin of Vertebrates (eds R.LC. Spearman & PA. Riley), p. 199. Linnean Society Symposium Series, No. 9. Parakkal, PE. (1969) The fine structure of the anagen hair follicle of the mouse. In: Advances in Biology of the Skin, vol. IX, Hair Growth (eds W. Montagna & R.L. Dobson), ch. 29, Pergamon Press, Oxford. Parakkal, PF. & Maltoltsy, A.G. (1964) A study of the differentiating products of the hair follicle. Journal of Investiga- tive Dermatology, 43, 23. Powell, B.C. & Rogers, G.E. (1986) Hair keratins: composition, structure and biogenesis. In: Biology of the Integu- ment (eds J. Bereiter-Hahn, A.G. Maltoltsy & KS. Richards), p. 696. Springer-Verlag, Berlin. Powell, B., Crocker, L. & Rogers, G. (1992) Hair follicle differentiation. Development, 114, 417. Powell, B.C., Nesci, A. & Rogers, G.E. (1991) Regulation of keratin gene expression in hair follicle differentiation. In: The Molecular Structure and Biology of Hair (eds K.S. Stern, A.G. Messenger & H.P. Baden}, pp. 1-20. New York Academy of Sciences, New York. Rogers, G.E. (1964a) Structural and biochemical features of the hair follicle. In: The Epidermis (eds W. Montagna & W.C. Lobitz), p. 202. Academic Press, New York. Rogers, G.E. (1964b) Isclation and property of inner root

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