INTRODUCTION

Hair is an important distinguishing feature for mammals, (Young, 1981), although some insects (bees, spiders, etc.) have a complex sensory system of tactile thread-like structures which give the insect a knowledge of its surroundings and its own body position. Mammalian hair fibres produced by the keratinisation of cortical cells extruded from the hair follicles in the epidermis, form the coat or ‘pelage’ characteristic of the mammals. All the vertebrates have developed a variety of glands and pigmented structures as derivatives of their epidermis (scales, claws, quills, nails, horns, feathers and hairs), as adaptations to changing environments. The epidermis thickens to give a topological epithelial appendage or structure with specialised functions; protection, insulation, hunting, flight, communication and so on. However, it is only in the mammals where ‘Endothermy’ occurs; the maintenance of a relatively constant body temperature independent of that of the surrounding environment allowing a high level of activity over prolonged periods, independent of ambient temperature changes. This single ability has given the mammals their huge evolutionary success.

The overriding importance of the mammalian coat is to insulate the warm blooded mammals against heat loss, (Vaughan, 1986), i.e. to give them the ability to control their own environment, however, the ‘pelage’ has important secondary functions. It maintains sensory support with tactile hairs and whiskers on the animal’s body, allowing sensory positioning and protection and it provides sexual and social communication (Oliver & Jahoda, 1989). The colouration and pattern of the pelage communicates camouflage or self-advertisement and is important for communicative behaviour (Cott, 1940).

The pelage has regenerative properties and ‘determinate’ growth occurs in most mammals, i.e. the coat is renewed by a periodic ‘moult’ (Ebling, 1965). A synchronised telogen effluvium occurs and a majority of the hair follicles in specific areas of the pelage enter the non-growing phase and are shed. The new anagen hair, which may vary in colour and texture from the preceding hair fibre, forms the new pelage, the pattern of moulting varying from species to species and within successive cycles in the same species (Ebling, 1965). In many mammals the moult proceeds in a ‘wave’ across the body in a seasonal regeneration controlled by the photoperiod – the duration of daylight – and the sexual cycle (Ebling, 1965). Moulting provides for replacement of ‘wear and tear’ and the ability to allow colour and density changes to adapt to seasonal and climatic changes. The thick white winter coat of the Arctic Fox, for example turns to a shorter, red-brown coat in the summer (Ebling, 1991). In Man, the hair growth is non-synchronous, or ‘indeterminate’ and proceeds on a continuous basis, although seasonal variations in human beings are present. Human scalp was shown to exhibit an annual cycle with 90% of hairs in the anagen growing phase in the spring and early summer, falling to 80% at the end of the summer, (Randall, 1991), confirming an environmental influence on follicular activity. In this mosaic pattern of moulting the activity of each hair follicle is independent of that of its neighbour, (Ebling, 1986), and any connection between the sexual cycle and the hair cycle has been lost.

In some mammals the hair coat is reduced; it is almost completely missing on the naked skin of whales, it grows sparsely on the skin of elephants and naked skin appears on the buttocks of some monkeys. In Man, hair, although covering almost the entire body, is drastically reduced in thickness and length and full hair growth effectively remains only on the scalp, beard, axillae and pubic areas. Small fine unpigmented vellus hairs cover the whole body except the palms, soles, lips and mucous areas. Thicker, longer, pigmented terminal hairs form the areas considered to be hairy. In man the primary insulating effect has been effectively lost and the role of social and sexual communication has become paramount.
HAIR GROWTH
Hair consists of long keratin fibres, twisted in a rope-like structure with a central, rigid medulla and an outer protective cuticle or coating of hardened, keratinised cells giving a structure of considerable tensile strength (Wolfram & Lindeman, 1971). The hair is produced from the hair follicle, an oblique downward indentation of the epidermis which protrudes into the dermis and encloses at its lower end the dermal papilla, a mesenchyme derived cluster of a small number of specific cells which regulate the behaviour of the epithelial cells or keratinocytes (Pinkus, 1958). The layer of cells immediately above the enclosed papilla constitutes the matrix from which a cone of cells differentiates, moving upward to form the hair shaft, or growing fibre structure which becomes keratinised and hardened to form the final hair structure, extruding from the skin or the scalp. The hair fibre at this point is dead tissue and it is only the growing or germinating root of the hair where the living, soft hair cells are to be found. These highly active hair follicles cover the whole of the human body, except for the palms of the hands, soles of the feet, and the mucous areas, the number of hair follicles remaining the same as we have at birth. The body cannot grow or produce any more hair follicles, although follicular loss can occur in some dermal tumours and cicatricial alopecias (Dalziel & Marks, 1986).

Hair growth proceeds on a cyclical basis through a repeated cycle of active follicular growth and rest phases (Kligman, 1959), orchestrated by the dermal papilla which produces the required proliferative or inhibitory stimuli for hair growth regulation. The length of each phase is determined by age, sex, genetic profile and follicular body site, and can be further influenced by systemic and external factors (Jarrett, 1997; Ebling, 1986). The length of the anagen (growing) phase determines hair length and in human scalp hairs, anagen lasts from 2 to 5 years or on average 1,000 days (Orentreich, 1969), although some Indian women may have an extended anagen cycle for scalp hair of 7 or 8 years. Conversely, the hair growth cycle on the finger may be 1½/3 months (Saitoh, 1970). Anagen commences with the downward movement of the follicle, enclosing the dermal papilla and accompanied by a dramatic increase in mitotic activity of the germinal cells at the base of the follicle, recreating the original morphogenesis of the follicle in foetal skin (Spearman, 1977). The follicle extends to its maximum length, melanin is formed by the melanocytes, and the new hair shaft is formed, keratinising just below the level of the sebaceous gland. The previous resting telogen ‘club’ hair is ejected from the follicle and the new hair emerges at the skin surface. Anagen proceeds until the onset of the catagen (regression) phase when mitosis at the germinating matrix ceases, and the catagen phase begins (Parakkal, 1970), lasting only a few days. The dermal papilla moves upward as the hair follicle shortens and the lower section of the hair shaft becomes club shaped, lacks pigment and is only partially connected to the epithelial cells as the hair follicle enters the telogen (resting) phase. The non-growing hair shaft is held in the upper section of the hair follicle in man for approximately 100 days (hence a normal anagen/telogen of 10:1, i.e. approximately 90%), and morphogenesis of the new anagen phase is re-commenced at the end of telogen. It has been suggested that the co-existence of the new anagen hair and the previous telogen hair ensures that the animal is never naked (Stenn, 1998), and as the process of active hair shedding may constitute a separate distinct phase in the follicular cycle; the term “exogen” has been proposed (Stenn, 1996).

The shedding of dead hair is a natural process, non-synchronised across the human scalp, and it is normal to lose hairs each day. A healthy scalp has 100,000 to 120,000 hair follicles and a hair fall of 100 to 300 per day would be normal, with the new hair already growing in the hair follicle alongside the previous dead hair which it helps to push out. Complex control systems mediate hair cell mytosis and hair growth with a genetically determined response to androgens at the onset of puberty. In adults differential gene expression within follicles from various body sites gives an intrinsic follicle response to the circulating androgens and produces the characteristic body hair patterns of humans.
HAIR SHAFT STRUCTURE
The mesenchyme derived dermal papilla, containing fibroblast-like cells, initiates cell division, keratinisation and hair shaft formation and the size of the papilla and surrounding bulb are directly related to the size of hair shaft produced (Durward, 1958). The inner root sheath (IRS) and outer root sheath (ORS) provide the funnel shaped mould through which the hair shaft emerges and determine the final cross section of the hair shaft. This hair shaft cross section is genetically determined and may vary from circular (Caucasian) to oval or flat (Negroid) with the hair produced varying in shape from cylindrical to a twisted “ribbon” pattern and a number of specific shaft defects, monilithrix, pilli torti, pilli annulati, etc., are known (Davies, 1996). Epidermal cells proliferate, differentiate and elongate, moving upward into the hair shaft, and human hair growth has been shown to be approximately 0.3 mm/day (Braun-Falco, 1959). Electron microscope studies (Mercer, 1957) have confirmed keratinisation to be complete approximately 1 mm from the germinating root area, and to be relatively rapid, with approximately 2½ days to completion (Forslind, 1996). Programmed cell death (apoptosis) occurs as the hair cells move upward; they are compacted and elongated, lose moisture and protein synthesis ceases with the eventual loss of the cell nucleus, and keratinisation is complete (Forslind, 1986).

The filament structure of the hair shaft has been reviewed (Forslind, 1990; Steinert, 1993). The central medulla, a hollow tube-like structure, which may be partially filled with melanine, spongy cellular matter and air spaces, is surrounded by ‘whorl-like’ cortical structures of straight protein filaments or macrofibrils aligned along the hair shaft axis in a twisted, helical, rope-like structure (Johnson & Sikorski, 1965) of high tensile strength and elasticity held together by a matrix of intercellular cement which is also composed of twisted polypeptide chains very rich in the amino acid cysteine. The outer cells of the cutex, 6-10 layers deep, are flattened, plate-like and overlap to form the protective cuticle structure with an outer lipid coating.
The chemical composition of hair is highly complex with the insolubility of the keratinous protein accounting for the very stable hair structure, and hair over 55,000 years old has been identified (Cooper, 2003). The main component of hair is protein, approximately 65-95% by weight (Gillespie, 1983) with water, lipids, pigment, trace elements (Passwater, 1983) and DNA also present (Cooper, 2003). Keratin is a protein containing abnormally high levels of sulphur and human hair contains approximately 5% sulphur (Forslind, 1986). The component amino acid units of the protein are chemically bound together by peptide linkages to form long chain polypeptides which in keratin are arranged in an alpha-helix configuration, like a coiled spring, with three or four amino acids in each turn of the helix. In the zone of keratinisation the polypeptide chains become connected by cross linkages between the coils of the chain and between adjacent coils. The strong S-S disulphide bond (or cysteine linkage) between coils gives keratin its ladder-like structure and considerable tensile strength.

In the keratin structure the weaker ionic bonds and hydrogen bonds between the coils contribute to the integrity of the structure whilst allowing elasticity of the hair. The low-sulphur containing microfibrils are formed first in the lower bulb with the cysteine-rich, high sulphur proteins being produced later (Rudall, 1964) as the elongating cells ascend in the hair follicle.

The extruded hair shaft initially retains its integrity but may subsequently be damaged by chemical treatment or weathering with Fragilitis Crinium (split ends) common at the distal end as the cortical structure collapses. The outer cuticle layer breaks down or is lost to expose the inner cortical structure which unravels and breaks down, losing the shaft integrity. The root of the hair shaft will exhibit the telogen “shaving brush” pattern when growth has ceased or the anagen appearance of a plucked hair with the soft cellular tissue trail and possibly other follicular remnants present.

HAIR FOLLICLE BIOLOGY
In man, at approximately 50 days gestational age, basal epidermal cells concentrate to form a cluster or hair germ and protrude downwards into the dermis surrounding the cluster of mesenchymal cells that will form the dermal papilla. They aggregate together to form a “hair peg” in a flat-bottomed concave bulb-like structure enclosing the mesenchymal cells of the dermal papilla to form the hair follicle.

At 12-15 weeks gestational age, the hair follicle bulge partially differentiates to form the sebaceous gland and the arrector pilli muscle, the presumed site for stem cell formation (Cotsarelis, 1990). At nineteen weeks the first laguno hair emerges (Holbrook, 1991) to be shed usually immediately before birth (Kligman, 1961). A second laguno synchronised shedding occurs during the first three or four months of life, following which the mosaic pattern of shedding becomes established. The cells overlying the top and sides of the dermal papilla ascend and keratinise to form the three layers of the presumptive hair shaft (medulla, cortex and cuticle), the three layers of the inner root sheath (IRS), the cuticle, the Huxleys layer, the Henleys layer, and the outer root sheath (ORS) which coat and support the emerging hair shaft. The inner root sheath hardens and is keratinised before the hair fibre which it encases and thus determines the resultant hair shaft cross section (Swift, 1977). The inner cuticle layer closest to the hair shaft is only one cell deep and interlocks with the cells of the hair cuticle, and is held in intimate contact with it. As the developing hair fibre ascends to the zone of keratinisation approximately at the mid-point of the hair follicle shaft, intense protein synthesis occurs (Parakkal, 1969), the cells become elongated, the nucleus disintegrates and the final hair structure is formed at the completion of apoptosis. At the bulge area the inner root sheath layer desquamates and the outer root sheath keratinises to form the stratum corneum indistinguishable from the surrounding epidermis (Sperling, 1991).

Skin appendages, including hair, all develop from a common genesis, a thickening of the epidermis which protrudes outward, or invaginates downwards into the dermis to form the specialised skin structure. It has been shown (Chuong, 1998) that changes could be induced from this common genesis and that appendages form in multiple stages which can be interconverted. Some of the molecules involved in these early stages have been identified (Hardy, 1992) and a molecular pathway proposed for:-

Induction → Morphogenesis → Differentiation → Cycling

The hair follicle of an adult mammal is unusual in that it retains its morphogenic code and signals, enabling it to regenerate itself throughout the life of the animal (Sten, 1996). Our current understanding of the molecular ‘morphogenes’ that modulate skin appendage morphogenesis and the several molecular pathways proposed have been comprehensively reviewed (Tobey, Wu-Kuo, 2000).

Many molecules have been found to influence the formation of skin appendages including signalling molecules and cell adhesion molecules, some of which are known growth factors (Peus, 1996). The main molecular pathways for hair growth are thought to be SSF (secreted signalling factors, morphogenes that have an effect on skin appendage morphogenesis), nuclear factors (the morphogenesis designers) and transmembrane molecules with extra cellular matrix proteins (or cell adhesion molecules – the morphogenesis designers). It appears that skin appendage morphogenesis represents controlled molecular signalling and cellular activity, whereas skin tumours represent uncontrolled cell activity. Further research could provide the possibility of mapping a gene route by which skin appendages, such as the hair follicles, are formed (Chuong, 2000).

HAIR FOLLICLE STEM CELLS
Stem cells are undifferentiated multi-potent cells with a high proliferative potential whose function is the regeneration and re-population of their host and, since the hair follicle is able to regenerate itself regularly, it must have a source of epithelial stem cells. Their role and location has been reviewed (Miller, 1993 & Morrison, 1997).

It is now known that most tissues, e.g. epidermis, muscles, etc., possess stem cells to allow regeneration and re-population after wounding or trauma, giving the tissue self-renewing ability. The stem cell reservoir for the hair follicle lies at the bulge situated approximately at the arrector pilli muscle attachment point and maintains a column of cells for epithelial hair follicle keratinocytes. It is the ultimate cell reservoir for the highly active hair follicle. The bulge area is a prominent feature in human fetal skin development, but is less easily identified in adults and the arrector pilli attachment site is not necessarily an exact location (Wilson, 1994; Lyle, 1998).

The undifferentiated stem cells have a high proliferative potential and produce both other stem cells and proliferative transient amplifying cells which are responsible for replenishing the cells lost after apoptosis, and for regeneration and re-population after wounding or trauma. In the epidermis each stem cell maintains a column of cells and is referred to as an “epidermal proliferative unit” (Cotsarelis, 1999), producing approximately nine transient amplifying cells for each stem cell. In the hair follicle the stem cells from the bulge area generate the seven different cylindrical cell layers of the hair and follicle, and the bulge keratinocytes may be the ultimate reservoir for both epidermal and follicular keratinocytes (Cotsarelis, 1999).

The sequence for hair growth cycling has been proposed (Lyle, 1998): (i) Bulge activation at the onset of anagen in response to a signal from the dermal papilla, (ii) Dermal papilla activation; dermal papilla cells proliferate in early to mid-anagen, (iii) Finite proliferation of matrix keratinocytes that will determine the duration of the anagen phase, and (iv) the upward migration of the dermal papilla during catagen which comes to rest adjacent to the bulge area during telogen.

The hair follicle bulge is the lower most part of the ‘permanent’ hair follicle and most keratinocytes below the bulge are lost during catagen, although there is a remnant of epithelial cells around the base of the hair follicle. This bulge area of the outer root sheath, which provides the cell reservoir for continued hair growth, may be the target area for agents involved in various scarring and non-scarring alopecias. If the bulge area remains intact during alopecia, hair growth may re-commence as in alopecia areata reversal (Olsen, 1994), or it may be permanently damaged and re-growth will not be possible as in androgenic alopecia (Jaworsky, 1992).

It has also been suggested that epithelial stem cells may be the point of origin for certain tumours. Some of these highly active stem cells may be pre-disposed to any accumulation of genetic alterations and tumours may arise from the hair follicle bulge (Miller, 1993).

The signalling process and stimuli for this movement of the dermal papilla are not clear but the dermal papilla must ascend to the bulge and be aligned with it, or the hair growth cycle will not recommence and a new hair will not be formed (Cotsarelis, 1990).



HAIR PIGMENTATION
Melanocytes in the hair bulb synthesise the dark sulphur-containing pigment, melanin, in highly concentrated organelles, the melanosomes, which are transferred to the keratinocytes and incorporated into the developing hair shaft structure to produce the final hair colour.

Embryogenesis of the pigment cell system has been studied (Holbrook, 1989) and the melanocyte distribution in human skin determined. Melanoblasts from the neural crest proliferate and differentiate into active melanocytes migrating to the epidermis and the hair bulb. The mechanism for proliferation and differentiation of pigment cells is not clear, but activation by stem cell factor and tyrosinase kinase receptor activity are important to support melanoblast survival and migration to the hair follicle in embryo (Nishikawa, 1991).

Adult melanogenesis mediates hair and coat colour by varying the amounts of different melanins, synthesised under genetic controls (Hearing, 1991). After the initial common, metabolic pathway, the amino acid tyrosine is converted into “eumelanin” (black/brown in colour and insoluble) and “pheomelanin” (reddish-brown and alkali soluble) mediated by enzymes, principally the copper containing enzyme tyrosinase and its metabolites, and it has been suggested that white hairs might contain less copper than black hairs (Bertazzo, 1996). Pheomelanins arise by oxidative polymerisation of the amino acid cysteine and are sulphur containing (Prota, 1998). A third group “oxymelanins” are similar to the pheomelanins but contain no sulphur. The switching mechanism between eumelanin synthesis and pheomelanin synthesis by the follicular melanocytes is complex and is not fully understood (Prota, 1998). Melanin biosynthesis takes place in the melanosomes with the progressive deposition of melanins on the internal matrix.

Mature melanosomes are transported by motor proteins and embedded in the hair shaft keratin. Some melanosomes are deposited in the sponge-like keratin of the medulla, but most are in the hair cortex aligned parallel to the hair shaft axis. There are no melanosomes in the cuticle and inner root shaft (Yamamoto, 1994). Melanogenesis is intimately linked to the cyclical activity of the hair cycle and melanosomes increase in size and number during anagen, reducing in number and pigmentation at the close of anagen. There is no tyrosinase activity during catagen and telogen and pigmented melanocytes disappear from the hair bulb. The hair bulb melanocytes may die in early catagen by apoptosis (Tobin, 1998), or they may survive successive cycles, possibly in a different undifferentiated state (Sugyiama, 1976).

Follicular melanocyte activity and proliferation are regulated by biochemical signals from the hair follicle and linked to the hair follicle cycle. By contrast epidermal melanocyte production is regulated by UV exposure. Reduced levels of melanin, hypomelanosis, presents clinically as “Poliosis” (piebaldism) and “Vitiligo” of the skin which are characteristically not diffuse (Comings, 1966). In cases of alopecia areata, a partial failure of the auto-immune system (Friedmann, 1981), re-growing hair is frequently white and may not regain full pigmentation indicating impaired melanisation of keratinocytes.

The white colour hair seen when melanin is absent is an optical effect caused by reflection and refraction of the incident light at the hair surface (Findlay, 1982). Non-pigmented hair with a broad medulla appears whiter than non-medullated hair and is used to effect camouflage by artic animals.

The progressive reduction in melanocyte function and the gradual dilution of pigment leads to “canities” or “grey hair”, which is variable in age and degree but is generally considered to be part of the ageing process. The mechanism for this loss of pigmentation is not fully understood, but a decrease in the number of hair follicle melanocytes might be linked to a defect in redox-regulated melanin synthesis, which may increase auto-cytotoxicity of some intermediates associated with a decrease and eventual cessation of tyrosinase activity in the lower bulb (Kukita, 1955). BCL-2 is a human proto-oncogene located on chromosome 18 and is a known apoptosis inhibitor (Hockenberg, 1993). BCL-2 deficient mice turn grey with second hair follicle growth, presumably the absence of an apoptosis regulator allows uncontrolled melanocyte loss and hair pigment disappears. BCL-2 might be implicated in grey hair growth in humans (Veis, 1993).

In mammals the colour of the pelage is important for camouflage, and sexual attraction, although in man hair colour has no essential biological function and is purely decorative. Lanugo hair present ‘in utero’ is unpigmented and vellus hair remains unpigmented until puberty. Terminal hair colour varies according to body site (Wasserman, 1974) and terminal hairs vary in colour both between individuals and in their different stages of an individual’s life. Loss of scalp hair colour occurs with old age while hairs in other regions become darker after puberty, e.g. in the beard area.
ANDROGENS – HAIR GROWTH REGULATORS
Androgens are the main hair growth regulators and this was known from very early times. The circulating androgens have a differing effect on individual hair follicles, which are known to be site-specific. In children, scalp hair, eyelashes and eyebrows grow normally with no androgens present. The appearance of male and female sex hormones at puberty alters the hair growth pattern in both sexes into well defined patterns and the androgens have both a stimulatory and inhibitory effect. The follicles of the male beard are changed from vellus hair production to terminal hair production (Hamilton, 1958), whereas in cases of androgenic alopecia the reverse process occurs in the defined areas (Hamilton, 1942, 1960). The hairs of the ear canal by contrast start to produce longer hair in males at about 50 years of age in response to androgens (Setty, 1969), whereas the hair growth of the eyebrows remains unchanged. Androgens and the differing hair growth response present a paradox.

Androgens are the normal regulators of human hair growth, although other hormones can influence follicular activity; hormones secreted by the thyroid, increased oestrogen levels during pregnancy, and melanocyte stimulating hormone (MSH) have a stimulatory or inhibitory effect on the hair growth cycle.

At puberty, in response to androgen stimulation, the vellus hairs of the axillae and pubis, which are fine, soft, poorly pigmented and with no central medulla, are converted to thicker, medullated terminal hairs with pigmentation. Following puberty, plasma androgen levels rise with a gradual change of beard growth from vellus to terminal, fully established at around 30 years of age (Hamilton, 1958), and hair canal hair growth not established until 50 years of age (Hamilton, 1946).

Successive hairs from the same follicle are therefore able to change in density and colour as, for example, in cases of androgenic alopecia (Hamilton, 1951), and it is probable that the same hair follicle is capable of producing lanugo, vellus and terminal hair. The cell biology for these different androgen responses is not completely clear.

Puberty requires functioning androgen receptors as well as increased androgens to occur and terminal axillae, pubic and beard growth is often a marker of this endocrine change. In the absence of 5-α-reductase [the enzyme that catalyses the irreversible reduction of testosterone to the more active metabolite dihydrotestosterone (DHT)], only axillae and pubic hair growth occurs, mediated by the testosterone itself. Patients with complete androgen insensitivity syndrome have no body hair at puberty and do not suffer androgenic alopecia despite normal or raised androgen levels (Quigley, 1998). Individuals with complete androgen insensitivity syndrome thus develop none of the adult body hair changes after puberty, nor do they develop androgenic alopecia confirming the essential role of androgens and androgen receptors in adult human hair growth. Men with 5-α-reductase type 2 deficiency have axillary and feminine pubic hair patterns with very little beard growth and no androgenic alopecia but their body shape becomes masculinised at puberty (Wilson, 1993). The secondary sexual hair patterns in the male are dependent on the effective presence of DHT.

Elevated androgen levels in women, as in cases of polycystic ovaries (PCO) can produce hirsutism, excess hair growth in the male pattern (Conway, 1989). This can be idiopathic in nature with a case reported of hirsutism on one side of body (Jenkins, 1973).

Beard growth and androgenic alopecia do not revert to pre-pubertal levels following castration (Hamilton, 1942 and 1958). This suggests that the androgens are needed to switch or trigger these changes and there is also some dependence on continued androgen presence to maintain the status quo.

The current hypothesis for androgen action proposes that androgens in the blood stream enter the hair follicle via the capillaries in the dermal papilla and bind to specific intra-cellular androgen receptors (of androgen sensitive follicles), some having first been converted to DHT which also enters and binds to the appropriate receptors. This in turn stimulates alteration of paracrine factors resulting in changed keratinocyte and melanocyte activity. Cultured dermal papilla cells can secrete proteinaceous agents that promote growth in other dermal papilla cells (Randall, 1991; Thornton, 1998).

Several paracrine factors can be altered by androgens, insulin-like growth factor (IGF-I) (Itami, 1995), and stem cell factor (SCF) which may play a role in androgen-regulated changes in hair pigmentation.

Androgen response in individuals depends on their personal gene expression but they appear to act on the hair follicle by altering the production of paracrine factors which as yet are not fully identified.
ANDROGENIC ALOPECIA
DESCRIPTION
The replacement of pigmented terminal hairs by smaller pale vellus hairs in a distinctive pattern usually on the crown and frontal areas post puberty characterises androgenic alopecia and produces a slow and degenerative change in the hair growth of the scalp (Hamilton, 1951). Universally referred to as common baldness or male pattern and female pattern alopecia.

The length of the anagen phase of the hair cycle begins to decrease in the affected areas of the scalp, producing hairs of successively reduced length, colour and diameter. Miniaturisation continues until follicular activity ceases and atrophy of the hair follicle occurs. The process has until recently been considered irreversible (Simpson, 1991).

At puberty the male sex hormone, testosterone, appears in both sexes and is partially converted by the enzyme 5--reductase into the more active metabolite dihydrotestosterone (DHT), and the steroids androstenedione and androstanedione (Schweikert, 1974). The enzyme, 5--reductase, appears to be involved in androgenic alopecia and higher 5--reductase activity has been found in balding scalp follicles, compared with non-balding follicles (Schweikert, 1974). Also finnasteride, a 5--reductase (type 2) inhibitor, has been used orally to halt progression or partially reverse androgenic alopecia in stump-tailed macaques (Rhodes, 1994) and in humans (Kaufman, 1996). Individuals with complete androgen insensitivity syndrome do not exhibit androgenic alopecia showing that effective androgen receptors are a prerequisite for balding to occur (Quigley, 1998).

The scalp begins to show the characteristic bi-temporal recession and movement of the front hair line in men with thinning of the frontal and crown areas, proceeding in pre-determined stages, leading ultimately to complete baldness in some cases. The occipital and parietal areas do not usually exhibit hair loss.

Women have a different pattern of hair loss. The hairline is retained and thinning occurs behind the hairline on the frontal and crown areas, and the occipital areas may also be affected. Complete baldness in women is unusual, although it is possible for some women to experience hair loss in the male pattern (Ferriman, 1961). The hair loss patterns are described as “Hamilton” for men, modified by Norwood, and “Ludwig” for women (Hamilton, 1951; Ludwig, 1977; Norwood, 1975).

The incidence of androgenic alopecia is very high in male Caucasians approaching 100% (Dawber, 1988), with wide genetic variations, and is as low as 50% in Japanese and Afro-Caribbean men (Takashima, 1981). The incidence of androgenic alopecia is lower in women (approximately 50%) but there is claimed to be currently an increase in occurrence in young women, while post menopause it is claimed that 37% of women have a marked recession in the male pattern (Venning, 1988). Some of the other primates exhibit androgenic alopecia: Orang-utans, chimpanzees, gorillas and stump-tailed macaques, although both sexes are thought to pattern in the male form. Conversely, androgens stimulate increased hair growth in adult males of some animals, the mane of the lion, the antlers of the deer and the beard of the goat (in both sexes apparently).

Whilst an increased hair growth in adult males would seem logical to distinguish a dominant breeding male particularly the oldest leading animal, there is no convincing evolutionary theory for the natural progression of hair loss and baldness, with the attendant stress and reduced life quality when this shift is premature (Cash, 1992).

PATHOGENESIS
Androgenic alopecia proceeds with a shortening of the anagen (growing) cycle, and as the telogen phase on the scalp lasts approximately three months (Kligman, 1959), the anagen/telogen ratio is changed and this can be detected by unit area, trichogram measurement (Rushton, 1983). It is also thought that the length of the telogen phase may increase in androgenic alopecia, further distorting the anagen/telogen ratio.

The gradual miniaturisation of the hair follicle produces smaller, less pigmented, hair and the sebaceous gland (also an androgen dependant tissue) becomes enlarged and the scalp has an oily and greasy appearance. There is also a reduced blood supply to the follicle, the blood capillaries becoming partially atrophied, but it is not clear whether this is the cause or the effect of this androgen stimulated change (Crovato, 1968; Randall, 1996). The hairs produced are progressively shorter (Rushton, 1991), and miniaturisation of the follicle can be seen histologically (Whiting, 1993) as the process proceeds over several follicular cycles. Perivascular degeneration in the lower third of the connective sheath of otherwise normal anagen follicles occurs, followed by perifollicular lymphohistiocytic infiltration at the level of the sebaceous duct. The inflammatory component in androgenic alopecia is controversial and does not present clinically. The remains of the connective tissue sheath can be seen as “streamers” (Kligman, 1988), and this destruction may account for the irreversibility of hair loss.

The arrector pili muscle also reduces in size, but this reduction proceeds more slowly (Maguire, 1963). Electron microscopy studies of hair shaft structure in common baldness showed no abnormality (Puccinelli, 1968), and no abnormality in chemical composition of the hair shaft has been found (Salamon, 1971). Miniaturisation continues until cessation of hair growth and the scalp area appears bald. The miniaturised quiescent hair follicles lay dormant and the unsupported nerve network is coiled, twisted and truncated.
The progression of androgenic alopecia is under genetic control and Hamilton (1942) established that common baldness was a normal process activated by the androgens at puberty and the genetic influence was pronounced. It was shown that the balding response to androgen replacement in castrated men depended on family history and balding could not be induced by androgens where there was no family history of baldness (Hamilton, 1942). Androgenic alopecia is considered to be an autosomal dominant trait with variable penetration (Bergfeld, 1955). Racial variation in the progression of common baldness confirms the genetic influence, but it has not yet proved possible to identify the specific genes involved.

ROLE OF ANDROGENS
The central role of androgens in the progression of androgenic alopecia has been observed since earliest times. Aristotle recorded that eunuchs did not go bald and that the testes were associated with maleness. The first systematic correlation was made by Hamilton who showed that men castrated before puberty did not go bald and that eunuchs treated with testosterone therapy subsequently developed androgenic alopecia, and that the process arrested when therapy was withheld (Hamilton, 1942). More specifically, it is known that males born with androgen receptor deficiency exhibit no androgen effects post puberty and appear as phenotype women with no external testes and no axillary, pubic or body hair growth (Kuttenn, 1979), and that androgenic alopecia does not proceed (Quigley, 1998). It was also shown that in males with 5--reductase deficiency where testosterone is not converted to dihydrotestosterone (DHT) partial masculinisation occurs. Axillary and pubic hair grows but there is little or no hair on other body sites (Fisher, 1978). It is probable that testosterone is necessary for the expression of terminal hair and that DHT is needed to regulate hair growth.

In cases of androgenic alopecia in men circulating androgen levels are not elevated (Phillipou, 1981), and normal androgen levels trigger the follicular regression in the genetically determined areas which is related to the inherent response of the follicles themselves. In women androgen levels do appear to be related to hair loss (Georgala, 1986) in women with an inherited pre-disposition. Excess androgen production in women can produce hirsutism, the growth of excess hair in women in the male pattern (Ferriman, 1961).

Androgens circulate in the blood stream and are absorbed into the cells through the plasma membrane where they bind to the specific androgen receptors. Testosterone and DHT both bind to these androgen receptors and the androgen message is transmitted to the nucleus by specific messenger proteins. Human hair follicles are known to contain androgen receptors (Messenger, 1988), and as the DHT has greater binding power than the testosterone itself (Wilson, 1976). DHT is one of the key agents in the mechanism for the progression of androgenic alopecia.

The current hypothesis (Randall, 1990) for the androgen mechanism in the hair follicle suggests that androgens bind to androgen receptors in the mesenchyme derived dermal papilla which then alter the expression of paracrine factors and modify the subsequent follicle growth activity. The androgens either initiating the production of inhibitory growth factors or reducing the production of stimulatory growth factors. It is known that androgen stimulated cells from beard, axilla and pubic hair follicles contain androgen receptors and metabolise testosterone in vitro (Randall, 1994).

Similarly dermal papilla cells cultured from human androgenic alopecia hair follicles showed higher levels of specific androgen receptors than non-balding follicles, and that these receptors had the same pattern of binding affinity and were of the same type (Hibberts, 1998).

Androgens are assumed to act via the dermal papilla where they bind to specific intro-cellular receptors to give a conformational change in hormones which alter the specific gene expression, altering the resultant protein synthesis (Randall, 1994). The response to circulating androgens varies between different hair follicles with a pronounced genetic dependency and occurs at the post-receptor stage.

Androgenic alopecia does not reverse in men castrated after puberty (Hamilton, 1942), and there is clearly a triggering mechanism which requires androgen stimulus and androgens are also required for further progression.

TREATMENT
The ideal treatment for androgenic alopecia could be developed after isolation of the specific gene or set of genes responsible, but the high incidence has prevented this so far.

A number of drug therapies are available, but the genetic nature of the condition makes effective treatment very difficult, and a reduction of the rate of progression represents a realistic expectation.

Anti-androgens are not the first drug of choice as they would tend to block all systemic androgens with consequent loss of masculinity in men, and possible feminisation of a male fetus in women. However, a number of these anti-androgens have been used, cyproterone acetate, spirolactone, and they may have some clinical effect on progression (Burke, 1985). There has also been some success with systemic and topical oestrogen treatment, although the use is restricted to women. Oestrogens are indirect anti-androgens increasing the production of sex hormone binding globulin (SHBG) and giving a decrease in bioactive testosterone. They were shown to prolong the anagen cycle, and inhibit sebum secretion (Winkler, 1969; Moretti, 1977).
Inhibition of 5--reductase and hence inhibition of DHT synthesis offers a more elegant approach and a number of these blocking agents are known, a number of which occur naturally.
The best researched drug for this application is finnasteride, a 5--reductase type 2 inhibitor, used originally for the treatment for benign prostatic hyperplasia, and shown in clinical trials to have a hair growth effect (reviewed by Kaufman, 1998). The conversion of testosterone to dihydrotestosterone is blocked and the miniaturisation of the hair follicle does not proceed. Finnasteride is a systemic treatment administered orally at a dose of 1mg per day (although used at 5mg per day for prostatic disorders). Three double blind, placebo controlled trials totalling 1,879 men aged 18-41 years with mild to moderate androgenic alopecia showed reduced hair loss and increased scalp coverage increasing the length and girth of existing miniaturised hairs (Kaufman, 1998). The beneficial effect is lost within twelve months if treatment is discontinued due to the underlying genetic pre-disposition with the androgen receptors still present. It was not effective in the treatment of post-menopausal women and it is contra-indicated in women of childbearing age due to possible birth defects of the male fetus. Some side effects (less than 2%) have been reported in men, including reduced libido, erectile dysfunction and reduced ejaculate volume.

The topical application, transdermal approach is probably the most useful to reduce potential side effects and to control the delivery point. Minoxidil is the best known of the topical applications and was groundbreaking when discovered in the 1970s, the first time androgenic alopecia had been shown to be partially reversible. Minoxidil is a vasodilator (Olsen, 1985) used orally for the treatment of hypertension which was found as a side effect to stimulate hypertrichosis. A topical preparation was developed for the treatment of androgenic alopecia and in some cases alopecia areata. Minoxidil was found to increase the length of the anagen phase of the hair cycle and was effective in partially reversing the miniaturisation process and the appearance of more terminal hairs gave a measurable cosmetic response (Olsen, 1985). Approximately 25-30% of men in a study of 2,294 balding men treated with minoxidil 2% or 3% had moderate re-growth (Olsen, 1989) apparent after 4-6 months which plateaued after approximately one year. Cessation of treatment resulted in loss of the re-grown hair within 3-4 months. The response to minoxidil treatment in cases of alopecia areata is controversial (Fielder, 1992; Epstein, 1993) especially as spontaneous reversal can be a feature of this condition. Clinically Minoxidil treatment for androgenic alopecia was found to be useful, but not ideal. The re-growth was in most cases modest, and the hair was lost when treatment ceased. Minoxidil is a vasodilator and the increased blood and nutrient (and androgen) supply to the dermal papilla would seem beneficial. The exact mode of action of minoxidil is not known, but it probably acts as a potassium channel opener and it is helpful in cases of androgenic alopecia.

Countless other remedies have been proposed for the treatment of androgenic alopecia (Lambert, 1961), and probably cover most of the spectrum of the material world. There is often a body of anecdotal supporting evidence but only limited clinical data, but an open mind is always essential when reviewing treatments. The topical route is the preferred option to reduce systemic effects, control dose and point of delivery at the hair follicle and particularly the dermal papilla. There are without doubt other agents available that could have a physiological effect and could be used to control, or partially reverse the progression of androgenic alopecia, and traditional Chinese medicine and Ayuverdic medicine provide documented systems of health care that could provide such active agents.

The ultimate treatment for androgenic alopecia and certainly the most effective is the employment of a surgical procedure for the rearrangement of the hair follicles on the scalp. The response to androgens is intrinsic to the individual hair follicle and this site-specificity forms the basis of cosmetic hair transplant surgery. It was shown that the dermis of the fronto-parietal region of the quail chick develops from the neural crest during embryogenesis, whereas the occipital-temporal areas of the scalp developed from the mesoderm (Ziller, 1996), and if this is mirrored in humans it may explain this differing response to androgens in cases of androgenic alopecia.

- posted by andrew @ 8:30 AM