31 Oct

Hair Growth Study

Introduction

Hair provides no vital function for humans, but its psychological effect is nearly immeasurable. Luxurious scalp hair expresses femininity for women and masculinity for men. The lack of scalp hair or the presence of excessiver> facial or body hair is often as distressing to females as the loss of beard and body hair is to males. Male pattern baldness, although accepted in our society, is still distressing to most men, and they will often go to great lengths to preserve, restore, or regrow hair on their scalps. The hair responsible for secondary sexual characteristics, such as the beard or mustache in males and pubic and "axillary" hair in both males and females, serves no particular function. Axillary hair is a characteristic almost exclusive to humans. Most likely, such hair exists to disseminate glandular odor from the apocrine glands, which become functional when the hair develops. Hairs emerge in patterns on the skin's surface.1 Although axillary hair grows in rows, hair on the sacral region, on the umbilicus, and occasionally on areas of the abdomen grows in whirls.2,3 Hair on the vertex of the scalp can grow in rows or whirls. Mongoloids have straight hair because their hair follicles are straight and perpendicular to the surface of their skin. Blacks have spiral- shaped hair because their hair follicles are curved. Whites, on the other hand, may have hair that is straight, spiral, or wavy. All forms of hair are chemically indistinguishable and are dependent upon polygenic traits.4 Hair color is dependent on the number and types of melanosomes present in the cortex of the hair. Brown or black hair contains many melanized eumelanosomes, red hair contains pheomelanosomes, and the eumelanosomes in blond hair are incompletely melanized. Gray hair contains few melanocytes in the hair bulb, and its melanosomes are also incompletely melanized.

Morphologically, there are three types of hair: vellus, terminal, and intermediate. * Vellus hairs are short, fine, soft, usually non-pigmented, and un-medullated. * Terminal hairs are large, darkly pigmented, and medullated. Ninety percent of the hairs on the chest, trunk, shoulders, legs, and arms of men are terminal hairs, whereas only 4500 of hairs in the same regions on women are terminal.5 * Intermediate hairs occur on the scalp, and they demonstrate a morphology between those of terminal and vellus hairs. Intermediate hairs are medullated and contain a moderate amount of pigment, i.e., less than that found in terminal hairs.6

The balding process is a conversion of the follicles so that they produce vellus hairs rather than terminal hairs.7 Each type of hair undergoes repeated cycles of active growth and rest. The relative duration of each cycle varies with the age of the individual and the region of the body where the hair grows. The length of the cycle is often modified by a variety of physiologic and pathologic factors. The cyclic phase of the hair follicle is identified by an active growth period, known as anagen; an intermediate period, catagen; and a resting stage, telogen.

In the anagen phase, the follicle reaches its maximum length, and there is proliferation of the matrix cells, which produce the internal root sheath, the cortex and medulla of the hair shaft, and the cuticular layers of the hair shaft and inner sheath. Anagen hair generally has a thick shaft; and in given segments, its medulla is clearly visible. The proximal-most part of the bulb in anagen hair is deeply pigmented.

The bulb gradually tapers and becomes lighter in color at and beyond the keratogenous zone of the follicle. In "epilated" anagen hair the inner and outer root sheaths are intact and are wrapped around the bulb portion of the hair. Catagen hair, in its involutional form, differs from telogen (clubbed) hair in two ways: (1) its keratinized (proximal) part is darker than that of clubbed hair and (2) its inner and outer root sheaths are better preserved.8

Telogen hair or clubbed hair is easily recognized because it generally contains a thin shaft, which is transparent near the root and devoid of a medulla and keratogenous zone. Epilated telogen hair may be wrapped in the remains of an epithelial sac, which is absent from nongrowing, spontaneously shed clubbed hair.

Of the 100,000 to 150,000 scalp hairs on a human adult (regardless of sex), 90% are in the growing, or anagen, phase (Table 1). The remaining 10% are in the resting (telogen) phase, which lasts for about 100 days. Approximately 50 to 100 clubbed hairs are shed each day. All of this, of course, differs among individuals.

On the scalp, human hair grows at a rate of 0.44 mm/day at the vertex and 0.39 mm/day at the temples,9 and scalp hair grows slightly faster in women than in men. The darkest hairs on the human body are usually the eyelashes. These hairs and the hairs that form the eyebrows are the first terminal hairs to appear. Eyelashes grow

Table 1 Hair dynamics

Scalp hairs 100,000 to 150,000 Anagen (90%), grows 4 to 8 years Telogen (10%), rests 2 to 4 months

Eyelashes. trunk, and extremities Anagen, grows 1 to 6 months Telogen, rests 2 to 4 months

Growth rate (mm/day) Scalp series 0.44 Temple 0.39 Body, heard 0.27

for approximately 30 days, undergo quiescence for 15 days, and remain dormant for about 100 days. Coarse body hairs and beards grow about 0.27 mm/day. Axillary hair is characteristically curled and twisted about its linear axis, and this hair varies from 1 to 60 mm in length.9 Hair in the pubic area typically grows in an inverted- triangle pattern in women; but in men, it grows in a rhomboid pattern with the apex of the rhomboid's long axis pointing toward the umbilicus.

The character of human hair is constantly changing from the prenatal period to old age; and under given physiologic conditions, the same hair follicle can successively form different types of hair. Lanugo, the first-generation hair appears during intrauterine life and is silky and glossy and contains no pigment or medulla.10 Near the end of pregnancy, lanugo is replaced by second- generation hair which is already pigmented and can grow to a maximum length of 2 cm.

Fine vellus hairs begin to change to terminal hairs before the onset of puberty; and with advancing age, the terminal hairs develop and thicken on all parts of the body. Eyelashes and eyebrows become fully formed before puberty. They grow steadily thicker during childhood but remain relatively unaltered throughout adulthood. Eyelashes have the widest diameter of body hairs and are the most highly pigmented of the terminal hairs.11 Maximum development of terminal hair in men occurs during the fourth decade. The formerly nonpigmented vellus hairs that occur in the ears develop into long, coarse terminal hairs particularly on the tragus, antitragus, and external auditory meatus. Long, coarse hairs also begin to grow on the lateral two thirds of the eyebrows.11 Despite differences among individuals, follicle development for all types of hair is virtually the same.

The Growth and Development of Hair

Hair grows from primary follicles, which are formed by the differentiation of cells in the embryonic epidermis, and further growth causes the hair to become embedded in the dermis (Figure 1). The hair papilla is formed from mesodermal cells. Completion of the terminal pilosebaceous unit requires (1) a vascular network, (2) nerve tissues to surround the follicle, and (3) the arrector pill muscle being inserted into the wall of the follicle.

Primitive hair germs, which are observed as a focal crowding of basal-cell nuclei in the fetal epidermis, are formed in the ninth week of intrauterine life and first appear in the regions of the upper lip, eyebrows, and chin. All further

figure 1. Embryonic development of follicle

primary follicle germs begin to develop over the surface of the body during the fourth month of gestation. As the fetus grows, new primary germs form among the existing ones, and secondary germs develop in such an orientation to the primary germs so as to form new follicles in groups of three. The mesenchymal cells that surround the new follicles are undifferentiated but begin to look like fibroblasts upon maturation of the follicles.12 Rapid, oblique proliferation of cells into the mesenchyme transforms the hair germs into hair pegs.

A solid column of epithelial cells, with radially arranged cells at its base, forms the matrix of the follicle. The free end of the peg becomes progressively clubbed and indented, and the concavity at the tip deepens to enclose the dermal papilla. At this stage, two solid epithelial swellings begin to appear on the posterior side of the follicle. The one nearest the epidermis differentiates into the sebaceous gland. Just below this gland, the mesenchymal cells arrange themselves in a linear, slender band that is parallel to the posterior border of the follicle. These cells gradually extend downward and become attached to the bottom bulge and form the arrector pili muscle. Melanocytes, already present at the hair-germ stage (and at later stages), can be seen in the bulb and at all levels of the outer root sheath.13 In fetuses, Merkel's cells (unassociated with neurites) tend to concentrate around the outer root sheath, but they are not present around postnatal follicles.13

Hair follicles are not vascularized in the early stages of their development. When the follicles enlarge and contain hair; capillary networks develop nearby, and capillary loops are formed in the dermal papillae. As noon as an embryonic follicle attains its definitive length, mitotic activity in the cone of cells in the upper part of the bulb increases, and the differentiation of these cells produces hair A second concentric cone of cells surrounds the first and becomes the future internal root sheath. The inner cone produces the cortex and hair cuticle, but no medulla exists in fetal hair The cone of the internal root sheath extends upward and protects the tip of the hair as it grows into the hair canal. In the upper part of this canal, the internal root sheath breaks; and later the hair emerges on the surface of the skin. During its development, the follicle grows both downward into the dermis and upward into the epidermis. Its intra epidermal segment terminates at the infundibulum of the follicle. No race-related or fundamental sex differences occur in the number or distribution of primordial embryonic follicles.

The first coat of long, fine lanugo is shed in utero about one month before full- term birth. The second coat, which consists of short lanugo and appears on all areas except the scalp (where the hair is long and large), is shed during the first three to four months of life. Scalp hairs grow in groups of two to three or more, but each hair has its own follicular membrane. Active follicles are long and are embedded deep in the skin. In the pilosebaceous units - from the center of the face - the sebaceous gland is predominant, and rudimentary follicles (together with the hair) almost disappear among the mass of sebaceous tissue cells. Beard hairs sometimes grow pili multigemini from a double papilla, but each has separate epithelial follicular layers surrounded by a joint-connected tissue sheath.

Microstructures of the Follicle and Hair

Actively growing hair follicles penetrate the entire epidermis and dermis; and on the scalp, these follicles extend into subcutaneous adipose tissue. At its lower end, the follicle expands into the bulb whose ovoid central cavity is filled by a connective-tissue papilla.

The Hair Bulb

The dermal papilla (the connective tissue within the invagination at the bottom of the hair bulb) has an abundance of cell components, which include fibroblasts, histiocytes, melanophages, mast cells, and Langerhans' granule-containing cells. The papilla also contains a loose texture of fibrous elements. The dermal papilla is supplied by a profuse system of small blood vessels, which are comparable with subepidermal capillaries. Their vascular walls are lined by a single layer of flat endothelial cells that rest on a distinct basal lamina, which is incompletely surrounded by pericytes. The intercellular junction of the endothelium contains an intermediate junctional complex. The flat endothelial cells are frequently fenestrated by 0.1-um pores.14 The pores are irregularly spaced and are closed by a thin diaphragm, which appears to be continuous with the cell membrane. Near the base of the follicle, the vascular basal lamina consists of at least two or three thin membranous layers, which show no age-related variations. The basal lamina in the dermal papilla, however; is characterized by concentric multilaminations that range from two to more than 20 layers, each of which display an onionskin-like arrangement. These concentric multilaminations are not prominent in individuals 10 years of age or younger; but in older individuals, these features are significant and unmistakable.

Thickening of the perivascular basal lamina is a physiologic effect of aging, and it characterizes various disease conditions, including diabetes mellitus.14 Extensive accumulation of basal lamina in capillaries has been noted in patients who have diabetes mellitus, and this accumulation appears to be the result of repeated episodes of endothelial injury. When examined by alkaline phosphatase techniques, dermal papillae in telogen reveal no capillaries.

When telogen follicles become anagen again, the developing hair bulb advances through the collapsed vessels below the dermal papilla, and a new vascular network is generated. As catagen proceeds, the blood vessels still remain intact, but they finally disappear from the dermal papilla; and the lower plexus forms a tight bundle of vessels around and beneath the papilla. It can be argued, therefore, that the amount of concentric multilamination of the perivascular basal lamina, in the dermal papilla of human bait; intimately relates to the episodes of repeated death and regeneration of endothelial cells and to the number of hair cycles.14

Connective-tissue cells of dermal papillae are separated from follicular epithelia by basal laminae, the continuity of which is interrupted only rarely by pseudopod-like extensions of basal cells.12 The mesenchymal cells in the dermal papilla are attached together at sites along their plasma membranes, and this forms an intermediate junction. The function of the attachment sites is unknown; but, presumably they allow the cells to work in concert. Because it is likely that control of cell growth is, at least in part, biochemical in nature, intracellular substances that alter growth and development preferentially pass through these junctions.

However, "gap" junctions have never been found. It has been noted that hair follicles devoid of a dermal papilla fail to form hairs. If dermal papilla cells are transplanted to the base of a hair follicle that has a severed matrix, a new matrix will form and produce hair.15

Two forms of concentric lamellar bodies have been observed14 in the cytoplasm of mesenchymal cells in the dermal papilla of normal anagen scalp hair: (I) those composed of agranular membrane arrays that are associated with beta- glycogen particles (known as glycogen lamellar bodies) and (2) those with a smooth-surfaced endoplasmic reticulum (known as smooth surfaced concentric lamellar bodies). Both forms have been found in mesenchymal cells of dermal papillae and in other types of cells in a wide variety of animals. No specific significance has been found for these cytoplasmic structures and

figure 2. Distribution of mitotically active cells in bulb of anagen follicle

no consistent relationships have been documented between cell type and the forms of lamellar bodies studied. The formation of these cytoplasmic structures could result from the degeneration of cells after injury or it could indicate a recovery process rather than a degenerative event.

The second portion of the hair bulb involves the hair matrix, which consists of rapidly dividing cells in the base of the bulb and is the part that surrounds the dermal papilla. The proliferative zone is the annular matrix in the portion of the bulb located below the "critical" level (Auber's line), i.e., below a line passing through the widest diameter of the papilla (Figure 2). Mitosis also occurs in a few of the germinal cells of the bulb above the apex of the papilla, but the bulk of mitotic activity occurs in the lower portion of the matrix. The nucleus of a matrix cell is large and spherical, and many ribosomes and mitochondria are located within its scanty cytoplasm. These cells are rich in RNA and contain desmosome attachments and gap junctions. Each matrix cell may divide every 23 to 72 hours during the anagen phase.

figure 3. Differentiation of cells in bulb

In the pre-elongation zone above the critical level, the cells first enlarge and then align themselves in a vertical direction. The cells that surround the dermal papilla are precursors of the hair fiber, and the peripheral matrix cells form the internal root sheath (Figure 3).

In the cellular elongation zone of the supra bulbar portion of the follicles, the cells become long and thin with distinct boundaries. Above this zone, in the prekeratinization zone, they acquire basophilic fibrils. The overall size of the cells and the relative amount of cytoplasm they contain noticeably increase as a result of their increased water content and increased intracellular protein synthesis. The nuclei and nucleoli remain prominent in this zone.17

Melanocytes, with few dendritic processes but with a dense accumulation of melanosomes, are located above the apex of the papilla, at the upper pole of the bulb. The dendrites project into the intercellular spaces between the developing medullary cells and cortical cells. In the phase of differentiation, parts of the dendrites (together with melanosomes and pigment granules) are phagocytized and migrate into the cytoplasm of the medullary and cortical cells.11,18

Medullary cells do not produce significant amounts of protein, but they do produce some filaments that aggregate into bundles and become randomly distributed in the cytoplasm. As differentiation proceeds, glycogen granules appear particularly near the nucleus. In the final stages of differentiation, the nucleus and other cytoplasmic organelles begin to disintegrate. Fully formed medullary cells become wedged between projections of cortical cells; and in fully developed hair, these cells are spaced along the hair's core. Vellus and lanugo hairs contain no medullary cells, and even terminal hair follicles may not contain medullary cells.

When hair bulbs are treated with arachidonate, melanocyte complexing and dissolution are altered.18 This evidence suggests that arachidonate, through the production of endogenous prostaglandins, may stimulate the dispersion of melanosomes into the dendritic processes of melanocytes by peripheral orientation of the microfilaments in the hair-bulb melanosomes.18

Cortical Cells

Cortex cells come from the concentric ring of germ cells localized in the bulb immediately above the apex of the papilla (Figure 3). Their successive keratinization occurs in the keratinization zone (Figure 4). In the lower segment of the keratinization zone, these spindle- shaped cells produce cytoplasmic filaments that are parallel with both the long axis of the cell and the hair follicle. Intense protein synthesis is evidenced by the occurrence of large numbers of polysomes and by strong nucleolar and cytoplasmic staining of RNA.19 The filamentous material is generally high in molecular weight (45,000 to 60,000 daltons) and low in sulphur content; it also has between 30% and 60% helical content (as measured by optical rotary dispersion or circular dichroism).20 These materials aggregate into dense alpha-keratin fibrils that have no obvious connection with the tonofibrils. Matrix material forms a bed in which the filaments are arranged in an organized fashion. It is thought that these two types of materials are connected by disulfide bonds.

The matrix material appears to be (1) much more heterogeneous, (2) lower in molecular weight, and (3) of consistently higher sulphur content than that found in the filaments.21 Halfway up the keratinization zone, tonofibrils begin to increase in number, and the rate of protein synthesis decreases. The amount of RNA diminishes and finally disappears at the distal end of the keratinization zone. The quantities of cysteine and phospholipids increase as an apparent consequence of cell membrane degradation. During cytolysis, nuclei lose their DNA, mitochondria and ribosomes degenerate, and incomplete nuclear- membrane structures are left behind in the cytoplasm. Above the keratinization zone, cysteine is converted to cystine, and the cell membrane becomes thicken The diameter of the fully keratinized hair decreases by 25% because of (I) the loss of water that results from the permeability of the plasma membrane and (2) the contraction of the keratin complex. The fully keratinized, dead cortical cells retain a membranous nuclear outline (nuclear ghost) that persists into the hair shaft. At this level, the prevalent -SH groups in the pre-keratin are replaced by S-S bonds.21

Hair Cuticle

Hair cuticles originate from primordial bulb cells that contain amorphous cytoplasm granules. The cuticular cells elongate in the suprabulbar region and become flattened (Figure 4). During differentiation, the cells increasingly overlap. Tonofibrils and desmosomes are present, but no alpha-keratin fibrils are observed. During hardening and keratinization, dense cytoplasmic granules are visible, and cystine disulfide groups are detectable. These groups form a matrix rather than fibrillar protein structures. The cuticular cells contain no fibrils, and the cystine matter in their cytoplasm is amorphous. The overlapping cells of the cortex's cuticle are directed outward, and they interdigitate with the cuticular cells of the inner root sheath.

The cells of the hair medulla, cortex, and cuticle all cornify without prior formation of keratohyalin granules or trichohyalin granules.22

Inner Root Sheath

The inner root sheath consists of three layers: the cuticle, Huxley's layer, and Henle's layer The cuticle is one cell-layer thick, the thickness of Henle's layer is one to two cells, whereas Huxley's layer is several cells deep (Figure 4). All three layers are formed from the peripheral mass of matrix cells in the hair bulb (Figure 3), and they undergo differentiation and hardening at different rates. These changes occur first within Henle's layer, then within the cuticle, and finally within Huxley's layer. The final stage of differentiation involves the disintegration of the nucleus while other organelles and the trichohyalin become diffusely distributed as dense materials between keratin filaments. Complete hardening and differentiation occur in the inner root sheath before they occur in the layers of the developing hair. The hardened regions of the medulla and inner root sheath strongly indicate the presence of citrulline whereas trichohyalin is no longer demonstrable.

When stain tests are used to detect the presence of arginine, the trichohyalin stains intensely.21 During the final stages of differentiation, some of the protein- bound arginine residues of trichohyalin are converted into protein-bound citrulline of the hardened proteins. This is particularly evident in the cuticle of the inner root sheath.21

The junction between the outer root sheath and the Henle layer is maintained by desmosomes and gap-junctions; and at the end of differentiation, this junction is maintained by intercellular cement and interdigitation between cells. Upon maturation, the inner-root-sheath cells deposit amorphous intercellular material and cause thickening of the plasma membranes. Cells shrink during keratinization, and the mature inner root sheath becomes a rigid cylindrical tube that surrounds the soft, ascending hair structure. The primary function of the inner root sheath is to shape the hair contained within it. Because the cuticles of the hair and the inner root sheath are closely apposed, the fully keratinized hair assumes the shape of the inner root sheath. At the level of the follicular canal, desmosomal contacts between adjacent cells begin to break; and the cells, either singly or in groups, are shed into the follicular canal

Outer Root Sheath

The outer root sheath surrounds the hair follicle (much like a sleeve), is several layers thick, and is continuous with the epidermis (Figure 4). It has two characteristic proliferation zones: (1) in the bulb and (2) in the basal layer of the epidermis. Two layers of cells surround the bulb; and during formation of the anagen follicle, vertical upward growth predominates. The outer layer of the cell is germinative and continuous with the epidermal basal cells, and differentiation occurs by the horizontal movements of cells from the basal layer of the outer root sheath to the center of the follicle.

Subdivision of the two proliferative zones reveals that the cells are significantly different: (1) those cells derived from the bulb are cylindrical and their long axis parallels the direction of hair growth and (2) those cells derived from the basal layer are irregularly shaped, and their cytoplasm contains many vacuoles.11,23 The outer-root-sheath cells nearest Henle's layer flatten and undergo autolysis. The exact fate of these cells is not known; however, movement toward the surface probably occurs, and they are probably shed into the follicular canal along with the inner root sheath

Keratinization of the outer root sheath occurs in those areas of the hair follicle where it is not apposed to the inner root sheath.23 These areas are (1) in anagen hair, located between the insertion of the hair erector pili muscle and the opening of the sebaceous duct (Straile's zone of sloughing) and (2) in catagen hair the sac of epithelium that surrounds its lower end after the inner root sheath has disappeared.23 This process is called trichilemmal keratinization, and it is the end product of the outer sheath; therefore, it is not derived from the hair matrix but from stratified squamous epithelium,23 which is transformed into nonnucleated keratinized cells without forming a keratohyalin layer. In catagen hair a trichilemmal sac surrounds the lower end of the dying hair shaft, and there it forms the club of telogen hair. Also in catagen hair as the outer root sheath undergoes trichilemmal keratinization, it converges on and occasionally fuses to the cortex of the remaining hair. This "brush" consists of keratinizing cells of the outer root sheath, which becomes elongated rather than flattened similar to the zone of sloughing of the anagen follicle. The function of the outer root sheath is not known.

Connective-Tissue Hair Sheath

The connective-tissue hair sheath is an important physical support of the hair follicle. In the follicle of anagen hair the structure of the upper half of the connective-tissue sheath differs from that of the lower halt, which changes during the growth cycle. Between the epidermis and the sebaceous-gland layer fine collagenous fibers are arranged longitudinally around the upper half of the hair follicle.24 Around the lower half, the connective-tissue sheath consists of fine collagenous fibers that are arranged circularly in the inner layer and longitudinally in the outer layer Prominent elastic filaments develop in the upper half of the connective-tissue sheath, but only a few elastic fibers are present in the lower half. The brush-like filaments that project into the dermal papilla and the circular filaments that occur in both the dermal papilla and its basal plates are present in most hair follicles. These fine, brush-like filaments appear to be connected to the longitudinally arranged fibers in the outer layer of the connective-tissue sheath, and the circularly arranged elastic filaments appear to be connected to those fibers of the inner layer. These elastic-like bodies occur in the follicles of adolescents, but they diminish with age.24

Amino Acid Analysis of Hair

Fibers of human hair are extremely complex; and, morphologically, they consist of several different chemical species. Amino acids that comprise the peptide chain, which forms the basis of the keratin molecules, are readily available in the body. For synthesis of follicular proteins, the most important amino acids are those that contain sulfur i.e., predominantly cystine, because it forms stable disulfide bonds between keratin molecules. Table 2 indicates that cystine is the amino acid of highest concentration in fully formed bait The cortex occupies the primary volume of human hair and contains the principal structural proteins, which are insoluble and contain extensive cystine disulfide cross-linkages (hard keratin).

Table 2 Histochemistry of hair

Cystine Disulfide cross-links. distal keratogenous zone

Cysteine Sulfhydryl groups, proximal keratogenous zone

Arginine In association with trichohyalin of inner root sheath

Citrulline Hardening products of inner root sheath and medulla

DNA Matrix cells and dermal papilla

RNA Basal cells of outer root sheath, medullary cells

Analyses of the fibrous proteins and matrix proteins of an entire human hair reveal that the matrix proteins contain high concentrations of sulfur and the filamentous proteins contain low concentrations of sulfur.25 No citrulline is found in the cortex of hair.

Proteins located in the medulla and the inner root sheath differ from cortical proteins. The large percentages of citrulline and glutamic acid found in medullary proteins indicate that these substances are not keratins and that they are synthesized differently than cortical proteins. Arginine residues from trichohyalin are converted to protein-bound citrulline of hardened proteins.21 These proteins contain typical lysine bonds, which occur neither in the hair cortex nor in the cuticle.11

The Cycle of Hair

In some animal species, such as rats and mice, all hairs are apparently in the same state of activity, and all cyclic changes are synchronized.26 In humans, however the cycle of each follicle occurs independently from that of neighboring follicles, exhibiting a mosaic pattern. Hair cycles are divided into three stages: (1) anagen, a growing or active phase, (2) catagen, a regressive stage, and (3) telogen, a resting stage.22-29 The relative duration of these phases varies with the individual's age, nutritional status, hormonal factors, and other physiologic and pathologic factors. Fully formed anagen follicles produce hair that is firmly fixed within the follicle. As soon as the growth phase is complete, degeneration begins.

The catagen stage exhibits bulbar involution and destruction of the lower part of the follicle. The onset of catagen is defined as an interruption of medullary mitotic activity and the simultaneous cessation of the melanogenesis by the melanocyte of the bulb. While the cortex continues to grow, the hair becomes thin and white as the transfer of pigment granules becomes defective. Cellular proliferation of the matrix is reduced and interrupted. The original glassy- smooth membrane, which divides the epithelial cells of the follicle from the connective- tissue layer develops folds and increases enormously in size. The inner root sheath disintegrates and disappears while the cells of the external root sheath form a sac at the base enclosing the germ cells of the follicle. The structure of the bulb disappears, and the dermal papilla is separated from the follicle. The cells of the bulb migrate to the keratogenic zone and surround the base of the nongrowing hair. The outer root sheath (together with the hair) shifts to the upper zone of the follicle. It subsequently atrophies, partially rolls up, and forms an epithelial envelope around the hair's root. A few layers of cells are then formed from this thin column.

Some of these cells are mitotically active and are in contact with the mesodermal papilla. The hair club is surrounded by a capsule of partially keratinized cells and becomes bound to the unkeratinized cells at the base of the sac. As soon as the glassy membrane has disintegrated and becomes nearly resorbed, catagen is complete; and the follicle enters the telogen, or resting phase of the hair cycle.25

The telogen follicle is short, and its base terminates in the vicinity of the sebaceous gland. It has a wide infundibulum; and here, the cells of the basal layer of the preserved part of the outer root sheath undergo the same mitotic and keratinization changes as occur in epidermal cells. The walls of the follicle firmly adhere to the stalk of the hair club, which has a frayed, brush-like base surrounded by the cell mass of the destroyed bulb. The telogen follicle is only seemingly quiescent, however because the germ of the new follicle is already beginning to form at its base.

The sequence of events in anagen is similar to that of the original morphogenesis of follicles in fetal skin.6-11 In stage one of anagen, the cells of the dermal papilla increase in size and show increased RNA synthesis; simultaneously, germ cells at the base of the sac undergo vigorous mitotic activity. In stage two of anagen, the lower part of the follicle grows down into the dermis and partially encloses the dermal papilla. In the matrix ring that surrounds the dermal papilla, differentiation of cells commences and represents the various layers of the hair and the inner root sheath. This differentiation of cells is a distinctive feature of stage three. In stage four of anagen, the melanocytes that line the papilla develop dendrites and begin to form melanin. Although the hair has formed, it is still within the cone of the internal root sheath and ends at the base of the original clubbed hair The keratogenous zone becomes established just below the level of the sebaceous duct. In stage five, the hair emerges from the cone of the external root sheath and forces its way to the surface along the original hair shaft, which gets pushed aside, and eventually the clubbed hair is discharged. Stage six begins as soon as the hair emerges at the skin surface and continues until the onset of catagen.

Regulation of Hair Growth

Hair growth is regulated by several factors.27,29 The influence of innervation on the growth of hair has been studied in animals, and the experimental methods that were used involve total denervation, sympathetic denervation, and excision in follicle transplantation. Experience in hair growth in humans originated with auto- grafts during hair transplantation. Here, the excision of tissue severs its innervation. In all such experiments, transplanted hairs continue to grow to the same extent and with the same thickness as they did at their original location. Questions about the relationship of the nervous system to hair growth remain unresolved, but the prevailing view today is that hair growth is not directly controlled by the nervous system.

The significance of vascularization is likewise not altogether clean Of course, hair will not grow without an adequate supply of blood to furnish the follicle with necessary metabolites. Also, large anagen follicles are vascularized better than the small ones, and hairs located over large vascular anomalies are frequently thicker and longer than adjacent hairs in the same area. Many attempts have been made to stimulate hair growth in alopecic skin by increasing blood flow by massage methods and by topical administration of vasodilators.30 With the exception of a few recent studies,31,32 all such attempts have been unsuccessful. Much like the association of hair growth to the innervation of the follicle, the relationship of vascularization to hair growth has not been completely resolved. It is generally thought that vascularization by itself does not stimulate follicular activity but that the active follicle determines its own blood supply from the dermal vascular plexus.

There is no doubt that sex hormones play an important role in the growth, distribution, and pigmentation of human hair. During puberty, secondary hair develops in the pubic and axillary regions. In males, the beard starts to grow and, on a smaller scale, terminal hairs appear on the trunk and limbs. With various endocrinopathies associated with overproduction of androgens, hypertrichosis is a significant feature. The different effects of circulating androgens on various groups of human hairs in various locations lead to the hypothesis that differences exist in the metabolism of hormones in follicular tissue.

The conversion of testosterone to the more active dihydrotestosterone (DHT) in certain target cells depends upon the presence of the enzyme 5-a-reductase.33,34

The DHT combines with a cytosol receptor to form a complex that enters the nucleus and joins with chromatin to initiate protein synthesis . Androgen metabolism in cells can be impaired either by decreased conversion of testosterone to DHT or by the cell's inability to accumulate DHT because of the absence of the cytosol-receptor protein. The primary catabolic product of androgen metabolism in either growing or resting hair follicles is androstenedione.35 The conversion of testosterone to androstenedione via 17-(l- hydroxysteroid dehydrogenase is tenfold the rate of the 5-a-reductase system that yields DHT.

figure 7. Mechanisms of protein synthesis

The effects of androgens on sexual-hair growth and scalp-hair loss might be mediated through changes in intracellular concentrations of cyclic AMP (cAMP) (Figure 8). The "second messenger" theory of cAMP states that the first messenger (a hormone) is carried to the plasma membrane of its target tissue where adenyl cyclase recognizes only the specific first messenger Simultaneously, a catalytic subunit of adenyl cyclase produces cAMP which initiates a specific physiologic function.35

The effects of various sex hormones on the activities of adenyl cyclase in the follicles of scalp hair indicate that dihydrotestosterone produces inhibition but that testosterone does not. Increased adenyl cyclase activity is observed when estrone is added to hair follicles. However estradiol (an active estrogen) does not activate adenyl cyclase. The intracellular concentration of cAMP is determined by the relative concentrations of synthetic enzymes, such as adenyl cyclase, and degenerative enzymes, such as cAMP phosphodiesterase.

Presumably, dihydrotestosterone inhibits energy production by keeping phosphodiesterase relatively inactive and by suppressing various protein (enzyme) synthetases. A relatively high concentration of cAMP may cause premature termination of the growing stages of hair follicles. Repetition of such processes over several years presumably transforms terminal follicles to vellus- type follicles and ultimately causes baldness. The diverse biologic effects of cAMP are mediated through activation of a family of protein kinases, which consist of a regulatory (R) and a catalytic (C) subunit; and when bound, these kinases are not active. Cyclic AMP binds to the R subunit, (a binding protein) for cAMP and subsequently releases the C subunit to form an active enzyme. Therefore, the more cAMP available in the androgen-sensitive hair follicles, the stronger the activation of the protein kinase. An increase in cAMP concentrations in hair follicles would produce diverse effects on various enzymes and reaction pathways. Inhibition of glycolysis - by the action of the active C subunit on the enzyme phosphofructokinase - decreases the energy available for the cell to maintain its metabolic functions . The same active subunit effectively slows posttranslational protein synthesis and interferes with cell cycles at the C1 and S phases.36 These combined effects of high cAMP concentrations could result in premature completion of the anagen stage; and this, in turn, could yield follicles that are thinner and shorter than those of normal terminal hair.35 Apparently, the differences in sensitivities for androgens of various types of hair follicles reside in the cAMP protein-kinase system. However; the specific effects of the cAMP system on the metamorphosis of terminal hair to vellus hair must be studied further.

It is common knowledge that undernourishment slows the growth rate of hair; and extreme starvation may render people totally alopecic. Basic amino acids, fats, and vitamins are all necessary for the growth of healthy hair. Generally, poor states of health lead to complicated processes that result in disturbed metabolic and endrocrine interrelationships. Individuals who are on diets that are unsuitable for weight loss, children who are starving and who have kwashiorkor disease, and adolescents who are suffering from anorexia nervosa all grow hair that is fine, short, and either unpigmented or copper colored. Marasmus is accompanied by reduction of anagen hairs and an increased number of clubbed hairs.37,38 In contrast to those of the preceding conditions, these hairs are short and very brittle.

Unlike inductive factors, inhibitory factors affect anagen follicles, reduce or completely suppress mitotic activity of the matrix, and impair keratinization. Hair growth can be inhibited by radiation, chemicals, heavy metals, cytotoxic agents, anticoagulants, large doses of vitamin A, and agents that block cholesterol synthesis.

The growth of hair in humans is controlled by complicated mechanisms that can differ among various locations on the body. Most of these mechanisms are only partially understood.

Conclusion

Hair follicles develop in the skin of fetuses early in their developmental phase. From that time on, i.e., throughout one's entire life, these follicles undergo many cycles of degeneration and regrowth. During the neonatal period and throughout adolescence, scalp hairs progressively thicken because their follicles gradually enlarge with each new cycle. Body hairs, however, remain short. This suggests that their cyclic changes do not lead to enlargement of new follicles. The biologic effects of androgens cause postpubertal< thickening of axillary, pubic, and facial hairs in men and cause hirsutism in women.

High rates of testosterone uptake and metabolism occur in scalp-hair follicles of men and women. Scalp hair is androgen independent. In hair follicles from scalps that have balding traits, the androgen hormone causes metamorphosis of terminal hair to vellus hair by shortening the cell cycle that leads to premature senescence of the follicles. It also exhausts further mitotic activity of the matrix cells. The pathogenesis (and androgenetic alopecia) is probably the same in men and women.

Perhaps further studies that involve metabolic controls of matrix cells of the hair bulb, and their interaction with the dermal papilla, will improve our treatment of hair-growth disorders.

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