Morphology of the Pilo-Sebaceous Unit

Lanugo hairs are long and fine. They cover the foetus in utero and are shed between weeks 28 – 32 of foetal life.
Research suggests that skin appendages develop via a series of messages passing between the dermis and epidermis. (Kollar 1970, Sengel 1976 and Hardy 1992).   Follicular embryogenesis is not fully understood but the aggregation of mesenchymal cells is seen as the essential element without which it cannot occur.
Much of our present understanding is based on observation, but new procedures utilising culture techniques and transgender animals will we hope serve to assist a greater understanding.
The first sign of follicular development is evident at week 9-12 of foetal life.
Sites: the upper lip and chin regions. Follicles develop initially from accumulations of epithelial cells with mesenchymal aggregation beneath. During this period of development the prospective ‘basal layer’ cells elongate as the columns of cells grow downwards into the dermis. Each dense column develops a concave tip which carries mesenchymal cells from which will derive the Dermal Papillae. Papillae are thought to retain the same number of cells throughout adult life.  As the follicle extends further into the dermis it becomes bulbous and engulfs the dermal papilla which will derive its blood supply from within the dermis. This first stage of follicular development will have taken approximately 20 – 23 weeks.
The second stage of follicular development creates the sebaceous gland, arrector pilorum muscle, apocrine gland in specific follicles viz: the axillae, areolae, genital skin and facial regions. The lower aspect of the bulbous hair ‘germ’ will form the hair bulb matrix. The mesenchymal cells surrounding the bulb will form the dermal sheath. Active melanocytes are present.
Hair follicles are self-renewing, due to the activity of stem cells which are undifferentiated (have not changed into a recognized cell type), so they remain unchanged and proliferate for the lifetime of the organism .
Subject to certain stimuli, epidermal stem cells undergo mitosis, producing two daughter cells. One will retain the properties of the `mother’ stem cell while the other will differentiate into a T.A.Cell (Transient Amplifying Cell) capable of generating large numbers of specialized differentiated cells within the epidermis. During this process the integrity of the original stem cells which are the source of skin renewal, is maintained. The main function therefore of TA cells is to increase the number of differentiating cells produced by one division of the stem cell.   TA cell activity allows the epidermal stem cells to remain quiescent in order to minimize mutations. TA cells are therefore direct descendents of stem cells in the epidermis and are responsible for tissue renewal and repair.  

Hair mineral analysis (overview)
Although this procedure is in popular usage in the America’s it has suffered criticism elsewhere. Scientists are aware of a relationship between minerals, trace elements and health and Hair Mineral Analysis employs techniques to test for the presence of these and other minerals and toxic metals in human hair samples.   Hair mineral analysis is a screening test, which measures the mineral content of hair and therefore the body’s tissues. A mineral abnormality within the hair usually indicates a similar abnormality within the body.
Nutritional physiology takes place at cellular level, not within blood or other location. Is what you eat reaching your body cells. Tissue mineral analysis provides information regarding cellular activity and nutritional metabolism.
Mineral levels are locked into formed hair shafts, so analysis identifies concentrations that have accumulated in the hair during the preceding twelve – sixteen weeks.
Toxic and nutrient elements may be thus identified and measured. The process is not considered a stand-alone diagnosis and should be used in conjunction with other laboratory tests (e.g. blood and urine).
Hair analysis indicates individual deficiencies or excesses and the presence of toxic metals. The test highlights any biological antagonism that exists between certain nutrients. Vitamins cannot function or be assimilated without the aid of minerals. The body cannot manufacture minerals.
Every living cell depends on minerals for proper function and structure. composition of body fluids, blood, bone, nerve function, muscle tone including that of the cardiovascular system.
Approximately seventeen minerals are essential in human nutrition.   Minerals function as co-enzymes, enabling the body to perform its functions, including energy production, growth, and healing.
Enzyme activities involve minerals, which are essential for the proper utilization of vitamins and other nutrients.
Minerals coexist with vitamins. Some B-complex vitamins are absorbed only when combined with phosphorus.
Vitamin C greatly increases the absorption of iron.
Calcium absorption requires vitamin D.
Zinc assists in the release of vitamin A from the liver.
Some minerals part of vitamins: Vitamin B1 contains sulphur and B12 contains cobalt.
Minerals are naturally occurring elements.
Rock formations consist of mineral salts. Rock and stone are gradually broken down into tiny fragments by erosion. Soil is teeming with microbes that utilize tiny crystals of mineral salts, which are then passed from the soil to plants. Herbivorous animals eat the plants. We obtain these minerals by consuming plants or herbivorous animals.
Minerals are stored primarily in the body’s bone and muscle tissue; it is possible to develop mineral toxicity if excessive quantities are consumed. No one mineral can function without affecting others.

Physical Properties of Hair – colour, elasticity, tensile strength. porosity, reaction to water (bending and swelling).
Hair colour – determined by the presence of melanin in the cortex. Melanin is a water-insoluble polymer of compounds derived from the amino acid Tyrosine which is located within the melanocytes . The cuticle is transparent so the pigment in the cortex is visible.
Melano-synthesis may produce :
Eumelanin – formed by the reaction of the enzyme tyrosinase with the amino acid tyrosine . It produces hair colours varying between reddish brown – black.
Phaeomelanin – formed by the reaction of the enzyme tyrosinase with the amino acids tyrosine and the sulphur rich cysteine. This produces hair colours varying from yellow blonde) to red (titian).
Variations in pigmentation relate to the number, size and distribution of Melanosomes (single melanin containing organelles) within the Melanocytes. These are specialised skin cells producing melanin and having branches (Dentrites) located within hair follicles through which tiny pigment granules are injected into the keratinocytes during hairshaft genesis.
Other considerations:
Melanin affords some skin protection by absorbing ultraviolet radiation.
Tyrosinase inactivity > nil melanogenesis = pigment free hair.
Grey hair is a illusion created by the blend of white and coloured hairs.

Tensile strength of Hair:
The tensile strength of hair is measured by the force needed to break it. There are a variety of specialised devices available.
A single mongoloid hair-shaft in its virgin state may have a tensile strength equal to copper wire of the same diameter.
A dry virgin hair-shaft can withstand weights of up to 200 gm. – the total scalp hair held together as a plait can support the entire body weight without causing damage.
Tensile strength reduces when a hair-shaft is cold-water wet and further reduces with high temperature water. Research figures claim that other contemporaneously harvested hair-shafts demonstrated higher levels of tensile strength following immersion in Glycerine or Almond oil. Individual hair shafts will however sever if a sudden violent jerking force is applied.

Water and Hair:
Water temporally affects the strength of hair-shafts by breaking the Ionic (salt) bonds and Hydrogen bonds of the alpha-helices. Relative humidity is the measurement of water in the air at a certain temperature expressed as a percentage of the maximum amount of water the air can hold (saturation).
With increased relative humidity (RH) hair shaft diameter may potentially increase by up to 14% – such swelling occurring between the microfibrils. Increases in length along the axis can be up to 2 %.
Hair-shafts change in response to exposure to excessive pH levels. At strong acidic levels (pH 3 -1) hair-shafts swell slightly, in strong alkali levels (pH over 10) hair-shafts can swell excessively to beyond the point of severance e.g. trichorrhexis nodosa.

The Trichological Society

 

PART 2

 From Dr Idalina Fialho MD MTTS

THE HAIR

Hair is an elongated,flexible, keratinized structure, derived from invaginations of the epidermal epithelium that extend down to the deep dermis. The Hair color, size and disposition may vary according to the age, sex, race and region of the body. It can be found mostly everywhere on the body except for few body sites such as palms, soles and mucocutaneous junctions.

Hair is one of the characteristic features of mammals and has various functions including thermoregulation, physical protection, camouflage, sensory and tactile activity as well as social and sexual interactions. In humans, body hair is mostly reduced and it does not play a large role in temperature regulation when compared with other mammals, but has a psychosocial importance in our society, patients with hair loss or excessive hair growth often suffer tremendously.

When humans are born, they have about 5 million hair follicles (the larger number of hair follicles a human will have) and only 2 percent (100,000 – 150,000) of these hairs are located on the scalp, that has the highest density of hair follicles that may range from 118-350 hair follicles/cm2.

There are three main types of hair: lanugo hair, vellus hair, and terminal hair. These differ in their pigmentation and structure, but follow the same principles of formation and development.

Lanugo hair is present during fetal development and in the post-natal period, and is structurally similar to the thin and lightly undeveloped hair found in adults called vellus hair. Terminal hair is the thick and pigmented hair found in the beard and in the axillary and pubic regions.

Keratin is the main component of hair, being comprised of amino acids such as :cysteine, arginine, and citrulline.

Structure of Hair

A hair is a thin, flexible tube of dead, and fully keratinised epithelial cells, made up of two parts: the hair shaft (fully keratinized nonliving part above the skin surface) and the hair follicle (the living part located under the skin).

Hair Shaft

The hair shaft is the distal part of the hair above the surface of the skin and is composed of three layers: an outermost cuticle, a middle cortex and an inner medulla for some types of hairs.

Cuticle

The cuticle is a transparent outer layer composed of keratinized cells with free edges that overlap, and are directly toward the distal end of the shaft. This layer plays an important role in protecting the cortex from various physical and chemical insults, in the maintenance of the hair in a clean and disentangled state, and have also an impact on its physical appearance.

Cortex

In humans, the cortex represents the majority of the hair fibre composition, and plays an important role in the physical and mechanical properties of hair . The cortex is composed of dense, compact, keratinized cells, that are hold firmly by desmosomes and are embedded in an amorphous matrix of high sulfur proteins enclosing the medulla and surrounded by the cuticle of the hair shaft.

The intermediate filament hair keratins, comprising 400–500 amino-acid residues in heptad sequence repeats, form hard keratin polypeptide chains which pair together to form protofilaments (Dawber and Messenger, 1997). The keratin chains have a large number of sulfur-containing cysteine residues, that form in adjacent keratin filaments covalent disulfide bonds forming a crosslink

between adjacent keratin chains. (Feughelman, 1977). These disulfide bonds contribute to the shape, stability, and texture of the hair.

The cortexcontains most of the pigment granules (melanin) that give the hair its color.

Medulla

In the center of the hair shaft is the medulla that can be a hollow tube or loosely filled with cuboidal or flattened cells. In some people the medulla is absent, in others it is segmented or fragmented, and in others it is continuous or even doubled. According to a textbook of forensic medicine , ordinary human and primate hair have discontinuous medullae. The medulla may not be detectable in lanugos of some mammals, including human babies. The degree of medulation varies in ethnic groups also. Head hairs in Caucasians (especially blond hair) often have no medulla. Limb hair is less medulated than scalp hair.

The medulla can contain pigment granules or be unpigmented.

Hair Follicle

Hair follicles vary considerably in size and shape, depending on their location, but they all have the same basic structure : (1) the upper segment (infundibulum) (2) the middle segment (isthmus), and (3) the lower segment consisting of bulb and supra bulb. The hair follicle can be divided into a permanent upper portion, which surrounds the infundibulum and the isthmus, and a lower portion that is continually renewed.

The hair follicle begins at the surface of the epidermis, some of them extend into the deep dermis and sometimes into subcutis – follicles that produce terminal hairs, and others extend only to the upper reticular dermis -follicles producing vellus hairs .

Fig 2: Pilo sebaceous’s unit parts schematic draw. Permanent upper region and lower parts of hair follicle and its subdivisions

(https://www.hilarispublisher.com/open-access/revisiting-hair-follicle-embryology-anatomy-and-the-follicular-cycle.pdf)

Infundibulim

The infundibulum segment, a funnel-shaped structure, is the upper portion of the follicle filled with sebum. It begins at the surface of the epidermis and extends to the opening of the sebaceous duct. This segment is lined with a keratinised epidermis containing a granular layer and basket weave keratin, and in the upper part, also known as acro-infundibulum, the epithelium is continuous with the keratinised epidermis, covered by an impermeable stratum corneum.

The infundibulum represents a major interface zone of mammalian skin epithelium with the environment, and harbors a rich residential microflora, endowing a specialized immune system and innate immune defenses. Clinically, the infundibulum is important, as it becomes prominently involved in many skin diseases such as infundibular folliculitis and cysts, acne, hidradenitis suppurativa, keratosis pilaris, Fox-Fordyce disease, and a subtype of basal cell carcinoma.

Isthmus

The isthmus is the area between the sebaceous gland duct and the insertion site of the arrector pili muscle, lined by the trichilemnal keratin, which is characterized by an eosinophilic compact keratin material, devoid of granular layer.

The lower region of the isthmus near the insertion of the arrestor pili muscle, referred to as the bulge, stores the epithelial and melanocytic stem cells, and marks the end of the permanent region. These cells have a long, slow, life cycle and are able to differentiate into three structures: epidermis, hair follicles, and sebaceous glands.

Hair bulb

The hair bulb is found in the deepest portion of the hair follicle, located below the insertion site of the arrector pili muscle.

The hair bulb contains the dermal papilla, the hair matrix and a small portion of connective tissue that is richly innervated and vascularized. It can be divided into two regions : a lower region with undifferentiated cells where the metabolically active portion of the follicle is located and an upper region consisting of differentiated cells. There is a line named Auber´s line crossing the widest part of papilla separating this two regions.

Outer Root Sheath

Doesn’t contain the granular layer and is rich in glycogen which accounts for a pale cytoplasm, forming a distinct bulge area between the insertion of the arrestor pili muscle and the duct of the sebaceous gland.

Inner Root Sheath

Begins in mid-isthmus and extends up to the base of the bulb. It is composed of three layers:

• • • • • • • • Innermost layer forming the cuticle of the inner roots sheath
              • Middle layer of Huxlex
              • Outer layer of Henle

The keratinocytes of the follicular matrix, are found in the region of the capillary matrix in the bulb, below the Auber line at the largest diameter of the dermal papilla. These cells are capable of

generating six different types of cells namely, the three layers of the Inner Root Sheath and the three layers of the stem itself.Between these cells are active melanocytes, which, depending on the production of eumelanin or feomelanin, will color the hair in the shaft blonde or brunette. The symmetry or asymmetry of the follicular matrix is one of the determinants of hair shape resulting in either straight or curly hair.

Fig 3. Hair follicle. Longitudinal section showing the three sections: the infundibulum, the isthmus, and the inferior segment. (https://plasticsurgerykey.com/hair-diseases/)

Fig4. Hair bulb. The outer and inner root sheaths mold and protect the growing hair shaft. The hair shaft consists of the medulla, hair cortex, and cuticle

(https://plasticsurgerykey.com/hair-diseases/)

Sebaceous glands

These glands are acinar glands closely associated with hair follicles, especially in certain areas of the skin such as the face. These glands contain lipid-laden sebocytes,localised close to the arrestor pili muscle insertion and secrete sebum on the surface of epidermis by holocrine mechanism.

The sebaceous glands together with the hair follicle and the arrestor pili muscle forms the pilosebaceous unit.

Sebaceous glands are found in almost all skin with exception of palms, soles and mucocutaneus 0membranes, and there is some zones where they congregate called sebaceous zones. These zones are seen in the scalp, face ( T Zone, including forehead, labella and nasolabial groove), sternal regions, armpits, naval, and external genitals.

Arrector pili muscles

The arrector pili muscle is a smooth muscle arising from the uppermost part of the dermis, just beneath the epidermis, and inserting into the hair follicle.

The zone of the attachment of the muscle with the bulge of the follicle contain epithelial stem cells that are responsible for regenerating has follicles, playing a crucial role in hair growth cycle.

In cold climates, sympathetic stimulation causes these muscles to contract, this raises the level of the skin slightly and causes the hair to stand erect, which is commonly referred to as “goose-bumps.”

Morphogenesis of Hair Follicles

In utero, the epithelium and underlying mesenchyma interact to form hair follicles. Development of human hair may begin at about 8 weeks of fetal life and by 22 weeks of fetal life the entire initial population of follicles is completed, including those on the scalp. During this time, the precise distribution of hair follicles over the surface of the body is established and the future phenotype of each hair (e.g., long scalp hair and short eyebrow hair) is determined. Hair follicle morphogenesis occurs only during the embryonic development, so each person is born with a fixed number of follicles (roughly 5 million), that normally don’t increase afterwards, although folliculogenesis can take place during a wound healing process. Although no additional follicles are formed after birth, the size of the follicles and hairs can change with time, primarily under the influence of androgens.

The precise spacing and distribution of the follicles are established by genes that are expressed very early in the morphogenesis of the follicles.

The induction of hair follicle formation results in the placodes (regularly spaced epidermal thickenings), which is followed by organogenesis and cytodifferentiation of the follicle. These three stages of development are split into eight phases, and each phase has its specific molecular interactions.

In the first phase also known as induction phase, a diffusion gradient between inhibitors and activators is generated by creating the pre-hair germ, a proliferative field. In this phase there is an aggregation of mesenchymal cells in the superficial level of dermis and simultaneous thickening of basal epidermal cells immediately above it. During the first stage of the first phase of induction, where the follicular germ is visible, the placodes are formed through the action of molecules such as EDA-A1, NF-κβ, Wnt/β-catenin, Noggin, and the surrounding area inhibited by Dκκ and BMPs.

In the second phase there is the organogenesis, the orientation of the hair follicle. The basal epidermal cells elongate and start bulging downward as the “hair-germ”, while at the same time the underlying mesenchymal cells begin to replicate to form the rudiment of what will become the dermal papilla. Later on, several molecular processes determine its polarization and the innervation of the trichocytes and germ formation. The organogenesis include phase 2 to phase 5, hair follicle germ and peg phase (here the epithelial cells of the hair-germ grow downward and form a column or “hair-peg” propelling the mesenchymal aggregate downward). In phase 5 the inner root sheath and the bulge can be found.

Cytodifferention comprise phases 6 to phase 8, characterizing bulbous peg phase. During cytodifferentiation, three areas of swelling appear along the hair peg, as the column extends downward. The most superior swelling tends to become the apocrine gland, whereas, the middle and lowest swellings develop into the sebaceous and the bulge area for the attachment of arrector pili muscle (AP) , respectively. The development of AP muscle is independent of that of hair follicle. The epidermal cells present at the advancing base of this column surround a portion of the underlying mesodermal cells, resulting in the formation of dermal papilla. At the phase 8 all hair follicle apparatus is completely formed.

The first primordial hair is characterised by having cells at the base of the column surrounding the dermal papilla, which start active proliferation resulting in the formation of the early matrix, and this initial hair shaft tends to move in the upward direction. Above this, the central cells of the follicular peg start degenerating, and emerging hair pushes out the plug to form a hair canal. Fine laguna hair may develop in an advancing wave-like pattern from the frontal to occipital scalp and is

usually shed by about 36 weeks. A second coat of laguna hair appears which is also shed in a synchronized wave pattern at about 3-4 months of life. The bare occipital patch, which is often seen

in infants, is usually physiological, and resulting from synchronized shedding of the final wave of laguna telogen hairs just before their replacement by normal scalp hairs. At the time of birth, there are 5 million hair follicles covering the human body with approximately 100.000 being scalp hairs.

The Wnt/β-catenin signalling pathway is the main pathway that defines the destiny of the hair follicle, and its deficiency results in the absence of placodes. The epithelial placodes generates a signal to the mesenchyme in order that it condenses and forms the dermal papilla. The Sonic Hedgehog signalling pathway is the major driver for the maturation and growth of the dermal papilla, which itself becomes an area of secretion and interaction with the mesenchymal cells that will eventually generate signals for the development of many follicular layers.

Not every keratinocyte becomes a trichocyte, then there are local inhibitory systems that allow for the regular and orderly distribution and development of placodes. While Wnt/EDA-A1 and Noggin are well described inducers of follicular development, the pathways involved in blocking this process haven’t been clarified.

In cytodifferentiation there is development of all the compartments of the hair follicle, various signalling molecules are related to this process. Inner root sheath differentiation is regulated by the Gata3 and Cutl transcription factors, while BMP signalling and transcription factors such as Msx2, FoxN1 and Hoxc13 regulate hair shaft differentiation. Other factors controlling differentiation include the Dlx3 transcription factor that controls differentiation of inner root sheath and hair shaft. Dlx3 is a direct target of Lef1 and up regulates expression of Hoxc13 and Gata3 transcription factors, regulators of hair shaft differentiation.

Fig 5. Schematic figure of hair follicle morphogenesis (https://www.hilarispublisher.com/open-access/revisiting-hair-follicle-embryology-anatomy-and-the-follicular-cycle.pdf)

Hair Follicle Life Cycle

The hair growth cycle describes the changing histological morphology of the shaft and of the follicle over time. A hair arises from the integrated activities of several keratinocyte layers in the hair follicle. The development of hair is a dynamic as well cyclic process in which the duration of growth cycles is very well coordinated by many hormones and cytokines and it not only depends on the site where the hair is growing but also on some other factors, such as the age of the individual, stage of development, nutritional habits, or environmental alterations ( like day-length).

There are important players in this cycle namedcytokines (hormones), which are able to instruct the follicle to undergo appropriate changes, so that each hair can be in a different stage of growth cycle compared to the adjacent hairs.

Hair follicles grow in repeated cycles, in which the stages growth and formation of hair shaft alternate with stages of apoptosis-driven hair follicle regression and relative hair follicle quiescence.

Each hair follicle perpetually goes through three stages: Starting with anagen or growth phase (rapid growth and hair shaft elongation); the follicle and its shaft progress through catagen or transitional phase (involution and apoptosis-driven regression), telogen or resting phaseand finally exogen (shedding).

All body hairs undergo a similar life cycle, although its extent, the duration of its phases and the length of individual shafts vary between different body areas and between individuals, depending on genetic programming, genre, age and health status.

Fig 6. Different phases of hair cycle

(https://www.maurolabanca.com/wp-content/uploads/2018/11/Labanca-2014.pdf)

Anagen Phase

The anagen phase is an active growth phase in which the hair undergoes morphological and molecular events similar to fetal hair follicle morphogenesis. During this phase the hair follicle enlarges reaching its characteristic onion shape and a hair fiber is produced.

Many key molecular regulators of hair biology not only activate morphogenesis, but also regulate anagen induction and duration. The anagen phase can be divided into six stages (I–VI). The durations of the first five stages differ little on different scalp sites, although only the duration of the last phase is the determining factor for hair length. During anagen I–V (proanagen), hair progenitor cells proliferate, envelope the growing dermal papilla, grow downwards into the skin, and begin to differentiate into the hair shaft and inner root sheath; then, the newly formed hair shaft begins to develop and the melanocytes located in the hair matrix show pigment- producing activity; Hair shaft synthesis and melanin production in melanocytes (melanogenesis) , only take place in anagen. Pigmentation begins after the initiation of shaft formation and ends before this process is terminated, which causes the shaft to have an unpigmented tip and root. In anagen VI (metanagen), full restoration of the hair fiber-producing unit is realized, which is characterized by formation of the epithelial hair bulb surrounding the dermal papilla, located deep in the sub- cutaneous tissue, and the new hair shaft appears from the skin surface.

This phase can last for several years in hair follicles. Between 90% to 95% of the scalp hairs are in the growing phase, and the variation in hair length is proportional to duration of the anagen, depending on the body site.

At the end of anagen, the hair follicle suffers an involution, which is accompanied with apoptosis and terminal differentiation of cells, a period designated as catagen.

The term anagen effluvium means an abrupt loss of hairs in their growth phase due to an event that impairs the mitotic or metabolic activity of the hair follicle. Radiation, chemotherapy, toxic chemicals, and sometimes inflammatory diseases such as pemphigus and alopecia areata are also capable of diminishing the metabolic activity of hair follicles resulting in anagen hair loss. Anagen effluvium is reversible, and hair regrowth occurs after a delay of 1 to 3 months.

Fig7.Woman with anagen effluvium due to

Chemotherapy-Trichoscopy shows black dots and broken hairs (Courtesy from Dr. Anzai University of São Paulo).

The anagen phase can be induced by a variety of factors, including trauma and healing, although its area of stimulation is limited, and it can only stimulate the area around the trauma. Other substances that are also capable of inducing the anagen phase, include the drugs : minoxidil, cyclosporin A,FK506, norepinephrine depleting agents, and tretinoin. There are many growth factors and neural mediators such as keratinocyte growth factor, hepatocyte stimulating factor, tumor promoting factor, Sonic hedgehog, substance P, capsaicin, parathyroid hormone antagonists,

ACTH, and the degranulation of mast cells that are able to induce anagen, but the pathways and its participation in the spontaneous induction of the signal is still unclear.

Catagen Phase

The catagen phase begins when the anagen phase ends. At the beginning of the catagen phase, differentiation and proliferation of hair matrix keratinocytes decreases significantly, the pigment-producing activity of melanocytes stops, and hair shaft production is completed. The papilla is released from the bulb, there is a loss of differentiation of the lower follicle layers, a remodelling of the follicle matrix, and shrinking of the distal portion of the follicle through an apoptotic process. Although the spontaneous signals leading to this phase are not well known, the many stresses that precipitate this phase are well-known and include : environmental and chemical factors such as trauma and dexamethasone, as well as hormones such as 17-β-estradiol and ACTH .The catagen phase can be divided into eight sub-phases in which begins at the late anagen phase and ends with the initial telogen phase. The first sign is the loss of the cellular projections from fibroblasts in the basement membrane of the dermal papilla, the extracellular matrix ceases the supply of substances and the papilla shrinks, cell division in the bulbar matrix ceases, and massive apoptosis occurs in specific regions of the regressing follicle. There are some changes that also occur with the cytoskeletal proteins and with the adhesion molecules such as trichohyalin, transglutaminase I, and desmoglein that stop being produced. Concomitantly, the lower follicle shrinks and becomes an epithelial cord.

The purpose of catagen phase is to delete the old hair structure and to bring up a new follicle , using the stem cells from bulge and from papilla. The cartagena phase lasts for few weeks.

If the dermal papilla fails to reach the bulge during the catagen phase, the follicle stops cycling and the hair is lost. This can be observed in humans that have mutations of the hairless gene. This gene encodes for a transcription factor whose disruption prevents the dermal papilla from ascending and interacting with the stem cells of the bulge, resulting in permanent alopecia.

Telogen and Exogen phases

After regression, the hair follicle enters the telogen phase, a phase where the follicle is found in the dermis covered by quiescent epithelial cells, the papillary fibroblasts forming an epithelial sac. The follicle remains in this stage until it is reactivated by intra and extra follicular signals, and this period can last few weeks (in eyelashes) to eight months (in scalp hair).

Later, that epithelial sac adopts a rod format that is adherent to the outer root sheath. Even though it is widely known as a resting phase, it is speculated that it is a much more active phase than we are able to identify today. During this final stage of hair cycle the hair ceases to grow any further and becomes fully keratinized. The dermal papilla enters a resting phase and does not supply any nutrition to the hair; which is fully grown and no longer needs sustenance. This hair is called club hair and it has matured and no longer has access to the blood supply because there is no longer a need to grow. The hair bulb is made of keratin and is ready to make an exit of the scalp.Approximately 10–15% of all hairs are in resting phase at any given moment. At the end of this stage, the hair falls (exogen phase). This process is independent of a possible new hair follicle cycle, in fact, it is most common in mammals that a new hair shaft regrows before the resting shaft sheds, assuring the animal is never completely naked. Apart from normal development, in pathologies like trichostasis, where multiple shafts are formed and retained within the same hair follicle, it also supports the thesis that follicle growth and shedding are independent events. Exogen phase ends when the shaft is released. A few weeks later, the hair follicle re-enters the growth phase by stimulating stem cells from the bulge area.

Recently, Rebora and Guarrera used the term “kenogen” to describe the interval in which the hair follicle remains empty after the telogen hair has been shed and before a new anagen hair emerges. The hair follicle in this phase remains completely empty and possibly inactive, and the frequency and duration of this phase are greater in men and women with androgenic alopecia.

Most people lose 50 to 150 scalp hairs per day,the telogen stage typically lasts for two to three months before the scalp follicles reenter the anagen stage and the cycle is repeated. The percentage of follicles in the telogen stage varies substantially according to the region of the body (e.g., 5 to 15 percent of scalp follicles are in the telogen stage at any one time, as compared with 40 to 50 percent of follicles on the trunk). An increase in the percentage of scalp follicles in the telogen stage leads to

excessive shedding. Therefore, drugs that maintained or reduced the percentage of follicles in this stage would be valuable in treating hair loss.

Telogen Effluvium is the most common cause of hair loss. It is a heterogeneous disorder that can be classified into three main categories: premature teloptosis, collective teloptosis, and the premature

entry into telogen induced by drugs.It can also be caused by dietary deficiencies and an “autoimmune” response. It is a self- limited condition such that hair regrowth occurs after three to nine months.

Neuromodulation

The nervous system acts directly or indirectly in the control of the follicular cycle, but it is difficult to establish the piloneural communication routes. Neurotrophins and their receptors are the key elements in follicular formation and its cycle. The hair follicle is the source and target of neurotrophins, neurotensins, and brain neurotrophic factor. Neurotrophins are prominently expressed in the isthmus and bulge region by Shawann cells and stimulate their receptors in the follicle and mesenchyme. The neurotrophins produced by the capillary cycle are able to remodel their innervation and alter the follicular cycle to influence the parafollicular cells in addition to mast cells and macrophages. Neuroendocrine control is established by hormones produced at a distance such as prolactin, melatonin, and ACTH, as well as hormones produced by the pilosebaceous unit itself namely, corticotropin releasing hormone, beta endorphin, and alpha melanocyte stimulating hormone.

Physical and psychological stresses may lead to disturbances in the capillary cycle. Examples include the hemi-hypertrichosis seen after thoracic surgery secondary to parasympathetic hyper-innervation, the canities subita phenomena seen in Marie Antoinette syndrome, and the abrupt hair fall out in a severe telogen effluvium are examples. Beta adrenergic receptors can be found in the bulge region in the early anagen phase and substance P can induce both anagen and catagen phases.

Immune system

Changes in the location and amount of immune cells have an impact on the cell cycle. Abnormal forms of hair loss are reversibly mediated by immune cells when they affect the bulb (alopecia areata) and are irreversible when they attack the isthmus and bulge (cicatricial alopecia). Immuno-modulatory drugs such as cyclosporin, induce the anagen phase whereas corticosteroids induce the

catagen phase.

Classification of the Hair

Humans have a variety of different types of hair and can be classified depending on their body position and form. Furthermore embryological time of first appearance, size, angle of penetrance through the skin, and structural variations in the hair follicles such as hair follicle density, size of follicular orifices, hair shaft diameter, volume, and surface of the infundibula are all taken into account when classifying hair types.

Hair shaft diameters show some little variations from 16 to 42 lm.The highest shaft diameter is observed in the thigh (29 lm) and sural (42 lm) regions, with the lowest in the forehead (16 lm).

The hair follicle density has its highest average on the forehead (292 follicles/cm2)

The highest follicular infundibula volume, which is interpreted as a potential follicular reservoir for dermally applied substances, is on the fore-head with 0.19 mm3/cm2 as well as in the sural region with 0.18 mm3/cm2.

Moreover, the cycle’s length varies on different parts of the body, for example in eyebrows the cycle is completed in about four months, while in scalp it takes three to four years to finish.

Types of hair follicles

Human hair could be classified in:

• • • • • Androgen independent hair, such as eyebrows and lashes
        • Hair on hormone-dependent body regions, like scalp, beard, chest, axilla, and pubic region. These hairs consist of terminal hair shafts, which are long (>2 cm), thick (>60 mm in diameter), pigmented, and medullated. The medulla is located in the large terminal hair fibers, but most scalp hair is not medullated. Terminal hair usually extends more than 3 mm into the hypodermis.

The rest of the body in adults is covered with vellus hair (androgen-independent hair)which are short (<2 cm), thin (<30 mm in diameter), often unpigmented, and extending just 1 mm into the dermis.

There are some hair follicles named as intermediate hair. They can exist in a transitional phase between terminal and vellus forms.

Type of hair

There are some data about features of the different types of hair in the literature, nevertheless the major documents mention the scalp, the pubic, the axillary hair, and the hair in the phalanges.

Scalp hair

In the scalp, the hair follicles are typically arranged in the follicular unit composed of one to four terminal hairs and one to two vellus hairs, sebaceous gland, and encircled by the arrector pili muscle. Each hair grows steadily, approximately 1 cm per month and continuously for three to five years (anagen phase), growth then stops and is followed by a short catagen phase and a two to eight month telogen phase, during which old hair is shed. With the onset of the anagen phase, new hair starts to grow from the same follicle.

Scalp hair is a fiber with 60 to 80 lm in diameter, and its exterior consists of a layer of flat, imbricated scales pointing outward from root to tip. The total length of the follicle and the length of the infundibulum differ significantly in terminal (3864605 lm) and vellus hair follicles (58084 lm). Moreover, the diameter of the terminal hair follicle opening on the skin surface level is twice as large as that of the vellus hair follicle and the thickness of the epithelial lining is significantly lower in vellus hair follicles (4514 lm) when compared to terminal hair follicles (6520 lm).

Disorders of the scalp frequently cause severe pathologic and cosmetic interference with skin disease and quality of life, creating the need for optimal medical surveillance.

Pubic and axillary hair

Pubic and axillary hair development indicates puberty in both females and males. Pubic hair is the hair in the frontal genital area of adolescent and adult humans, located on and around the sex organs, the crotch, and sometimes at the top of the inside of the legs. Although fine vellus hair is present in the area in childhood, pubic hair is considered to be the heavier, longer, and coarser hair that develops during puberty as an effect of rising levels of androgens. Pubic hair changes with hormonal diseases and reduces with age, typically after menopause in women.

Apart from the length and the natural color differences between scalp and public and axillary hair, hair displays a morphological diversity both macroscopically and microscopically. There is a significantly higher absence of medullation in scalp hair when compered with axillary and pubic hair. The quantitative variables in the different hair types revealed significantly higher shaft diameters in pubic hair compared to that of axillary and scalp hair.

Phalangeal hair

Phalangeal hair is concentrated in a particular region of the phalanx and is different from hair on other parts of the body. Their distribution may be influenced by some factors such as genes and environment. The proximal phalanges have the highest percentage, whereas middle phalangeal hairs are not common and distal phalanges are rare. The frequency of occurrence of midphalangeal hair is higher in males than females, generally females have low incidence of phalangeal hairs.

Racial Determination

Human hair has been commonly classified according to three conventional ethnic human subgroups:Caucasoid (European ancestry), Mongoloid (Asian ancestry), and Negroid (African ancestry) origin, all of which exhibit microscopic characteristics that distinguish one racial group from another. Such broad classification hardly accounts for the high complexity of human biological diversity, resulting from both multiple and past or recent mixed origins.

Head hairs are generally considered best for determining race, although hairs from other body areas can be useful.

Caucasoid (European)

Hairs of Caucasoid can be of fine to medium coarseness, are generally straight or wavy in appearance, and have the widest range of colours ranging from blonde to brown to black. The hair shafts of these hairs vary from round to oval in cross section and have fine to medium sized, evenly distributed pigment granules. The hair grows out of the skull at an oblique angle, at a rate of about 1.2cm a month.

Mongoloid (Asian)

Hairs of Mongoloid are regularly coarse, straight, and circular in cross section, with a wider diameter when compared with the other hairs of other racial groups. Its cuticle is usually significantly thicker than the cuticle of Negroid and Caucasian hairs, the medulla is continuous and wide and the cortex contains pigment granules that are generally larger in size than the pigment granules of Caucasian hairs and which often appear to be grouped in patchy areas within the shaft.

Mongoloid hair is nearly always black, but can have a characteristic reddish appearance as a product of its pigment.

The Mongloid hairs grows out of the scalp at a right angle, and are the fastest at an average of 1.3cm a month.

Negroid (African)

Hairs of Negroid origin are regularly curly or kinky. They have a flattened cross section, and can appear curly, wavy, or coiled. Negroid pigment granules are larger when compared withMongoloid and Caucasian hair and are grouped in clumps of different shapes and sizes. The density of the pigment in the hair shaft may be so great as to make the hair opaque. The hair shaft exhibits variation in diameter because of its flattened nature and the manner in which it lies on the microscope slide. Twisting of the hair shaft, known as buckling, can be present, and the hair shaft frequently splits along the length.

African hair grows the slowest, at about 0.9cm a day.It’s angle of growth is very small, nearly parallel to the scalp. In colour, it is nearly always black in Africans. The negroid hair can be with a different colour only if the individual is an albino, or has European ancestry.

Fig 8. Diagram of the implantation of an Asian, Caucasian and African hair

(https://activilong.com/en/content/96-ethnicity-and-hair-structure)

Other type of hair classification:Andre Walker Hair Typing System

Also known as The Hair Chart, is a classification system for hair types created in the 1990s by Andre Walker. It was originally created to market Walker’s line of hair care products but has since been widely adopted as a hair type of classification system. He simply classified hair into four main types, and each type has a subclass.

Type	Hair texture	Hair description
1a	Straight (fine)	Very soft, shiny, hard to hold a curl, hair tends to be oily, hard to damage.
1b	Straight (medium)	Has much body. (i.e. more volume, more full).
1c	Straight (coarse)	Hard to curl (i.e. bone straight).
2a	Wavy (loose waves)	Can accomplish various styles. Loose “S” pattern. Hair sticks close to the head.
2b	Wavy (defined waves)	A bit resistant to styling. Hair has more of a defined “S” pattern. Hair Tends to be frizzy.
2c	Wavy (wide waves)	Hair has wider waves. Resistant to styling. Hair tends to be frizzy.
3a	Curly (loose curls)	Thick and full with much body. Definite curl pattern. Hair tends to be frizzy. Can have a combination texture.
3b	Curly (tight curls)	Medium amount of space of the curls. Can have a combined texture.
3c	Curly (corkscrews)	Tight curls in corkscrews. The curls are very tightly curled.
4a	Kinky-coily (defined coil)	Tightly coiled. Has a very defined “o”-shaped pattern.
4b	Kinky-coily (z coil)	Tightly coiled. Little less defined kink pattern. Has more of a “Z”-shaped pattern.
4c	Kinky-coily (tight coil)	Tightly coiled. Almost no visible defined kink pattern, unless seen from up close. Has more of a very tight “o”-shaped pattern.

Clinical Observations on the Human Hair

Hormone and hair follicles

There are several clinical evidences about the involvement of neurohormones in hair pathologies:

• • • Overproduction of ACTH :It is a well-recognized cause of acquired hypertrichosis, which is a process in which non-pigmented vellus hair follicles are converted into large terminal

hair follicles with a strong and pigmented hair shaft. This induction of hypertrichosis by ACTH suggests evidence that the neuropeptide may stimulate and/or prolong the anagen phase.

• • • Severe psycho-emotional stress : May cause the onset of Alopecia Areata. This effect may be mediated by CRH release that acts as a direct proinflammatory peptide or through activation of mast cells leading to the destruction of the hair root.
    • Enhanced expression of CRH, ACTH, and a-MSH are also associated with Alopecia Areata

Ageing

The most common phenomenon of ageing in hair is greying, it occurs in the fourth decade regardless of gender, even if some clinical differences are noted between men and women. The temporal and occipital area are more involved in men than in women and, usually, greying starts in the temporal area in men and in the frontal area in women. Maintenance of hair pigmentation is dependent on the presence and function of melanocytes, which are maintained by the stem cells of the bulge area of the hair follicle. Loss of melanocytes and melanocyte stem cells is associated with the loss of hair pigmentation seen with human ageing. In particular, studies for pMel17 and microphthalmia-associated transcription factor demonstrated a decreasing number of unpigmented melanocytes in the bulge region of the hair follicle. In addition, recent data suggest a complete depletion both of mature melanocytes and of immature melanoblasts in aged hair follicles, which results in melanocyte stem cell depletion and subsequent hair greying.

Advancing age is also accompanied by a decrease in the number of hair follicles on the body and scalp and an increase in the proportion of telogen hair follicles. In some areas, such as the face, hormone modification can improve the number of hairs or change their shape. The remaining hairs may be smaller in diameter and may grow more slowly.

Diagnostic Use

Hair shaft can be used for diagnostic purpose and, in particular, for testing psychoactive drugs, and for determining the concentration of metals in relation to sex and age, such as poisoning. Moreover, the condition of hair cuticles has the potential to assist in the diagnosis of health disorders and can be used forensically to provide information on the identity and lifestyle of the hair’s owner.

Bibliography

1. Anatomy, Hair Follicle ; Julianna L. Martel; Julia H. Miao; Talel Badri.
2. Deciphering the functions of the hair follicle infundibulum in skin physiology and disease; Marlon R. Schneider & Ralf Paus
3. Revisiting Hair Follicle Embryology, Anatomy and the Follicular Cycle; Laura Maria Andrade Silva1, Ricardo Hsieh, Silvia Vanessa Lourenço, Bruno de Oliveira Rocha1, Ricardo Romiti, Neusa Yuriko Sakai Valente, Alessandra Anzai and Juliana Dumet Fernandez
4. The Biology of Hair Follicles; Ralf Paus, George Coasters
5. IADVL Textbook of Trichology; Madura C, BS Chandrashekar
6. The human hair: from anatomy to physiology; Barbara Buffoli1, PhD, Fabio Rinaldi2, MD, Mauro Labanca1, MD, Elisabetta Sorbellini, MD, Anna Trink, MD, Elena Guanziroli, MD, Rita Rezzani1, PhD, and Luigi F. Rodella, MD
7. Biology of Human Hair: Know Your Hair to Control It; Rita Araújo, Margarida Fernandes, Artur Cavaco-Paulo and Andreia Gomes
8. Forensic science communications; Douglas W. Deedrick
9. Andre Walker Hair Typing System; Wikipedia