Hair cycle
Hair cycle
The hair growth cycle, whether terminal or vellus, is divided into three stages: active growth (anagen), involution (catagen), a period of rest (telogen), and, as an extension of this last stage, two additional stages: hair shaft-extrusion (exogen) and empty hair follicle (kenogen) (Fig. 22.25). The duration of the anagen phase determines the length of the hair stem. Human beings
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Ostium
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Upper segment
1
Infundibulum
Itsmus
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Bulge
2
1
Lower segment
Stem
Adamson’s fringe
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2
Bulb
2
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differ from other mammals in that these stages occur continuously rather than synchronously. There is no periodic change of the hair covering the body. The duration and relative proportion of each stage is variable: anagen 2–7 years (85–100%), catagen 2–3 weeks (0–1%), and telogen 100 days (0–15%). The cycles of miniaturized hair follicles and vellus hairs cycles are much faster, thus shortening the anagen phase.
The interaction of numerous growth factors, cytokines, hormones, neurotransmitters, and their receptors are important in the development and cycling of normal hair follicles. It appears that the driving force of cycling, the ‘hair cycle clock’, is located in the hair follicle itself, in the immediate niche and in the dermal microenvironment. However, no single growth factor appears to exert ultimate control over these processes.1–4
Anagen lasts from 2 to 7 years and is characterized by continuous growth, giving origin to a long and pigmented pilar stem, which is easily visible. It
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Anagen Catagen Telogen
1
2
1
A
2
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is the phase that determines the length of the hair and the phase that varies the most depending on the body location. Morphologically, it corresponds to the already mentioned terminal hair follicles deeply situated in the subcutaneous fat (see Fig. 22.19). The pilar bulb of the follicles in anagen shows abundant melanin production and intense mitotic activity, resulting in the hair growing approximately 1.0 cm per month. At any particular moment, between 85% and 100% of the hair follicles are in anagen. As this is the phase with the highest mitotic activity, melanogenesis, and DNA synthesis, it is the most vulnerable to hormonal changes, drugs, and different toxins.
Pigmentation of the hair only occurs in anagen, and it is induced by interactions between bulbar melanocytes, keratinocytes, and dermal papilla fibroblasts (hair follicle pigmentary unit) (see Fig. 22.22).5 The coupling of hair follicle melanogenesis to the anagen phase distinguishes follicular melanogenesis from the continuous melanogenesis of the epidermis. Cyclic reconstruction of the hair follicle pigmentary unit occurs optimally during
only the first 10 hair cycles, i.e., until approximately 40 years of age.6 It is not clear if hair graying is a consequence of functional loss, or a selective melanocyte depletion of human hair.7
Catagen precedes telogen and during this phase, the inferior segment of the follicle undergoes massive apoptosis, reducing its size. It is the shortest phase and lasts from 2 to 3 weeks. Only 1% to 2% of the follicles are in catagen, and it is rare to find them in normal scalp biopsies. Horizontal sections are characterized by diffuse apoptosis and an absence of mitotic and pigmentary activity. Apoptotic cells have intensely eosinophilic cytoplasm and have a dark pyknotic nucleus (Figs 22.26 and 22.27). As the follicle retracts, the vitreous membrane collapses and appears thickened and corrugated (Fig. 22.28). It is important not to confuse this phenomenon with the thickening of the basal membrane observed in discoid lupus. The inner root sheath disappears and the outer root sheath appears morphologically similar to the epithelium of the isthmus, surrounding a club-shaped hair
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shaft and keratinizing in a trichilemmal manner (Fig. 22.29). Catagen follicles are frequent in trichotillomania.
Because of the brevity of the catagen phase which quickly follows the telogen phase, for quantifying purposes both the catagen and telogen follicles are counted together. Telogen lasts 100 days. Approximately 10–15% of the total number of hairs are in telogen phase at any given time and around 100 telogen hairs are shed per day. A hair follicle in telogen represents the final stage of involution of the lower segment. The hair papilla is present under the area of insertion of the arrector pili muscle and in a horizontal section appears as an aggregate of basaloid cells (the secondary germ: telogen germinal unit) (Figs 22.30 and 22.31). In the past, it was thought that the hair follicle stem cells were located in the telogen germinal unit. However, true stem cells are located in the bulge, in the insertion point
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of the arrector pili muscle; these cells are responsible for regenerating not only hair follicles but also sebaceous glands and epidermis8,9 (Fig. 22.32). In the human hair follicle, the bulge is rarely visible, thus its detection requires the use of immunohistochemistry (cytokeratin 15). Loss of bulge stem cells leads to the cicatricial types of alopecia.
Hair follicles also contain sebaceous glands that, with their secretion, lubricate the hair channel and skin surface. They are numerous and are easily identified in sections at the superior segment level. An early phenomenon in scarring alopecias is the loss of sebaceous glands. Apocrine glands are also associated with hair follicles in specific areas such as axillae, genital zone, medial abdomen, and areola.
The lower segment of the hair follicle involutes completely, leaving only a structure called a follicular stella (follicular streamer, fibrous streamer), which indicates the position in which the retracted follicle was formerly located (Fig. 22.33). The follicular stella is not specific of the telogen phase as it is also observed as a consequence of the miniaturization of the terminal hair follicles in androgenetic alopecia. These follicular stella as opposed to those found in scarring alopecias are not birefringent under polarized light (Fig. 22.34).10
Two other phases are considered final components of the telogen stage:
• Exogen (teloptosis) represents a telogen club which has lost the adhesion between cells of the club hair and those of its epithelial envelope, apparently by a proteolytic mechanism activating an active shedding process.11 This corresponds to the 100 hairs that are lost daily.
• Kenogen refers to an empty follicle after the follicle in telogen has been shed.12 Follicles in exogen and kenogen are not easy to classify histologically.
Hair follicle immune privilege The hair follicle immune system has distinctive configurations that maintain an area of relative immune privilege in the anagen stage of hair follicle cycle. The epithelium of the proximal hair follicle (the inner root sheath and hair matrix) is characterized by very low level of expression of major histocompatibility complex class Ia antigens, local production of immunosuppressive agents (transforming growth factor [TGF]-beta 1, alpha-melanocyte-stimulating hormone), and inhibition of natural killer (NK) cell activities. A collapse of this immune privilege is likely to play an important role in the pathogenesis of alopecia areata and possibly in some scarring alopecias.13–15
Fig. 22.16 Terminal anagen hair, vertical and horizontal sections of the upper segment: note the ostium, infundibulum and isthmus. The insets show horizontal sections through (1) the infundibulum and (2) the isthmus. The outer root sheath of the infundibulum is composed of squamous epithelium similar to the epidermis. Courtesy of M. Mejia, MD, Universidad Pontificia Bolivariana, Medellín, Colombia.
Fig. 22.17 Infundibulum. Horizontal section. The wall is made up of squamous stratified keratinized epithelium. The surrounding dermis is infiltrated by some lymphocytes. There are two hair shafts emerging from a single ostium.
Fig. 22.18 Isthmus and lower segment, vertical sections: note the isthmus and the outer root sheath which keratinizes in the absence of a granular cell layer. Its silhouette is wavy and intensely eosinophilic (trichilemmal). At the junction between the isthmus and lower segment is a small bulge that protrudes from the outer sheath toward the dermis. At this site, the inner root sheath is shed. On the right-hand side, note the proximity between the upper and lower segments with the normal shedding site of the inner root sheath.
Fig. 22.19 Terminal anagen hair, vertical and horizontal sections of the lower segment: note the shaft and the hair bulb deep to Adamson fringe. The horizontal sections show (1) the stem and (2) the upper part of the bulb. Note the loss of nuclei in the hair shaft and the inner root sheath. Courtesy of M. Mejia, MD, Universidad Pontificia Bolivariana, Medellín, Colombia.
Fig. 22.20 Terminal anagen hair section showing Adamson fringe: there is loss of trichohyalin granules and nuclei in the inner root sheath and the hair shaft at the junction of the stem (above) and the bulb (below). Above this level, the inner root sheath keratinizes completely.
Fig. 22.21 Terminal anagen hair, lower segment: the pink inner root sheath (anucleated) clearly contrasts with the outer root sheath (nucleated) in this vertical section. The cuticle has a serrated border orientated in the opposite direction to that of the inner root sheath. The cells of the outer root sheath have clear cytoplasm due to prominent intracytoplasmic glycogen at this level.
Fig. 22.22 Terminal anagen hair: hair bulb and hair follicle pigmentary unit, vertical and horizontal sections. In the vertical and horizontal sections, note the supramatricial cells with intracytoplasmic pigmentation transferred from the dendritic melanocytes that surround the dermal papilla. The latter is composed of connective tissue and blood vessels.
Fig. 22.23 Hair shaft: Note the cortex (2) and the cuticle (1). Sometimes, the medulla is easily visualized (3).
Fig. 22.24 Terminal anagen hair follicles: horizontal and vertical sections immediately below the Adamson fringe. Note the different layers of the hair follicle. (1) Medulla, (2) cortex, (3) cuticle of the hair and cuticle of the inner root sheath, (4) Huxley layer, (5) Henle layer, (6) outer root sheath, and (7) vitreous and external fibrous layer (perifollicular connective tissue sheath).
Fig. 22.25 (A, B) Hair follicle cycle: the hair follicle cycles continuously from anagen to catagen, telogen, and exogen, returning to anagen through growth of the lower segment. The duration and relative proportion of each stage is variable.
Fig. 22.26 Terminal hair follicle in catagen, vertical and horizontal sections: note the involution of the follicle and the deep red trichilemmal keratinization around the club-shaped hair shaft. The outer root sheath shows marked apoptosis. At the deepest part of the follicle, there is a hint of secondary germ formation.
Fig. 22.27 Terminal hair follicles in catagen and anagen, horizontal sections: note the differences between a catagen follicle (top left) with trichilemmal keratin surrounding the hair shaft, apoptotic cells and loss of melanin and an anagen, heavily pigmented terminal follicle (inferior).
Fig. 22.28 Terminal hair follicles in catagen and telogen, vertical sections: the involution of the hair follicle leaves behind a thickened basement membrane.
Fig. 22.29 Terminal hair follicles in late catagen: the outer root sheath has been lost and the keratinization is of trichilemmal type.
Fig. 22.30 Terminal hair follicle in telogen, secondary germ: note the condensation of basaloid cells in an asterisk or daisy shape in a horizontal section.
Fig. 22.31 Terminal hair follicle in telogen, secondary germ: horizontal section stained with Masson trichrome.
Fig. 22.32 Bulge and arrector pili muscle. In this vertical section, note the insertion of the arrector pili muscle erector in the bulge.
Fig. 22.33 Follicular stella, horizontal section: note the small blood vessels mixed with concentrically arranged connective tissue.
Fig. 22.34 Follicular stella: note the fibrovascular stella composed of collagen fibers, fibroblasts, and blood vessels in vertical and horizontal sections. The elastotic material is apparent between the collagen fibers. With polarized light, there is no birefringence of the follicular stellae.