4. Physiology of the hair

#### 4.1. Hair growth cycle

Hair development is a continuous cyclic process and all mature follicles go through a growth cycle consisting of growth (anagen), regression (catagen), rest (telogen) and shedding (exogen) phases (Figure 3). The duration of the phases changes based on the location of the hair and also personal nutritional and hormonal status and age [15, 33].

Figure 3. The hair cycle.

#### 4.1.1. Anagen

The inception of anagen phase is presented by the onset of the mitotic activity in the secondary epithelial germ located between the club hair and dermal papilla in telogen hair follicle [5, 16]. The anagen is the active growth phase in which the follicle enlarges and takes the original shape and the hair fiber is produced. Almost 85–90% of all scalp hairs are in anagen.

Six portion of the anagen stage is demonstrated. Through the anagen I–V, hair stem cells proliferate, encloses the dermal papilla, grow downwards to the skin and begin to proliferate hair shaft and IRS, respectively. Subsequently, hair matrix melanocytes begin to develop pigment and the form of the hair shaft begins to arise; in anagen VI, hair bulb and adjacent the dermal papilla formation is realized and the new hair shaft appears from the skin. This phase can last up to 6–8 years in hair follicles [1, 11, 18].

Hair shaft synthesis and pigmentation only take place in anagen [11]. The degree of axial symmetry within the hair bulb determines the curvature of the final hair structure [35]. Fiber length is often dependent on the duration of the anagen or actively growing phase of the follicle [17]. The featured regulatory proteins in anagen phase are BMPs, sonic hedgehog, several WNT proteins and receptors. Insulin like growth factor-1 (IGF-1), fibroblast growth factor-7 hepatic growth factor (HGF), and vascular endothelial growth factor (VEGF) are thought to be important for anagen maintenance [36].

#### 4.1.2. Catagen

In contrast to the continuous melanogenesis observed in epidermal melanocytes, follicular melanogenesis is a cyclic phenomenon. It is ceased in early the anagen-catagen transition, restarted with the down-regulation of key enzymes of melanogenesis, followed by hair follicle

Hair follicle melanocytes and their precursors reside in the hair matrix and along the outer root sheath of anagen hair follicles. However, production of hair pigment (black eumelanin and/or the reddish pheomelanin) only occurs in the specialized hair follicle pigmentary unit, located above and around the dermal papilla during anagen III–VI. Melanin synthesis is established in lysosome-related organelles named melanosomes. In the precortical matrix, these melanosomes are transferred to the hair shaft keratinocytes and formed a pigmented hair shaft. The hair follicle also contains melanocyte stem cells, which are located in the bulge and in the

Hair development is a continuous cyclic process and all mature follicles go through a growth cycle consisting of growth (anagen), regression (catagen), rest (telogen) and shedding (exogen) phases (Figure 3). The duration of the phases changes based on the location of the hair and also

The inception of anagen phase is presented by the onset of the mitotic activity in the secondary epithelial germ located between the club hair and dermal papilla in telogen hair follicle [5, 16]. The anagen is the active growth phase in which the follicle enlarges and takes the original

shape and the hair fiber is produced. Almost 85–90% of all scalp hairs are in anagen.

melanocyte apoptosis.

22 Hair and Scalp Disorders

secondary hair [33–35].

4.1. Hair growth cycle

4.1.1. Anagen

Figure 3. The hair cycle.

4. Physiology of the hair

personal nutritional and hormonal status and age [15, 33].

At the end of anagen, mitotic activity of the matrix cells is diminished and the follicle enters a highly controlled involutionary phase known as catagen. Catagen lasts approximately 2 weeks in humans, regardless of the site and follicle type [37]. During catagen the proximal of the hair shaft is keratinized and forms the club hair, whereas the distal part of the follicle is involuted by apoptosis [16, 38].

Catagen phase is consisted of eight different stages. The first sign of catagen is the termination of melanogenesis in the hair bulb. Follicular epithelium, mesenchyme, neuroectodermal cell populations and also perifollicular vascular and neural systems demonstrates cyclic changes in differentiation and apoptosis. However, any apoptosis is occurred in dermal papilla due to the expression of suppressor bcl-2 [11].

Catagen is a process of bulbar involution. The perifollicular sheath collapses and vitreous membrane thickens. Eventually, the lower hair follicle becomes reduced to an epithelial strand, bringing the dermal papilla into close proximity of the bulge [36]. The epithelial strand begins to elongate and finally reaches to just below the insertion of pilar muscle. After the keratinization of the presumptive club hair, the epithelial strands begin to involute and shorten progressively followed by the papilla which condenses, moves upward and locates to rest below the bulge. The column eventually reduces to a nipple and forms secondary hair germ below the club. The club hair itself is formed from cortical and cuticle cells only, and it is characterized by a lack of pigmentation [2, 37]. The presence of hairless gene mutation contributes to the failure of dermal papilla migration toward the bulge area in catagen phase [3]. FGF5 is a key inducer of catagen and FGF5-deficient mice have a prolonged anagen phase. In addition to FGF5, TGF-β1, IL-1b, the neurotrophins NT-3, NT-4 and BMP2/4 and TNF-α have been described to induce catagen [36].

#### 4.1.3. Telogen

The telogen stage is defined as the duration between the completion of follicular regression and the onset of the next anagen phase. Telogen stage lasts for 2–3 months. Approximately 10– 15% of all hair is in telogen stage. During the telogen stage, the hair shaft is transformed to club hair and finally shed. The follicle remains in this stage until the hair germ which is responsive to anagen initiating signals from the dermal papilla, starts to show enhanced proliferative and transcriptional activity in late telogen, leading to the initiation of anagen [2, 39].

Telogen is one of the main targets of hair cycle which is influenced by several modulatory agents like androgens, prolactin, ACTH, retinoids and thyroid hormones [40]. No unique molecular markers associated with the telogen follicle are determined yet; however, estrogen receptor expression is reported to be limited to the telogen papilla fibroblasts. Germ cells of telogen follicles also express basonuclin and FGF-5 [33]. The bone morphogenic protein-4 (BMP-4) as a growth factor plays an essential role in suppressing follicular growth and differentiation at telogen stage [16].

The macro-environment surrounding the hair follicle also takes part in regulating cycle transitions. BMPs in the subcutaneous fat are capable of maintaining follicles in a "refractory" telogen, and cessation of this inhibitory activity by BMPs enables the follicle to progress to a "competent" telogen with a hair germ that is responsive to anagen-initiation signals and capable of entering a new anagen phase [2, 41].

#### 4.1.4. Exogen

There is less interest for the mechanism of the hair shedding but from the patient's perspective it is probably the most important part of the hair growth. It is not unusual for human telogen hairs to be retained from more than one follicular cycle and this suggests that anagen and exogen phases are independent. The shedding period is believed to be an active process and independent of telogen and anagen thus this distinct shedding phase is named exogen [16, 33].

#### 4.2. Hair cycle clock

Based on the observations: the hair follicle has no need for intact innervation, vascularization or other extrafollicular components to maintain cycling, and the basic oscillator system which controls hair cycling is located presumably in the follicle [42]. The principal challenge is to define the underlying "oscillator" system. Probably, the hair cycle clock is controlled by regulating the balance of the interactions between the follicle epithelium and the surrounding mesenchyme. This might be provided by the rhythmic secretions of growth/modulatory signals from follicle epithelium or mesenchyme as well as the rhythmic alterations in the expressions of corresponding receptors [40].

### 5. Conclusion

In this chapter, the basic anatomy and the amazing and complicated biology of the hair follicle is reviewed. Enhanced knowledge on the normal dynamics of the hair provides understanding the basis of how the follicle behaves during a disease. However recent progress in our understanding of the biology and pathology of hair follicles should lead more effective therapies for hair disorders.
