Changes in hair biology and its impact on hair loss and growth


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Embryogenesis and the hair cycle clock in hair growth disorder development

Importance of embryogenesis in congenital hair growth disorders

Numerous congenital hair growth disorders can be caused by defects in embryogenesis and hair follicle formation. They can be classified into hypotrichoses and atrichoses and can be with or without associated musculoskeletal abnormalities. Some of the conditions result from the failure of follicle development (e.g. congenital hypotrichosis, temporal triangular alopecia), the rest occur due to incorrect or incomplete follicle development (e.g. generalized atrichia, hypotrichosis of Marie-Unna) resulting in a lack of continued hair growth.

As for example, EDA gene mutations cause X-linked anhidrotic ectodermal dysplasia (ED). This is a syndrome that involves a decreased number of hair follicles, teeth and sweat glands - all these symptoms are epidermal appendages with similar mechanisms of embryogenic development. An identical phenotype results from EDA receptor (EDAR) gene mutations in autosomal recessive and dominant hypohydrotic ED. The recessive hairless gene hr encodes for a transcription factor which is defective in a condition called generalized atrichia or congenital atrichia with papular lesions. The dermal papilla in both the hairless mouse and affected homozygotic humans shows the tendency of disintegration shortly after morphogenesis. As a result, the follicles cease to undergo another hair growth cycles; instead now they undergo cystic degeneration. Another example relates to the autosomal recessive condition where hereditary vitamin D-resistant rickets causes a similar phenotype due to a mutation in the vitamin D receptor (VDR). VDR functions as a transcription factor and as such it may have a key regulatory role in hair follicle development.

These and other genetic defects, are the proof of the importance of correct gene expression cascades in hair follicle embryogenesis and their failure results in various congenital hypotrichoses and hair loss diseases.

Importance of hair cycle clock in acquired hair diseases

Many acquired hair diseases are followed by the altered pulse of the hair cycle clock. The development of alopecias or hypotrichoses is often accompanied by potentially one or more of several changes to the hair cycle clock. When there is a prolongation in the anagen growth phase duration (or alternatively a delay in the onset of catagen), it may lead to hypertrichosis, and ultimately unwanted hair growth. On the other hand, a reduction in the anagen growth duration (induction of catagen) would result in the growth of short hair fibers due to truncated cycling, though hair density would be maintained on its own. A prolongation of the telogen phase of the clock cycle in scalp hair follicles is followed by a progressive thinning and alopecia development. Independent of the hair clock cycle, Telogen hair fibers would continue to be shed through the exogen mechanism. But when the follicles fail to enter a new anagen phase, new hair fiber would not be produced to replace old, shed fibers. The defined rodent models are the best way to show these consequences. For example, prologation of the anagen growth phase in Angora mice with a spontaneous mutation in exon 1 of FGF5 (Fgf5go) results in a pelage coat of hair 50% longer than normal. Truncated anagen in growth in mice transgenic for the Wingless-related MMTV integration site 3 (Tg(Wnt3)7Gsb) results in very short hair growth, though density is maintained. Mice with a targeted mutation of the telomerase RNA component (Terctm1Rdp) have a decreased percentage of hair follicles in anagen, an increased percentage in telogen, and a progressive alopecia as exogen shedding of telogen hair is apparently normal.

So far as the human beings are concerned, changes to hair clock cycling due to pilosebaceous diseases are less well characterized. However, telogen effluvium involving premature cessation of anagen can be caused by various external factors such as drugs, fever, severe illnesses or surgery, malnutrition, iron deficiency and anemia as well as endogenous influences such as thyroid dysfunction or parturition. In the condition of telogen effluvium the hair follicles respond to an adverse biochemical environment by truncation of anagen growth and prolongation of telogen dormancy. Certain cytostatic drugs, such as those used in chemotherapy, may lead to temporary hair loss. There can also be either loss of dystrophic anagen hairs after some days or telogen effluvium after several weeks---it all depends on the duration, dose and type of toxic agent. In the latter case a reduction in the telogen phase has also been observed.

Changes in the hair clock cycle do not generally take place in isolation from other morphological alterations to the pilosebaceous unit. In androgen mediated conditions, this becomes particularly evident. As for example, hirsutism involves prolongation of the anagen growth phase in association with a change in the size of hair follicles from vellus to terminal hair production. On the other hand, progressive shortening of anagen duration, and prolongation of the telogen phase is almost invariably follows androgenetic alopecia. This disorder involves miniaturization of follicles, and the regression of terminal scalp follicles to vellus-like hair production. A genetically susceptible dermal papilla receptive to androgen influence mainly triggers off this process. Current therapeutic measures can reverse the process, but only partially.

Thus in acquired alopecias, the disease mechanism usually overrides or modifies the hair clock cycle. A truncation of anagen growth and/or a prolongation of the telogen dormant state are typical of this disorder. Since the hair follicle, especially the stem cell reservoir, is not destroyed, it is ideally possible to reverse these alopecias. Some of these conditions are caused by genetic factors and are due to internal autoimmunologic inflammation or hormonal influence (e.g. androgenetic alopecia, alopecia areata). The rest of the cases are mainly caused by the environmental or external action (e.g. telogen or anagen effluvium, traction alopecia). In a nutshell, alopecia or hirsutism sets in as a result of a change in the hair cycle clock and it can be treated by “normalizing” the hair cycle clock in disease affected hair follicles.

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