Androgenetic alopecia, or male pattern baldness, is a genetic predisposition in which there is thinning and loss of the hair on the temples and crown of the scalp in an "M"-shaped pattern (Springer et al., 2003). The cause is sensitivity of hair follicles in these regions to the hormone dihydrotestosterone (DHT), which is formed in scalp cells from testosterone by the action of the enzyme 5-a-reductase. DHT acts to progressively shorten the anagen stage of hair growth while lengthening telogen, resulting in smaller hair follicles, thinner and shorter hairs and ultimately, many empty and involuted hair follicles. The follicles on the sides and back of the scalp are not responsive to DHT and so are spared.
The standard treatment for pattern baldness is the transplantation of clusters of 1-4 follicles from the sides and back of the scalp to the temples and crown, very close together, a time-consuming and expensive process. Two over-the-counter medications, minoxidil (marketed as Rogaine and applied topically) and finasteride (marketed as Propecia and taken orally) are available to combat hair loss. Minoxidil is converted to minoxidil sulfite, which activates potassium channels in follicle
FIGURE 4.6 Regrowth of hair in cyclophosphamide-treated mice after intradermal injection of the Shh gene in an adenoviral vector. Top, histological appearance of cyclophosphamide-treated control skin (A) and skin treated with adenoviral vector alone (B), showing dystrophic hair follicles. (C) AdShh-treated skin showing large growing hair follicles. Middle and bottom, gross appearance of control skin (D) and skin treated with adenoviral vector alone (E), showing lack of hair growth. (F, G) Mice treated with Shh, showing robust growth of hair. Reproduced with permission from Sato et al., Effect of adenovirus-mediated expression of sonic hedgehog gene on hair regrowth in mice with chemotherapy-induced alopecia. J Natl Cancer Inst 93:1858-1864. Copyright 2001, Oxford University Press.
cells, slowing hair loss by a mechanism that is unclear (Baker et al., 1994). Finasteride blocks the conversion of testosterone to DHT by inhibiting 5-a-reductase, restoring the length of anagen and promoting hair growth in 66% of men after two years of treatment (McClellan and Markham, 1999).
Transient expression of shh induces anagen in the hair follicles of postnatal mice (Sato et al., 1999) and is essential for hair development and regeneration (Wang et al., 2000). Hair loss in mice can be induced by administration of cyclophosphamide, which is cytotoxic for cycling cells because it binds to and cross-links DNA strands. Shh, delivered by intradermal injection in an adenoviral vector to the skin of mice suffering from cyclophosphamide-induced alopecia, stimulated rapid hair regrowth (Sato et al., 2001), suggesting that Shh or its agonists may be useful in the treatment of alopecias (FIGURE 4.6).
While research continues to better understand the molecular elements and pathways involved in hair regeneration in order to identify targets for drug intervention, the transplantation of stem cells from hair follicles is viewed as another promising therapy to regenerate hair (Costarelis and Millar, 2001). Intact dermal papilla or cultured dermal papilla cells (Horne et al., 1989; Jahoda et al., 1984), as well as pieces of lower dermal sheath or cultured dermal sheath cells (Horne and Jahoda, 1992; Jahoda et al., 1992) can form new dermal papillae in association with follicle epidermis. Current research aims to culture follicular bulge stem cells with dermal papilla cells from DHT-insensitive follicles in vitro to create unlimited numbers of cell pellets that can be implanted into the scalp, where they would form normal follicles (FIGURE 4.7).
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