Is the “Comb Over” Dying? A Mouse Model for Male Pattern Baldness (Androgenic Alopecia)

Abstract

Androgenic alopecia (AGA) is also known as male pattern baldness, but it affects males and females. In males, AGA results in the commonly observed loss of hair from the top of the head but not on the sides. In women, the result is a general thinning of hair. At least 50% of men will have AGA by their 50th birthday and up to 70% of males will have AGA in later life. It is estimated that 6% of women under age 50 are affected and 30–40% of women aged 70 and over have AGA (1). Hair growth initiates at the base of the hair follicle in the hair bulb (Fig. 1). Cell proliferation occurs in the matrix of the hair bulb, after which the keratinocytes move up into the follicle, differentiating into the layers of the hair and its surrounding sheaths. The process occurs in a repeating cycle initiated with a growth phase (anagen) of 2–7 yr in humans followed by regression (catagen, 2 wk), and a quiescent phase (telogen, 3 months) during which hairs are shed until reentry into anagen to generate a new hair shaft in the existing follicle (2, 3). For individuals with AGA, there is progressive shortening of anagen, resulting in increased shedding of the short-lived hairs, while the follicles produce shorter, finer hairs. The dermal papilla composed of specialized fibroblasts located below the hair bulb is thought to supply the inductive signals needed to control the growth and differentiation of the hair shaft (4, 5). Paradoxically, androgens are major contributors of hair loss for the scalp but stimulate hair growth in other areas. Men castrated before puberty do not develop AGA, but AGA can be triggered in castrated men after injection of testosterone (6). The levels of androgen receptor (AR) are elevated in balding scalp (7, 8) and individuals who lack AR (androgen insensitivity syndrome) do not display AGA (9). The enzyme 5 -reductase that converts testosterone to the more potent dihydrotestosterone (DHT) is also elevated in the balding scalp, and AGA is not observed in men with a congenital deficiency of 5 -reductase (8). Elevated 5 -reductase levels are thought to be the major cause of AGA. In fact, the 5 -reductase inhibitor finasteride can be used to treat AGA, but the use of finasteride is contraindicated in pregnant women because it can cause malformation of the external genitalia of male fetuses (10). The mechanisms by which androgens and AR regulate hair growth have not been fully established. However, it is accepted that androgens can act by at least two pathways to alter cellular physiology. In the classical pathway, androgen binding to the intracellular AR results in a conformational change in AR that frees it from heat shock proteins that sequester AR in the cytoplasm. AR then translocates to the nucleus and binds to specific DNA sequences called androgen response elements that regulate gene expression (11). In the nonclassical pathway, androgen binding to AR in the cytoplasm or at the plasma membrane rapidly (within seconds to minutes) causes the activation of a set of protein kinases including Src, ERK, protein kinase A, Akt, and protein kinase C as well as expression of genes downstream (reviewed in Refs. 12 and 13). Androgens can also increase intracellular levels of inositol-1,4,5-triphosphate (IP3) and diacylglycerol as well as increase calcium influx and calcium-mediated cell signaling (14). In this issue of Endocrinology, Crabtree, Kilbourne, and colleagues (15) report the development of a mouse model that should permit characterization of the molecular mechanisms responsible for AGA. Specifically, transgenic mice were produced that express human AR under