The mechanism of androgen action in the hair follicle

6.4.1 Hair growth in androgen insufficiency syndromes

As described in Chapters 1 and 2 of this book, androgens from the blood stream enter the cell and bind to specific, intracellular androgen receptors, usually in the form of testosterone or its more potent metabolite, 5a-dihydrotestosterone. The hormone-receptor complex, generally in combination with transcriptional regulators then activates the appropriate gene transcription for that cell type.

Androgen insufficiency patients without functional androgen receptors demonstrate the essential requirement for androgen receptors within hair follicles for the development of the hair growth ascribed in 6.3.2 to androgens (Hiort, this volume Chapter 3). These individuals produce no body hair at puberty, even with high circulating androgen levels, nor do they go bald (Fig. 6.3).

Men with 5a-reductase deficiency also contribute to our understanding because they exhibit axillary and female pattern pubic hair, but very little beard growth; they are not reported to have male pattern baldness either (Griffin and Wilson 1989) (Fig. 6.3). A role for 5a-reductase in male pattern baldness is also supported by the ability of oral finasteride, a 5a-reductase type 2 inhibitor, to promote hair regrowth (Kaufman et al. 1998; Shapiro and Kaufman 2003). This suggests that the formation of terminal pubic and axillary hair can be mediated by testosterone itself, while that of the secondary sexual hair of men requires the presence of 5a-dihydrotestosterone. This demonstrates a third paradox in androgen effects on hair follicles. Why does the stimulation of increasing size in some follicles e.g. beard require 5a-dihydrotestosterone formation, while follicles in the axillary and pubic regions carry out the same changes in the absence of 5a-dihydrotestosterone? Since androgens are stimulating the same transformation, presumably via the same receptor, this is currently difficult to understand, although it is further evidence of the intrinsic differences within hair follicles. It suggests that some less well known aspects of androgen action are involved in hair follicles normally specific to men which requires 5a-dihydrotestosterone, such as interaction with a specific transcription factor. Interestingly, androgen-dependent sebum production by the sebaceous glands attached to hair follicles is also normal in 5a-reductase deficiency (Imperato-McGinley etal. 1993). The identification of two forms of 5a-reductase, type 1 and type 2, has made the situation more complex, but all individuals with 5a-reductase deficiency so far have been shown to be deficient in 5a-reductase type 2 (reviewed by Randall 1994b) which appears to be the important form for much androgen-dependent hair growth.

6.4.2 The current model for androgen action in the hair follicle

6.4.2.1 The role of the dermal papilla

The mesenchyme-derived dermal papilla plays a major role in determining the type of hair produced by a follicle as shown by an elegant series of experiments involving the rat whisker by Oliver, Jahoda, Reynolds and colleagues (reviewed by Jahoda and Reynolds 1996). Whisker dermal papillae transplanted into ear or glabrous skin stimulated the production of whisker follicles and hair growth could

Basement membrane

Blood capillary

Epithelial cells

(indirect target)

Basement membrane

Blood capillary

Epithelial cells

(indirect target)

Dermal papilla cells

(direct target)

Melanocyte

(indirect target)

Extracellular matrix

Hair

Hair bulb

T CIRCULATING ANDROGENS

Dermal papilla cells

(direct target)

Melanocyte

(indirect target)

Extracellular matrix

Hair

Hair bulb

T CIRCULATING ANDROGENS

Fig. 6.5 The current model of androgen action in the hair follicle

Androgens from the blood enter the hair follicle via the dermal papilla's blood supply. They are bound by androgen receptors in the dermal papilla cells which then alter their production of regulatory paracrine factors; these then alter the activity of follicular keratinocytes and melanocytes. T = Testosterone; ? = unknown paracrine factors (modified from Randall 1994a).

also be stimulated by cultured dermal papilla cells reimplanted in vivo (Jahoda etal. 1984).

In many embryonic steroid-regulated tissues, including the prostate and the breast, steroids act via the mesenchyme (Cunha et al. 1987). Since hair follicles recapitulate the stages of embryogenesis during their growth cycles to reform a new lower hair follicle, they may behave like an embryonic tissue in the adult. Studies on testosterone metabolism in vitro by plucked hair follicles, which leave the dermal papilla behind in the skin, from different body sites did not reflect the requirements for 5a-reductase in vivo (reviewed in Randall etal. 1991; Randall 1994a), leading to the hypothesis that androgens would act on the other components of the hair follicle via the dermal papilla (Randall etal. 1991; Randall 1994a). In this hypothesis androgens would alter the ability of the dermal papilla cells to synthesise or release controlling factors which would affect follicular keratinocytes, melanocytes and connective tissue sheath cells and also probably the dermal endothelial cells to alter the follicles' blood supply in proportion to its change in size (Fig. 6.5). These factors could be growth factors and/or extracellular matrix proteins. This model would facilitate a mechanism for precise control of the follicle during the complex changes needed to increase or decrease the size of a follicle in response to androgens.

This hypothesis has now received a great deal of experimental support. Androgen receptors have been localised by immunohistochemistry in the dermal papilla and not the keratinocyte cells (Choudhry et al. 1992; Itami et al. 1995a). Cultured dermal papilla cells derived from androgen-sensitive follicles such as beard (Randall etal. 1992) and balding scalp (Hibberts etal. 1998) contain higher levels of specific, saturable androgen receptors than androgen-insensitive non-balding scalp in vitro; this has been confirmed by studies using RT-PCR (Ando etal. 1999). Most importantly, metabolism of testosterone by cultured dermal papilla cells also reflects hair growth in 5a-reductase deficiency patients with beard, but not pubic or non-balding scalp, cells forming 5a-dihydrotestosterone in vitro (Itami et al. 1990;Hamada etal. 1996; Thornton etal. 1993); similar results have been obtained examining gene expression of 5a-reductase type 2 by RT-PCR (Ando etal. 1999). All these results have led to wide acceptance of the hypothesis.

Recently the lower part of the connective tissue sheath, or dermal sheath, which surrounds the hair follicle and isolates it from the dermis has been shown to form a new dermal papilla and new human hair follicle development in another person of the opposite sex (Reynolds et al. 1999). Cultured dermal sheath cells from the beard hair follicles contain similar levels of androgen receptors to beard dermal papilla cells (Merrick et al. 2004) and balding scalp dermal sheath expresses the mRNA for 5a-reductase type 2 like the dermal papilla (Asada etal. 2001). Clearly the dermal sheath also plays an important role in the hair follicle. This may be as a reserve to replace the key inductive and controlling role of the dermal papilla cells if they are lost. Alternatively, or in addition, it seems highly probable that the dermal sheath cells may respond directly to androgens to facilitate the increase or decrease in size of the sheath or even the dermal papilla in the development of a new anagen follicle; this would enable the new hair follicle to be larger or smaller depending on the follicle's specific response to androgens. These results merit a modification of the model to include a direct action of androgens on the lower dermal sheath too.

6.4.2.2 Paracrine factors implicated in mesenchyme-epithelial interactions in the hair follicle

The production of growth factors by cultured dermal papilla cells derived from human and rat hair follicles has been investigated by several groups on the basis of the primary role of the dermal papilla, its potential probable role in androgen action and the retention of hair growth-promoting ability by cultured rat cells (discussed above). Cultured dermal papilla cells secrete both extracellular matrix factors (Messenger etal. 1991) and soluble, proteinaceous growth factors (Randall et al. 1991). Bioassays demonstrate that human dermal papilla cells secrete factors which stimulate the growth of other dermal papilla cells (Randall et al. 1991; Thornton etal. 1998), outer root sheath cells (Itami etal. 1995a), transformed epidermal keratinocytes (Hibberts and Randall 1996) and endothelial cells (Hibberts etal. 1996c). Importantly, testosterone in vitro stimulated greater mitogenic capacity of beard cells to affect beard, but not scalp, dermal papilla cells (Thornton et al. 1998), outer root sheath cells (Itami et al. 1995a) and keratinocytes (Hibberts and Randall 1996). In contrast, testosterone decreased the mitogenic capacity of androgenetic alopecia dermal papilla cells from both men (Hibberts and Randall 1996) and stump-tailed macaques (Obana et al. 1997). As well as supporting the hypothesis for the mechanism of action, these results demonstrate that the paradoxical effects of androgen on hair follicles observed in vitro are reflected in vitro, strengthening the use of cultured dermal papilla cells as a model system for studying androgen action in vitro.

The main emphasis of research now lies in identifying specific factors whose production by dermal papilla cells is altered by androgens (reviewed Randall etal. 2001a). To date only insulin-like growth factor (IGF-1) has been identified as androgen-stimulated in vitro (Itami et al. 1995b), but stem cell factor (SCF), the ligand for the melanocyte receptor c-kit, is secreted in greater quantities by beard dermal papilla cells than non-balding scalp cells (Hibberts et al. 1996a) unlike vascular endothelial growth factor (Hibberts et al. 1996b). Other factors which have been implicated in the follicular dermal papilla include keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), though many more have been located in the epidermis (reviewed by Philpott 2000). The expression of mRNA for the protease nexin-1 in dermal papilla cells is also altered by androgens (Sonada et al. 1999). This may play a role by altering the amount of extracellular matrix components produced (discussed Randall et al. 2001b) and therefore the size of the follicle and hair produced (Elliott etal. 1999). Recently, dermal papilla cell conditioned media from balding scalp follicles has been shown to inhibit the growth of both human and rodent whisker dermal papilla cells in vitro and delay mouse hair growth in vivo (Hamada and Randall 2003). This suggests the active secretion of an inhibitory factor or factors. A possible candidate is transforming growth factor-p 1 (TGF-^1) which has been induced by androgens in balding dermal papilla cells with transfected androgen receptors (Inui etal. 2003). TGF-p also inhibits hair follicle growth in vitro (Philpott 2000) and a probable suppressor of TGF-^1 delayed catagen progression in mice in vivo (Tsuji et al. 2003). Further study of this area should increase our understanding of the complex hair follicle and lead to better treatments for hair follicle disorders.

Hair Loss Prevention

Hair Loss Prevention

The best start to preventing hair loss is understanding the basics of hair what it is, how it grows, what system malfunctions can cause it to stop growing. And this ebook will cover the bases for you. Note that the contents here are not presented from a medical practitioner, and that any and all dietary and medical planning should be made under the guidance of your own medical and health practitioners. This content only presents overviews of hair loss prevention research for educational purposes and does not replace medical advice from a professional physician.

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