L-16   ANDROGEN RESEARCH AND THE HUMAN HAIR FOLLICLE: 30 YEARS OF PROGRESS

S. Takayasu. Oita Medical University, Japan.

The role for 5alpha-reduction in androgen action became apparent with the findings in 1968 that dihydrotestosterone, the 5alpha-reduced derivative of testosterone, is formed in many androgen target tissues. Later, the type2 isozyme of 5alpha-reductase (5alphaR2) was found to play an essential role in the androgen action. We demonstrated the presence of 5alpha-reductase activity in plucked human hair follicles containing epithelial portions only in 1972. However, the enzyme activity does not appear to have any correlation with androgen dependent hair growth, and it has the characteristics of 5alphaR1. Cultured beard dermal papilla cells (DPCs) express 5alphaR2, while occipital DPCs express 5alphaR1. The effect of androgens on the hair follicle is considered to be mediated through the dermal papilla as seen in epithelial-mesenchymal interaction in the prostate. We developed a coculture system using human DPCs and outer root sheath cells/epidermal keratinocytes. Androgen stimulated the proliferation of epithelial cells, when they were cocultured with beard or axillary DPCs. The result suggests the DPCs produce androgen dependent diffusible growth factors. Insulin-like growth factor-1 was identified as one of such growth factors. We also found the protease nexin-1, which is expressed in the dermal papilla of late anagen stage, was also expressed in cultured human DPCs. Its mRNA expression was decreased by androgens in the cultured DPCs obtained from the balding scalp. Although the role for nexin- 1 in the hair growth is unknown at present, our recent findings on the expression of protease-activated receptor- 1 (thrombin receptor) in the human dermal papilla suggests that thrombin is a possible target of nexin-1. The following work was recently done by Itami's group. In the coculture system described before using DPCs from androgenetic alopecia, androgens did not affect the growth of keratinocytes. In the modified coculture where those DPCs were transiently transfected with the androgen receptor expression vector, androgens significantly suppressed the growth of keratinocytes. Since androgens stimulated the secretion of both total and active TGF-beta1 in the conditioned medium, the activation process of TGF-beta1 seems to be involved in the androgen-induced suppression of epithelial cell growth. We propose this modified coculture system is a useful model to study the pathomechanism of androgenetic alopecia.