Cultured human skin fibroblasts: a model for the study of androgen action |
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Authors: | Terry R Brown Claude J Migeon |
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Institution: | (1) Dept. of Pediatrics, Division of Pediatric Endocrinology, The Johns Hopkins University School of Medicine, 21205 Baltimore, MD, U.S.A. |
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Abstract: | Human skin may be considered as a target organ for androgens, as are male sex accessory organs, since all events involved
in testosterone action have been observed in this tissue. As a corollary, the mechanism of androgen action can be studiedin vitro in cultured skin fibroblasts. The advantages of this system are that studies can be performed with intact human cells under
carefully controlled conditions, differentiated genetic and biochemical characteristics of the cells are faithfully preserved
and the biological material is renewable from a single biopsy specimen. The metabolism of androgens, in particular the 5α-reduction
of testosterone to the active metabolite, dihydrotestosterone, the intracellular binding of androgen to its specific receptor
protein and its subsequent translocation to the nucleus have been studied in skin fibroblasts. The intracellular androgen
receptor content of genital skin fibroblasts is higher than that from nongenital skin sites. In addition, the androgen receptor
has been characterized as a specific macromolecule with properties of high affinity and low capacity similar to that of other
steroid hormone receptors.
The pathophysiology of three genetic mutations which alter normal male sexual development and differentiation has been identified
in the human skin fibroblast system. In 5α-reductase deficiency, an autosomal recessive disorder in which dihydrotestosterone
formation is impaired, virilization of the Wolffian ducts is normal but the external genitalia and urogenital sinus derivatives
are female in character. At least two types of X-linked disorders of the androgen receptor exist such that the actions of
both testosterone and dihydrotestosterone are impaired and developmental abnormalities may involve both Wolffian derivatives
and the external genitalia as well. These two forms of androgen insensitivity result from either the absence of androgen receptor
binding activity (receptor(−)form) or apparently normal androgen receptor binding with absence of an appropriate biological
response (receptor (+) form). In addition, studies with human skin fibroblasts may also be of value in defining the cellular
mechanisms underlying the broad spectrum of partial defects in virilization.
In summary, we have correlated our studies of the molecular mechanism of androgen action in human genital skin fibroblasts
with those of other investigators as these studies contribute to our understanding of male sexual development and differentiation. |
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