Disorders of androgen action

Basic and clinical science have interacted in the analysis of androgen action to provide insight into sexual differentiation during embryogenesis and the process of virilization during postnatal life. As a consequence, our understanding as to how the male and female phenotypes develop has been revolutionized. In addition, the unraveling of androgen action has provided insight into the operation of other hormonal systems. The importance of androgen physiology for these advances stems from several distinctive features. The metabolism of androgens has served as a paradigm for the elucidation of extraglandular hormone formation and for the analysis of complex hormonal interaction at the cellular level. Although essential for reproduction, androgens are not critical for the life of individuals; thus, mutations that either block or enhance androgen action are compatible with life. Androgens play a central role in the embryonic differentiation of their own target tissues and hence in the development of the male phenotype; as a consequence, mutations that impair androgen action have a high rate of ascertainment. The receptor protein and many of the enzymes critical for androgen action are expressed in cultured skin fibroblasts; spontaneous mutations that influence these functions and cause human disease can, therefore, be characterized in vitro. Because the gene for the androgen receptor protein is X-linked and hence expressed in the hemizygous state, disorders of the androgen receptor appear to be relatively common in man and animals. Thus, while many aspects of androgen action are still unexplained, phenotypic sexual differentiation is the best understood aspect of embryogenesis, and major insight has been obtained into several disorders of human intersex.