Pathophysiology of the androgen receptor

The final biological steps in the cellular cascade of normal male sexual differentiation are initiated by the molecular action of androgens in androgen-responsive target tissues. Lack of androgenic steroids leads to defective sexual differentiation in embryos with 46, XY karyotype; while their excess is associated with virilization in 46, XX children. Furthermore, androgens lead to specific changes during male puberty and are required for male fertility. A key player in the translation of androgen action is the androgen receptor (AR), a nuclear transcription factor which can bind various androgenic steroids as ligands and then act via differential DNA targeting and genetic control. With the elucidation of the X-chromosomal localization and the genetic structure of the AR more than 20 years ago (Fig. 3.1), it was thought that most 46, XY patients with presumed defects of androgen action would carry mutations in the coding regions of the AR gene. While this holds true for the majority of patients with complete androgen insensitivity syndrome (CAIS), to an increasing proportion patients clinically assigned as partial (PAIS) or minimal androgen insensitivity syndrome (MAIS) do not carry relevant mutations in the AR. Therefore the clarification of the time- and cell-specific mechanisms of androgen action and the factors acting in concert with the AR is of utmost importance. They lead to the cell-specific modulation of androgen-dependent transcription of several hundred target genes (Holterhus et al. 2003; 2007).