Novel cellular phenotypes and subcellular sites for androgen action in the forebrain

Historically, morphological studies of the distribution of androgen receptors in the brain led to conclusions that the major regional targets of androgen action are involved in reproduction, that the primary cellular targets are neurons, and that functional androgen receptors are exclusively nuclear, consistent with the classical view of steroid receptors as ligand-dependent transcription factors. In this review, we discuss three separate but interrelated recent studies highlighting observations made with newer methodologies while assessing the regional, cellular or subcellular distribution of androgen receptors containing cells in the forebrain. Regional studies demonstrated that the largest forebrain target for androgen action in terms of the number of androgen receptor expressing cells is the cerebral cortex, rather than the main hypothalamic and limbic centers for reproductive function. Cellular studies to determine the phenotype of androgen receptor expressing cells confirmed that most of these cells are neurons but also revealed that small subpopulations are astrocytes. The expression of androgen receptors in astrocytes is both region and age dependent. In contrast, reactive astrocytes in the lesioned adult rat brain do not express androgen receptors whereas reactive microglia do. Finally, androgen receptor immunoreactive axons were identified in the cerebral cortex of the rat and human. These observations do not overturn classical views of the cellular and subcellular locus of steroid action in the nervous system, but rather broaden our view of the potential direct impact of gonadal steroid hormones on cellular function and emphasize the regional and developmental specificity of these effects on the nervous system.