The role of androgen receptors in sexual differentiation of the brain: Effects of the testicular feminization (Tfm) gene on androgen metabolism, binding, and action in the mouse

The effects ofthe testicular feminization (Tfm) mutation on androgen metabolism, binding, and action were studied in the mouse. Cytosolic binding of ['H] dihydrotesterone (DHT) was reduced by approximately 90% in the brains, pituitaries, submaxillary glands, and kidneys ofTfmIY males, as compared to wild-type male controls. N uclear ['H] DHT binding was abolished in tissues from Tfm male animals. Implantation of testosterone-eontaining (T -eontaining) Silastic capsules elevated nuclear estrogen receptor (ERn) concentrations to a similar extent in the brains of all four genotypes studied (normal males, Tfm-affected males, normal females, and Tfm carrier females). Administration ofT to normal males led to elevations of cytosolic progestin receptors (PRc) and monoamine oxidase (MAO) activity in the brain, and of alcohol dehydrogenase (ADH) and glucose-6-phosphate dehydrogenase (G6PDH) in the kidney. In Tfm-affected males, only the PRc response to T was observed, at a somewhat reduced level compared to that in normal male and female controls: no effect of T was observed with respect to either MAO in the brain, or ADH and G6PDH activities in the kidney. Estradiol (E,) administration increased the activity of pituitary G6PDH and lactic dehydrogenase (LDH) in all four genotypes. However, brain MAO activity was increased by E, only in normal and carrier females. The lack of an MAO response to E, in Tfm-affected males is consistent with the hypothesis that the central nervous system ofthis genotype is at least partially masculinized, despite the loss of androgen receptor-mediated responses-most probably as a result of local conversion of T to E, within the brain itself.