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The androgen receptor (AR) is generally considered an autoregulated protein. However, studies in brain have produced mixed results regarding sex differences, which should be present given the higher endogenous levels of androgens in males, and the effects of gonadectomy, which presumably should lead to a loss of AR. Resolving these issues is a necessary step in developing a model of AR regulation in the central nervous system and, more broadly, in determining how regulation of this receptor may mediate neural target tissue responsiveness to androgen. To further investigate these issues, the distribution, density, and regulation of neural AR were compared among male and female mice that were intact, gonadectomized, or gonadectomized and given testosterone propionate (TP) through immunocytochemical and Western blot analyses. Four brain areas that have been linked to the regulation of male-typical behavior were evaluated: bed nucleus of the stria terminalis, posterior aspect, medial preoptic area, and dorsal and ventral aspects of the lateral septum. In the immunocytochemical study, integrated particle density, which reflects the average intensity of AR staining, was assessed among the six groups 24 h after surgery using PG-21, a peptide-based AR antiserum. Major findings included regional differences in the intensity of immunostaining; a robust sexual dimorphism in each region, with males exhibiting more intense staining than females; a loss of AR in both sexes after gonadectomy, with more dramatic changes evident in males; and significant up-regulation of AR in response to TP that was equivalent in both sexes. The Western blot analyses of AR in limbic system extracts prepared from the six groups showed a pattern of differences that mirrored the immunocytochemical results, indicating that PG-21 recognized both liganded and unliganded AR. In addition, a dose-response study, in which gonadectomized males and females were administered from 25-1000 microg TP, demonstrated a significant linear trend in up-regulation of AR in both males and females, with no sexual dimorphism in the response to hormone treatment. These results demonstrate that the regulation of AR in both male and female neural tissue is comparable and that the critical determinant of AR expression is the presence or absence of androgen.

There are multiple pathways involved in the regulation of male typical aggression by T, and the functional pathway is determined by genotype. Target-tissue sensitivity to the aggression-promoting properties of T and its estrogenic and androgenic metabolites is determined by a complex sequence of events in which steroid receptors play a critical role. To date, it appears that the relative density of AR may be an important factor in the biobehavioral effects of androgens. Regarding sensitivity to estrogens, characterization of ER-NM interactions, and understanding of the contribution of the two activating functions within ER, appears to be necessary to comprehensively describe the cellular basis for responsiveness to the aggression-promoting effect of this T metabolite. In broader terms, these observations indicate that understanding the relationship between T and the expression of aggression in humans will require models that incorporate cellular aspects of steroid hormone action, including metabolism, receptor function, and gene regulation.

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