Androgen Receptor in Mouse Brain: Sex Differences and Similarities in Autoregulation¹

Abstract

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.

Androgen Affects the Inhibitory Avoidance Memory by Primarily Acting on Androgen Receptor in the Brain in Adolescent Male Rats

“…In both immunohistochemistry and Western blotting, we detected that decreased AR-immunoreactivity in the amygdala and hippocampus of OCX rats, whereas AR-immunoreactivity were augmented in either DHTor T-treated OCX rats. The effects of androgen on AR-immunoreactivity in the amygdala or in hippocampus of male rats in our present study is similar to that reported previously in the in different brain regions including the hippocampus, preoptic area, hypothalamic and amygdaloid areas of young or adult rodents [14,20,62]. It has been known that among the amygdaloid nuclei the basolateral amygdala is primarily responsible for the association between the conditioned stimulus (dark compartment) and unconditional stimulus (foot shock) [63].…”

The influence of maternal androgen excess on the male reproductive axis

“…Androgens exert their effects via the androgen receptor (AR), a ligand dependent nuclear transcription factor 52 that is highly regulated by circulating androgen levels 53,54 . Testosterone propionate administration to gonadectomised mice results in a significant linear trend in AR expression up regulation within various regions of both male and female brains 53 . PNA-treated female mice are hyperandrogenic and exhibit increased AR-positive cells within the AVPV, an important hypothalamic region for regulating female ovulatory cycles in rodent species 23 .…”

Sex Differences in the Incidence of Obesity-Related Gastrointestinal Cancer

“…Estrogen-treated male animals have been reported to show decreased levels of visceral fat with an increase in subcutaneous fat levels compared to control animals [22]. It has been shown that SAT has higher levels of ERs and progesterone receptors than androgen receptors (AR) in female animals [24]. One multicenter clinical study showed that cross-sex hormonal therapy in trans women and trans men resulted in a more female-like body fat distribution in trans women and vice versa in trans men, emphasizing the role of hormones in body fat distribution [25].…”