Sex Differences in Androgen Responsiveness in the Rat Brain: Regional Differences in the Induction of Aromatase Activity

Abstract

The transformation of testosterone (T) to estrogens in brain tissue by cytochrome P-450 aromatase is required for the expression of sexual behaviors in adult male rats. Androgens regulate aromatase activity in the medial preoptic nucleus (MPN), as well as in a reciprocally connected group of forebrain nuclei involved in the regulation of male sexual behaviors. The levels of aromatase in these nuclei are generally greater in males than in females due to sex differences in circulating androgen levels. However, the mechanism of enzyme induction also appears to be sexually dimorphic. The current experiments were undertaken: (l)to characterize and compare the kinetic properties of aromatase in male and female rats and (2) to study sex differences in the dose-response relationship between the administered doses of T and the induction of aromatase in microdissected brain regions. Saturation analysis of aromatase activity in the MPN, bed nucleus of the stria terminalis (BNST), periventricular preoptic area (PVPOA), anterior hypothalamus (AH), and ventromedial hypothalamic nucleus (VMN) indicates that the greater aromatase activity observed in intact males reflects a sex difference in the maximal enzyme velocity, and not a sex difference in the apparent affinity of enzyme for substrate (Michaelis constant). The dose-response study of aromatase induction in the BNST, PVPOA, and VMN indicated a sex difference in aromatase activity over a range of circulating T levels varying from 0.3 to 35 ng/ml. No sex difference in inducible aromatase activity in AH was observed at any dose of T. The results of this study clearly demonstrate a sexually dimorphic effect of androgen action in the rat brain. Since T both regulates and is the substrate for aromatase in the brain, this sexual dimorphism is potentially an important limitation to the action of T in females and may relate to the enhanced expression of T-stimulated copulatory behavior in males compared to females.

Sex Differences in Male-Typical Copulatory Behaviors in Response to Androgen and Estrogen Treatment in Rats

“…This result agrees with other studies that directly demonstrated that the conversation of T to E 2 in MPOA of adult male rats is important for activation of male sexual behavior [33, 34]. The finding that E 2 , but not T, stimulated equivalent levels of mounting in males and females suggests that the previously established sexual dimorphism in the capacity for aromatization in the rat brain [8]is functionally related to sex differences in motivational responses to T. These results support the hypothesis that locally formed estrogens contribute to sexual motivation in males. It is likely that unmodified or nonaromatized androgens also contribute to sexual motivation, because the level of mounting achieved in males and females with T treatment was significantly greater than observed with E 2 treatment.…”

“…The expression of aromatase activity in the MPOA is regulated by androgen [6]. The capacity for synthesis of estrogen in MPOA is sexually dimorphic because males exhibit a greater aromatization than females even after both sexes are Gdx and treated with a range of T doses [8]. Measurements of aromatase mRNA in the MPOA of androgen-treated Gdx rats demonstrate that the sex difference is evident at the transcriptional level [9, 10].…”

Expression of aromatase in the embryonic brain of the olive ridley sea turtle (Lepidochelys olivacea), and the effect of bisphenol-A in sexually differentiated embryos

“…In sexually mature organisms, as in quails, immunohistochemistry and in situ hybridization studies have revealed that aromatase is specifically expressed in the dimorphic preoptic nucleus, showing higher expression in males (Schumacher and Balthazart, 1986;Aste et al, 1998;Balthazart et al, 1990;Foidart et al, 1995;Voigt et al, 2007), in which the activation of the copulatory behavior is controlled by an estrogenandrogen synergism, therefore, the action of testosterone along with aromatase and 5a-reductase is necessary and sufficient for the activation of the male sexual behavior (Panzica et al, 1996). Similar results have been found in rats (Roselli et al, 1996).…”

Estrogen potentiates treatment with T-cell receptor protein of female mice with experimental encephalomyelitis

“…The samples were centrifuged, and the sera were collected and stored at -80°C until hormone analysis was performed. Serum levels of estrogen were determined by radioimmunoassay (RIA) after Sephadex LH-20 column chromatography, as described previously (38). All samples were analyzed in a single assay.…”