Sex specific occurrence of androgen receptors in rat brain

The metabolism and binding of [1,2,6,7 ³H]testosterone in male and female rat brain has been studied in an attempt to find an explanation for the relative androgen unresponsiveness characterizing the female hypothalamo pituitary axis involved in regulation of hepatic steroid metabolism. The most significant sex differences in the pattern of 6=[³H]testosterone testosterone metabolites recovered from several brain regions (including pituitary, pineal gland, and hypothalamus) after intraperitoneal administration of [³H]testosterone were the predominance of testosterone and androstenedione in male brain compared to the quantitative importance of 5α androstane 3α,17β diol, 5α androstane 3β,17β diol, epitestosterone, and dihydroepitestosterone in female brain. One possible explanation for the androgen unresponsiveness of female rats is, therefore, the faster metabolism of testosterone to inactive compounds in female brain. Experiments both in vivo and in vitro showed the presence of high affinity, low capacity binding sites for [³H]testosterone in male pituitary, pineal gland, and hypothalamus (Kd values in the region of 1 x 10^-10 to 1 x 10^-9 M and number of binding sites 1.0 to 1.4 x 10^-14 mol per mg of protein). The steroid macromolecular complexes generally had a pI of 5.1, were excluded from Sephadex G 200, were heat labile, and were sensitive to protease. Competition experiments indicated the following order of ligand affinities: testosterone > 5α dihydrotestosterone and estradiol > androstenedione >> corticosterone. No steroid binding proteins of similar nature were found in pituitary, pineal gland, or hypothalamus from female rats. On the basis of these results it is suggested that the androgen unresponsiveness of female rats referred to above relates to the absence of receptor protein for androgens in female rat brain. In support of this hypothesis, 28 day old female rats, which are known to be affected by androgens with regard to liver enzyme activities, were shown to contain receptor proteins for androgen in the brain. In conclusion, the relative androgen unresponsiveness of the female hypothalamo pituitary axis is probably explained by the absence of receptor proteins for androgen in female hypothalamus and pituitary. The fast metabolism of testosterone in female rat brain also serves to decrease the availability of active androgen to potential receptor sites. It may be speculated that the presence of androgen receptors in male brain is the result of neonatal programming ('imprinting') by testicular androgen.