Estrogen, But Not Androgens, Regulates Androgen Receptor Messenger Ribonucleic Acid Expression in the Developing Male Rat Forebrain1

Testosterone is the principal gonadal hormone responsible for the masculinization of the rat nervous system. Sex differences in both the ligand and receptor availability may play a role in the process of sexual differentiation. In some brain regions, males express more androgen receptor (AR) messenger RNA (mRNA) than females by postnatal day (PND) 10. Gonadectomy on the day of birth (PND-0) eliminated the sex differences in AR mRNA expression at PND-10, and exogenous testosterone replacement restored this sex difference. Because testosterone can be converted to both androgenic and estrogenic metabolites in the brain, the present experiments were performed to determine whether androgenic or estrogenic metabolites of testosterone are responsible for region-specific regulation of AR mRNA content in the developing rat forebrain. We used a 35S-labeled riboprobe and in situ hybridization to assess relative steady-state levels of AR mRNA in animals killed on PND-10. In the principal portion of the bed nucleus of the stria terminalis (BSTpr) and medial preoptic area (MPO), males gonadectomized on PND-0 and treated daily with dihydrotestosterone propionate (DHTP), a nonaromatizable androgen, had low levels of AR mRNA that were not significantly different from AR mRNA levels in intact females. In contrast, males gonadectomized on PND-0 and treated daily with diethylstilbestrol (DES), a synthetic estrogen, maintained high, male-typical levels of AR mRNA in the BSTpr and the MPO. AR mRNA content in the VMH was not sexually differentiated in PND-10 rats and was unaffected by gonadectomy or hormone replacement. To further assess whether AR mRNA was autologously regulated, neonatal male rats were treated with the androgen receptor antagonist, flutamide. Flutamide at a dose of either 40 microg/day or 300 microg/day had no effect on AR mRNA expression in any area examined. Thus, AR mRNA is up-regulated by estrogen but is not regulated by androgen during the early postnatal period.