The ERβ Ligand 5α-androstane, 3β,17β-diol (3β-diol) Regulates Hypothalamic Oxytocin (Oxt) Gene Expression

The endocrine component of the stress response is regulated by glucocorticoids and sex steroids. Testosterone down-regulates hypothalamic-pituitary-adrenal (HPA) axis activity; however, the mechanisms by which it does so are poorly understood. A candidate testosterone target is the oxytocin gene (Oxt), given that it too inhibits HPA activity. Within the paraventricular nucleus of the hypothalamus, oxytocinergic neurons involved in regulating the stress response do not express androgen receptors but do express estrogen receptor-beta (ER beta), which binds the dihydrotestosterone metabolite 3 beta,17 beta-diol (3 beta-diol). Testosterone regulation of the HPA axis thus appears to involve the conversion to the ER beta-selective ligand 5 beta-androstane, 3 beta-diol. To study mechanisms by which 3 beta-diol could regulate Oxt expression, we used a hypothalamic neuronal cell line derived from embryonic mice that expresses Oxt constitutively and compared 3 beta-diol with estradiol (E2) effects. E2 and 3 beta-diol elicited a phasic response in Oxt mRNA levels. In the presence of either ligand, Oxt mRNA levels were increased for at least 60 min and returned to baseline by 2 h. ER beta occupancy preceded an increase in Oxt mRNA levels in the presence of 3 beta-diol but not E2. In tandem with ER beta occupancy, 3 beta-diol increased occupancy of the Oxt promoter by cAMP response element-binding protein and steroid receptor coactivator-1 at 30 min. At the same time, 3 beta-diol led to the increased acetylation of histone H4 but not H3. Taken together, the data suggest that in the presence of 3 beta-diol, ER beta associates with cAMP response element-binding protein and steroid receptor coactivator-1 to form a functional complex that drives Oxt gene expression. (Endocrinology 153: 2353-2361, 2012)