Developmental action of estrogen receptor-α feminizes the growth hormone-Stat5b pathway and expression of Cyp2a4 and Cyp2d9 genes in mouse liver

We have studied the roles of estrogen receptor-alpha (ER alpha) and the Stat5b form of STAT (signal transducers and activators of transcription) in sex-specific expression of Cyp2a4 (steroid 15 alpha-hydroxylase) and Cyp2d9 (steroid 16 alpha-hydroxylase) genes using ER alpha-deficient mice. ER alpha deficiency resulted in the repression of the female-specific Cyp2a4 and expression of the male-specific Cyp2d9 genes, respectively in females. In ER alpha-deficient males, the Cyp2d9 gene continued to be expressed. Nuclear localization of Stat5b occurs in both sexes of ER alpha-deficient mice, although it is normally observed in only wildtype males. Nuclear localization of Stat5b correlates with the repression of Cyp2a4 and expression of Cyp2d9, respectively. Because Stat5b was not detectable in liver nuclear extracts prepared from hypophysectomized ER alpha-deficient females, the regulation by ER alpha appeared to be mediated through a pituitary hormone (i.e., growth hormone). Thus, ER alpha appears to play a key role in the mechanism that inhibits nuclear localization of Stat5b in female mice, leading to feminization of a ER alpha-Stat5b pathway and Cyp expression. Defaulting to this ER alpha-dependent mechanism results in localization of Stat5b to nuclei, which masculinizes the expression of Cyp genes in male mice.