Estradiol and Progesterone Exhibit Similar Patterns of Hepatic Gene Expression Regulation in the Bovine Model

Female sex steroid hormones, estradiol-17β (E2-17β) and progesterone (P4) regulate reproductive function and gene expression in a broad range of tissues. Given the central role of the liver in regulating homeostasis including steroid hormone metabolism, we sought to understand how E2-17β and P4 interact to affect global gene expression in liver. Ovariectomized cows (n = 8) were randomly assigned to 4 treatment groups applied in a replicated Latin Square design: 1) No hormone supplementation, 2) E2-17β treatment (ear implant), 3) P4 treatment (intravaginal inserts), and 4) E2-17β combined with P4. After 14 d of treatment, liver biopsies were collected, allowing 28 d intervals between periods. Changes in gene expression in the liver biopsies were monitored using bovine-specific arrays. Treatment with E2-17β altered expression of 479 genes, P4 472 genes, and combined treatment significantly altered expression of 468 genes. In total, 578 genes exhibited altered expression including a remarkable number (346 genes) that responded similarly to E2-17β, P4, or combined treatment. Additional evidence for similar gene expression actions of E2-17ß and/or P4 were: principal component analysis placed almost every treatment array at a substantial distance from controls; Venn diagrams indicated overall treatment effects for most regulated genes; clustering analysis indicated the two major clusters had all treatments up-regulating (172 genes) or down-regulating (173 genes) expression. Thus, unexpectedly, common biological pathways were regulated by E2-17β and/or P4 in liver. This indicates that the mechanism of action of these steroid hormones in the liver might be either indirect or might occur through non-genomic pathways. This unusual pattern of gene expression in response to steroid hormones is consistent with the idea that there are classical and non-classical tissue-specific responses to steroid hormone actions. Future studies are needed to elucidate putative mechanism(s) responsible for overlapping actions of E2-17β and P4 on the liver transcriptome.