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

Abstract

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.

Effects of female sex hormones on folic acid–induced anti‐angiogenesis

“…These might explain why E2 and P4 have the same prevention effects on FA‐induced inhibitions in endothelial cell proliferation and migration. The overlapping actions of E2 and P4 were also demonstrated previously on the regulation of liver transcriptome …”

TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis

“…Given the central role of the liver in the regulation of glucose homeostasis, we also assessed the effects of E 2 and P 4 on hepatic glucose metabolism. Although the opposing effects of E 2 and P 4 on oxidative stress processes have been reported in vitro 31 32 33 , a recent in vivo study using microarray analysis showed that E 2 , P 4 , and their co-treatment actually displayed similar patterns and networks of hepatic gene expression 34 . Consistent with the previous study, we found that E 2 and P 4 presented similar phenotypes and protein content profiles in regulating hepatic glucose metabolism.…”