Estradiol Up-Regulates Estrogen Receptor and Progesterone Receptor Gene Expression in Specific Ovine Uterine Cells1

Abstract

The regulation of estrogen receptor (ER) and progesterone receptor (PR) genes is critical to estrogen and progesterone responsiveness of the uterus during the estrous cycle. A low dose of estradiol, given to ovariectomized ewes to mimic the preovulatory estrogen surge, acutely enhanced ER and PR gene expression in most uterine cells. Estradiol effects were measured at 12, 24, and 48 h post-injection (n = 6 ewes per time) with immunohistochemistry and in situ hybridization. Whereas vehicle-treated ovariectomized ewes demonstrated low to moderate ER and PR mRNA and protein expression, estradiol enhanced PR mRNA and protein expression (at 12 h and 24 h, respectively) more rapidly than ER mRNA and protein expression (at 24 h and 48 h, respectively) in most uterine cells. However, the timing and extent of the estradiol response depended partly upon cell type (epithelial, stromal, or myometrial), cell region (luminal, superficial, middle, or deep endometrial or myometrial), adjacent cells, and prior progesterone treatment. For example, PR mRNA up-regulation was prolonged in middle and deep endometrial stroma, but increases in PR protein expression were highest in superficial and middle endometrial compartments, including the luminal epithelium. The luminal epithelium and myometrium were unique in that estradiol failed to up-regulate ER gene expression within them. ER mRNA levels rose within these compartments only when estradiol followed steroid hormone treatment designed to induce an artificial estrous cycle (estradiol-progesterone-estradiol [EPE] treatment). The EPE treatment also augmented the rise in ER mRNA concentrations within stromal cells compared to estradiol treatment alone. Within uterine cell compartments, subpopulations of adjacent cells showed distinct estradiol responses, e.g., very high levels of ER and PR gene expression within stromal cells directly underlying glandular epithelial cells. Because the estradiol response did not always correlate with initial ER protein levels and was partly dependent upon cell compartment and adjacent cells, we must conclude that direct transcriptional and/or posttranscriptional actions of estradiol cooperate with other cellular and paracrine regulatory factors to regulate ER and PR gene expression and, thus, the steroid responsiveness of uterine cells.