Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.

Abstract

Although progesterone has been recognized as essential for the establishment and maintenance of pregnancy, this steroid hormone has been recently implicated to have a functional role in a number of other reproductive events. The physiological effects of progesterone are mediated by the progesterone receptor (PR), a member of the nuclear receptor superfamily of transcription factors. In most cases the PR is induced by estrogen, implying that many of the in vivo effects attributed to progesterone could also be the result of concomitantly administered estrogen. Therefore, to clearly define those physiological events that are specifically attributable to progesterone in vivo, we have generated a mouse model carrying a null mutation of the PR gene using embryonic stem cell/gene targeting techniques. Male and female embryos homozygous for the PR mutation developed normally to adulthood. However, the adult female PR mutant displayed significant defects in all reproductive tissues. These included an inability to ovulate, uterine hyperplasia and inflammation, severely limited mammary gland development, and an inability to exhibit sexual behavior. Collectively, these results provide direct support for progesterone's role as a pleiotropic coordinator of diverse reproductive events that together ensure species survival.

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

“…This is in line with our findings about the CD8 + T cell response in stress-challenged mice, where progesterone supplementation reversed CD8 + T cell cytotoxicity. Together, these findings suggest that progesterone significantly dampens CD4 + and CD8 + T cell-mediated inflammation, potentially by opposing the proinflammatory activity of estrogen (72). Reduced levels of progesterone, as seen in response to stress challenge, may affect additional immune cell subsets or decidual markers in mice, such as in dendritic cells, NK cells, or Galectin-1, which can contribute to an impaired pregnancy outcome (25, 34).…”

“…Mice heterozygous for the genetic deletion of Pgr were generated on a C57BL6/129SvEv background by J. Lydon (Baylor College of Medicine), as previously described (72). The mice were maintained in an animal facility with a 12-hour light/ 12-hour dark cycle and food and water provided ad libitum.…”

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

“…The ovarian steroid hormones, estradiol and progesterone, control the ductal growth (1) and alveolar development (2), respectively, of the normal mammary gland and are believed to contribute to breast cancer development and progression. Similarly, epidermal growth factor receptor (EGFR) family members are expressed in both normal and malignant breast epithelial cells and their overexpression in breast cancers is predictive of a poor prognosis.…”

Progesterone signalling in breast cancer: a neglected hormone coming into the limelight

“…Both mouse strains are viable but the mutant females have complex endocrine abnormalities 39,40 . Tissue recombination experiments with either mutant mammary stroma or epithelium grafted into endocrinecompetent animals (FIG.…”