MICE LACKING PROGESTERONE-RECEPTOR EXHIBIT PLEIOTROPIC REPRODUCTIVE ABNORMALITIES

Although progesterone has been recognized as essential for the establi shment and maintenance of pregnancy, this steroid hormone has been rec ently implicated to have a functional role in a number of other reprod uctive events. The physiological effects of progesterone are mediated by the progesterone receptor (PR), a member of the nuclear receptor su perfamily of transcription factors. In most cases the PR is induced by estrogen, implying that many of the in vivo effects attributed to pro gesterone could also be the result of concomitantly administered estro gen. 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 s tem cell/gene targeting techniques. Male and female embryos homozygous for the PR mutation developed normally to adulthood. However, the adu lt female PR mutant displayed significant defects in all reproductive tissues. These included an inability to ovulate, uterine hyperplasia a nd inflammation, severely limited mammary gland development, and an in ability to exhibit sexual behavior. Collectively, these results provid e direct support for progesterone's role as a pleiotropic coordinator of diverse reproductive events that together ensure species survival.