Progesterone action and responses in the alpha ERKO mouse

Ovarian steroids have important inter-related roles in many systems and pro cesses required for mammalian reproduction. The female reproductive tract, ovaries, and mammary glands are all targets for both estrogen and progester one. In addition, the actions of these hormones are intertwined in that, fo r example, progesterone attenuates the proliferative effect of estrogen in the uterus, whereas estrogen also induces the progesterone receptor (PR) mR NA and protein, thus enhancing progesterone actions. The generation of mice that lacks the progesterone receptor (PRKO) or the estrogen receptor alpha (alpha ERKO) has provided numerous insights into the interacting roles of these hormones. The mammary glands of the PRKO mice develop with full epith elial ducts that lack side branching and lobular alveolar structures, where as the alpha ERKO mice develop only an epithelial rudiment. This indicates that estrogen is important for ductal morphogenesis, whereas progesterone i s required for ductal branching and alveolar development. Both the alpha ER KO and PRKO mice are also anovulatory, but exhibit different causal patholo gies. The alpha ERKO ovary seems to possess follicles up to the preantral s tage and shows a polycystic phenotype as a result of chronic hyperstimulati on by LH. The PRKO follicles seem to develop to an ovulatory stage, but are unable to rupture, indicating a role for progesterone in ovulation. The ut eri of these two strains seem to develop normally; however, the function an d hormone responses are abnormal in each. Because estrogen is known to indu ce PRs in the uterus, the progesterone responsiveness of the alpha ERKO ute rus was characterized. PR mRNA was detected but was not up-regulated-by est rogen in the alpha ERKO tissue. PRs are present in the alpha ERKO tissue at 60% of the level in wild-type tissue and show a similar amount of A and B isoforms when measured by R5020 binding and detected by Western blotting. T he PRs were able to mediate induction of two progesterone-responsive uterin e genes: calcitonin and amphiregulin. The alpha ERKO uterine tissue was als o able to undergo a decidual reaction in response to hormonal and intralumi nal treatments to mimic implantation: however, unlike normal wild-type uter i, this response was estrogen independent in the alpha ERKO uterine tissue. (C) 2000 Published by Elsevier Science Inc.