Introduction: Since progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 are highly expressed in the uterus, this study was designed to evaluate the impact of Pgrmc2 and Pgrmc1/2 deficiency on female fertility and uterine epithelial cell proliferation.
Materials and methods: Uterine PGRMC2 and Ki67 expression were assessed by immunohistochemistry. Mutagenesis studies were completed in which Pgr-cre was used to conditionally ablate Pgrmc genes.
Results and discussion: PGRMC2 was predominantly expressed in the cytoplasm of uterine epithelial and stromal cells with limited change in expression in response to steroid hormones. Breeding trials showed that Pgrmc2 conditional knockout (cKO) and Pgrmc1/2 double cKO (dcKO) female mice experienced a significant reduction in the number of pups/litter (control 7.7±0.80 vs Pgrmc2, cKO 4.1±0.43, P=0.0001; control 8.4±0.28 vs Pgrmc1/2, cKO 5.2±0.67, P=0.0006). The reduction in pup numbers, which was due to post-implantation embryonic loss, was not the result of luteal insufficiency, since serum P4 levels were higher in cKO mice (P=0.007). Reductions (P<0.05) in both the number of litters over the 6-month breeding trials and number of pups surviving to weaning were also observed. Uteri obtained from cKO and dcKO females showed development of cystic hyperplasia starting around 4 months of age. Compared to controls, this phenotype also showed an increase in mitotically-active uterine epithelial cells, as judged by Ki67 immunostaining. These findings demonstrate that members of the PGRMC family are required for normal pregnancy and that their deletion leads to uterine hyperplasia. This work is supported in part by NIH RR030264.
02 Sep 2014 - 04 Sep 2014