Circulating hormones and estrous stage predict cellular and stromal remodeling in murine uterus

The understanding of how estrogen and progesterone (P(4)) drive uterine remodeling in rodents has largely been based on studies involving administration of exogenous hormones, using steroid receptor-deficient mice, or relying on vaginal smears. In all these cases, the actual serum levels of 17beta-estradiol (E(2)) and P(4) are not directly measured, and the relationship between physiological levels of female sex hormones and uterine remodeling in cycling mice has not been fully explored. Here, we measured the circulating levels of E(2) and P(4) in cycling mice and performed correlation analysis between hormone levels and epithelial and stromal uterine parameters, irrespective of the estrous stage. In parallel, these parameters were analyzed in relation to the more conventional method of vaginal smear classification of estrous stage. We found that circulating P(4) inversely correlated with uterine width, luminal epithelial proliferation, stromal apoptosis, and degradation of luminal epithelial basement membrane collagen type-IV. Circulating E(2) positively correlated with uterine width, stromal cell proliferation, and collagen type-I content, while it negatively correlated with glandular epithelial proliferation, loss of collagen type-IV surrounding glandular epithelium, and apoptosis in luminal, glandular, and stromal compartments. Our findings indicate that measuring P(4) or E(2) levels can predict many concurrent cellular and stromal events in the mouse uterus, suggesting that in naturally cycling mice cellular responses to hormone changes are not delayed, but occur very rapidly.