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

Department of Medical Biophysics and Department of Laboratory Medicine and Pathobiology, Ontario Cancer Institute, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9

Correspondence should be addressed to R Khokha; Email: rkhokha{at}uhnres.utoronto.ca

The understanding of how estrogen and progesterone (P₄) 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 17ß-estradiol (E₂) and P₄ 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 E₂ and P₄ 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 P₄ inversely correlated with uterine width, luminal epithelial proliferation, stromal apoptosis, and degradation of luminal epithelial basement membrane collagen type-IV. Circulating E₂ 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 P₄ or E₂ 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.

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