PARENT SESSION

(W636) ESTROGEN INDUCES ALTERED LUMINAL EPITHELIAL HISTO-ARCHITECTURE AND INCREASED UTERINE GLAND DEVELOPMENT IN TIMP-1 NULL MICE.

Zhang, Xuan¹, Nothnick, Warren¹, ¹ University of Kansas School of Medicine, Kansas City, KS

ABSTRACT- TIMP-1 is a multifunctional protein capable of regulating cell proliferation in a variety of tissues. TIMP-1 deficient mice display an altered uterine phenotype characterized by profound branching of the uterine lumen and altered adenogenesis. We postulate that these alterations may be due to increased proliferation of uterine epithelial cells. To test this hypothesis, ovariectomized wild-type and TIMP-1 null mice (N=3 to 4 mice/treatment group/time point/genotype) were treated with estrogen (E2) or estrogen + progesterone (E2 + P4). Mice were sacrificed at 0, 8, or 24 h after a single injection of steroids or 24 hours after the last of three consecutive injections, 24 hours apart (72 h after the start of treatment). Uteri were removed and prepared for immunohistochemical localization of proliferating cell nuclear antigen (PCNA). The general pattern of PCNA staining was similar between genotypes for both E2 and E2+P4 treatments at 0, 8 and 24h post steroid treatment. No significant differences were detected among treatment groups between genotypes with respect to luminal epithelium histo-architecture or height, number of endometrial glands or epithelial cells expressing PCNA. In contrast, marked differences were noted between wild-type and TIMP-1 null mice in the 72 h E2 treatment group. More specifically, epithelial invaginations were more prevalent in the luminal epithelium of TIMP-1 null mice and the height of the luminal epithelium was significantly (P<0.05) greater compared to wild-type counterparts. Further, TIMP-1 null mice had more endometrial glands/cross section (P<0.10) and the percentage of endometrial glands expressing PCNA was significantly greater (P<0.05) in the null mice compared to wild-type mice in the 72 h E2 group. In the 72 h E2 + P4 treated mice, the histo-architecture of the luminal epithelium, height of the luminal epithelium, number of endometrial glands and percent of glands expressing PCNA were similar between genotypes. In summary, prolonged E2 treatment is associated with altered luminal epithelium histo-architecture and adenogenesis in TIMP-1 null mice. These findings may be interpreted to suggest that TIMP-1 plays a modulatory role in estrogen regulation of luminal/glandular epithelial cell proliferation and adenogenesis. (Supported by NIH HD39765 to WBN)

KEY WORDS: Uterus, Estrogen, Adenogenesis, TIMP-1