Hum. Reprod. Advance Access originally published online on April 29, 2009
Human Reproduction 2009 24(8):1960-1967; doi:10.1093/humrep/dep115
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Lithium chloride treatment induces epithelial cell proliferation in xenografted human endometrium
1 Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine (AECOM), Bronx, NY, USA 2 Center for the Study of Reproductive Biology and Women's Health, Albert Einstein College of Medicine (AECOM), Bronx, NY, USA 3 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA 4 Department of Medicine, Albert Einstein College of Medicine (AECOM), Bronx, NY, USA
5 Correspondence address. Tel: +1-718-430-2090; Fax: +1-718-430-8972; E-mail: pollard{at}aecom.yu.edu
BACKGROUND: In mouse endometrium, glycogen synthase kinase-3ß (GSK3ß) is a key enzyme controlling nuclear localization of cyclin D1. We developed a functional model of xenografted human endometrium to test whether similar mechanisms are operative in the human by using Lithium chloride (LiCl), an inhibitor of GSK3ß.
METHODS: Human endometrial samples were obtained from normal volunteers, then implanted under the kidney capsule of nude mice, and treated with estradiol-17ß (E2) or LiCl. Xenografts were assessed for protein expression of MKI-67, mini-chromosome maintenance protein-2, estrogen receptor (ER), progesterone receptor (PR) and cyclin D1.
RESULTS: Both E2 and LiCl induced a robust proliferative response in the epithelium. Only lithium treatment produced clear nuclear localization of cyclin D1 consistent with the proliferative response observed. Regenerated endometrium had detectable ER and PR expression.
CONCLUSION: Xenografted human endometrium provides a dynamic model of uterine biology. Administration of LiCl in the absence of E2 induced epithelial proliferation, supporting the hypothesis that human and murine endometrial proliferation may share key regulatory pathways. These data suggest a possible link between the increased menstrual disturbances in women with affective disorders taking lithium and the consequent potential for the development of endometrial proliferative disorder.
Key words: estrogen/progesterone/cell cycle/endometrium/lithium
Submitted on November 11, 2008; resubmitted on March 30, 2009; accepted on April 6, 2009.