Lithium chloride treatment induces epithelial cell proliferation in xenografted human endometrium.
BACKGROUND
In mouse endometrium, glycogen synthase kinase-3beta (GSK3beta) 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 GSK3beta.


METHODS
Human endometrial samples were obtained from normal volunteers, then implanted under the kidney capsule of nude mice, and treated with estradiol-17beta (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.


CONCLUSIONS
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.
Polotsky
Alex J
AJ
Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Zhu
Liyin
L
Santoro
Nanette
N
Pollard
Jeffrey W
JW
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004717:Endometrium / Q000502:physiology / Q000637:transplantation*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D051379:Mice; D014183:Transplantation, Heterologous
C530104:CCND1 protein, human; D019938:Cyclin D1; D004958:Estradiol; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride