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Role of Systemic and Local IGF-I in the Effects of Estrogen on Growth and Epithelial Proliferation of Mouse Uterus

Department of Veterinary Biosciences (T.S., P.S.C.) and Division of Nutritional Sciences (P.S.C.), University of Illinois, Urbana, Illinois 61802; Departments of Anatomy (T.K., G.R.C.) and Urology (G.R.C.), University of California, San Francisco, California 94143; and The Population Council (G.W., M.P.H.), Center for Biomedical Research, New York, New York 10021

Address all correspondence and requests for reprints to: Dr. Paul S. Cooke, Department of Veterinary Biosciences, 2001 South Lincoln Avenue, University of Illinois, Urbana, Illinois 61802. E-mail: . p-cooke{at}uiuc.edu

IGF-I is a critical regulator of uterine growth, and locally produced uterine IGF-I could mediate the effects of 17ß-E2 on growth and cellular proliferation. We used IGF-I knockout (KO) mice and tissue grafting to determine the roles of local and systemic IGF-I in uterine growth and E2 responsiveness. Uteri from adult KO mice and neonatal and adult wild-type (WT) mice were grown under the renal capsule of female athymic mice for 4 wk. Initial uterine weights of adult KO and neonatal WT mice were 5% or less of those of adult WT uteri. Weights of adult WT uterine grafts did not increase during grafting. Weights of adult KO and neonatal WT uteri exposed to normal systemic levels of IGF-I in athymic hosts increased 20- to 30-fold to equal or exceed those of adult WT grafts. Uterine epithelial height, reduced in KO mice, was restored to WT levels in KO uteri grafted into athymic hosts. The absence of local IGF-I production in KO uteri did not impair E2- induced epithelial proliferation in KO uterine grafts. Neonatal WT uteri grafted into KO hosts showed minimal growth, providing evidence that local uterine IGF-I production is insufficient to support uterine growth in the absence of systemic IGF-I. E2 treatment of KO females produced minimal uterine growth, confirming that lack of IGF-I, rather than E2, caused the uterine hypoplasia. In summary, systemic IGF-I supports normal uterine growth and E2 response in the absence of local IGF-I. Local IGF-I is not a direct mediator of E2 action in uterus, and systemic IGF-I may be more important than previously thought for growth of the uterus and other tissues.

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