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Brain Infusion of Lipopolysaccharide Increases Uterine Growth as a Function of Estrogen Replacement Regimen: Suppression of Uterine Estrogen Receptor- by Constant, But Not Pulsed, Estrogen Replacement

Department of Physiology and Pharmacology (L.K.M., L.C.S., R.A.S., D.M.D.), Oregon Health and Science University, Portland, Oregon 97239; Division of Neural Systems, Memory, and Aging (K.R.M.-G.) and Biomedical Engineering Program (B.H.-W.), University of Arizona, Tucson, Arizona 85724; and Departments of Psychology and Neuroscience and Molecular, Virology, Immunology, and Medical Genetics (G.L.W.), Ohio State University, Columbus, Ohio 43210

Address all correspondence and requests for reprints to: Gary L. Wenk, Ph.D., Department of Psychology, 1885 Neil Avenue, Columbus, Ohio 43210. E-mail: wenk.6{at}osu.edu.

The effects of estrogen therapy can differ depending on the regimen of estrogen administration. In addition, estrogen can modulate the effects of stressors. To examine the interaction between these systems, we infused adult female rats with lipopolysaccharide (LPS) into the fourth ventricle of the brain for 6 d and compared the effects of constant and pulsed estrogen replacement. Constant, but not pulsed, estrogen treatment reduced estrogen receptor- (ER) protein by 90% in the uterus and increased heat-shock proteins 70 and 90 by 74 and 48%, respectively, whereas progesterone receptor levels increased in all ovariectomized rats receiving estrogen replacement. In contrast to the uterine decline in ER, no changes in ER were observed in the hypothalamus or hippocampus, and ERß levels were unchanged in all regions tested. Brain infusion of LPS did not alter these proteins but increased the number of activated microglia in the thalamus and reduced body weight in all rats as well as activated the hypothalamic-pituitary-adrenal axis in ovariectomized rats, as determined by elevations in circulating corticosterone and progesterone. Estrogen treatments did not alter these markers, and no differences were observed in cortical choline acetyltransferase activity or nitrotyrosine for any of the treatment groups. The current study found an unexpected increase in uterine weight in lipopolysaccharide-infused rats treated with constant, but not pulsed, estrogen. This report suggests that constant and pulsed regimens of estrogen administration produce different effects and that stress may be an important factor in the postmenopausal intervention with estrogen.

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