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Preferential Growth Stimulation of Mammary Glands over Uterine Endometrium in Female Rats by a Naturally Occurring Estradiol-17ß-fatty Acid Ester

Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208 [L. H. M., A. J. L., B. T. Z.], and National Hormone and Pituitary Program, Harbor-University of California Los Angeles Medical Center, Torrance, California 90509 [A. F. P.]

We hypothesize that the endogenously present lipoidal estrogen fatty acid esters may have a stronger mitogenic action in the fat-rich mammary tissues than in the uterus. To test this hypothesis, we compared the activity of estradiol-17ß-stearate (E₂-17ß-S) with that of estradiol-17ß (E₂) in stimulating the growth of mammary glandular cells versus the growth of uterine endometrial cells in ovariectomized female Sprague Dawley rats. Experimentally, an estimated 0.5 or 5 nmol of E₂-17ß-S or E₂ was released daily to ovariectomized female rats through an Alzet pump implanted under the back skin of the animal for 10 or 23 days. The growth-stimulatory effect of E₂-17ß-S and E₂ on mammary glandular cells was determined according to 5-bromo-2'-deoxyuridine labeling indices, and their effect on the uterus was determined by measuring both the 5-bromo-2'-deoxyuridine labeling index and the uterine wet weight. Our results showed that chronic treatment of ovariectomized female rats with 0.5 or 5 nmol/day E₂-17ß-S for 10 or 23 days had a stronger stimulatory effect on mammary glandular cell proliferation than treatment with equimolar doses of E₂. In the uterus, however, E₂ was more active in stimulating the proliferation of uterine endometrial cells than E₂-17ß-S at equimolar doses. Our results demonstrated, for the first time, that a naturally occurring estradiol-17ß-fatty acid ester has a differential, strong mitogenic effect in the fat-rich mammary tissues, and this effect was not observed with E₂. It is tempting to suggest that the fatty acid esters of the endogenous estrogens and their bioactive metabolites (e.g., 4-hydroxyestradiol and 16-hydroxyestrone) may be of unique importance for stimulating cell growth and possibly also for inducing tumor formation in the fat-rich mammary tissues as compared with the uterus. More studies are warranted to test these ideas.

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