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

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-17b-stearate (E2-17b-S) with that of estradiol-17b (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 E2-17b-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 growthstimulatory effect of E2-17b-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-bromo2*-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 E2-17b-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 E2-17b-S at equimolar doses. Our results demonstrated, for the first time, that a naturally occurring estradiol-17b-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., 4hydroxyestradiol and 16a-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.