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Estradiol-17[Beta] ([E.sub.2]) acts through the estrogen receptor (ER) to regulate uterine growth and functional differentiation. To determine whether [E.sub.2] elicits epithelial mitogenesis through epithelial ER versus indirectly via ER-positive stromal cells, uteri from adult ER-deficient ER knockout (ko) mice and neonatal ER-positive wild-type (wt) BALB/c mice were used to produce the following tissue recombinants containing ER in epithelium (E) and/or stroma (S), or lacking ER altogether: wt-S + wt-E, wt-S + ko-E, ko-S + ko-E, and ko-S + wt-E. Tissue recombinants were grown for 4 weeks as subrenal capsule grafts in intact female nude mice, then the hosts were treated with either [E.sub.2] or oil a week after ovariectomy. Epithelial labeling index and ER expression were determined by [3H] thymidine autoradiography and immuno-histochemistry, respectively. In tissue recombinants containing wt-S (wt-S + wt-E, wt-S + ko-E), [E.sub.2] induced a similar large increase in epithelial labeling index compared with oil-treated controls in both types of tissue recombinants despite the absence of epithelial ER in wt-S + ko-E tissue recombinants. This proliferative effect was blocked by an ER antagonist, indicating it was mediated through ER. In contrast, in tissue recombinants prepared with ko-S (ko-S + ko-E and ko-S + wt-E), epithelial labeling index was low and not stimulated by [E.sub.2] despite epithelial ER expression in ko-S + wt-E grafts. In conclusion, these data demonstrate that epithelial ER is neither necessary nor sufficient for [E.sub.2]-induced uterine epithelial proliferation. Instead, [E.sub.2] induction of epithelial proliferation appears to be a paracrine event mediated by ER. positive stroma. These data in the uterus and similar studies in the prostate suggest that epithelial mitogenesis in both estrogen and androgen target organs are stromally mediated events.

Consumption of diets rich in soy protein has shown promise as a dietary intervention to reduce blood cholesterol levels. However, the mechanism of soy's cholesterol-lowering effect is not fully understood. This study was designed to determine whether the mechanism requires the presence of estrogen receptor-[alpha] (ER-[alpha]) for cholesterol reduction. Male (aged ~55 d) ER-[alpha] knockout and wild type C57BL6 mice were assigned to receive 1 of 3 high-fat, cholesterol-containing diets: casein protein, low-isoflavone soy protein (ISP-), high-isoflavone soy protein (ISP+) (n = 12). A control group for each genotype was assigned to a standard laboratory pellet diet to determine usual cholesterol levels in C57Bl6 mice (n = 8). After 12 wk of feeding, mice were killed and total serum and hepatic cholesterol levels were evaluated. To date, two-thirds of the animals have completed the 3-mo feeding regimen. Although there were some trends, there was no significant difference in either serum and hepatic cholesterol or hepatic lipids due to genotype (ER-[alpha] knockout vs. wild type). There was a significant difference in serum cholesterol (P < 0.0001), hepatic cholesterol (P = 0.0016), and hepatic lipid (P = 0.0426) levels of mice due to diet (casein, ISP-, ISP+). Hepatic cholesterol was lower in mice fed ISP+ than either ISP- or casein whereas for serum cholesterol ISP- was higher than both ISP+ and casein. These preliminary results suggest in C57BL6 ER-[alpha] knockout and wild type mice that ER-[alpha] is not required for dietary modulation of either serum or hepatic cholesterol. These data also suggest that ethanol extraction of soy removes one or more compounds that are hypocholesterolemic to mice. (Supported in part by the Jonathan Baldwin Turner Undergraduate Research Scholarship Program, University of Illinois at Urbana-Champaign.)