Alterations in developing rat uterine cell populations after neonatal exposure to estrogens and antiestrogens

Exposure of rats to either estrogens or antiestrogens during early postnatal development reduces subsequent uterine growth as measured by uterine weight. However, individual uterine cell types respond differently to these agents and uterine weight alone cannot discern subtle or even large alterations in individual cell populations. Using a computerized planimetric technique, we estimated the prepubertal growth of the uterine luminal epithelium, endometrial stroma, glands, and circular and longitudinal muscle after exposure of neonatal rats (postnatal days 1-5) to the estrogens 17 beta-estradiol (E2), diethylstilbestrol (DES), or ethynylestradiol (EE), and the antiestrogens tamoxifen or clomiphene citrate. On postnatal day 26, the cross-sectional areas of the luminal epithelium, endometrial stroma, and circular muscle were reduced after estrogen exposure, compared to untreated controls, while longitudinal muscle cross-sectional area was not affected. Since cell densities (cell number/unit area) were increased, these estrogen-induced area reductions demonstrate a decrease in cell size. Total cell numbers, estimated as the product of cell type areas and their respective cell densities, were also reduced by neonatal estrogen exposure. The synthetic estrogens DES and EE were more potent than E2 with respect to reduction of uterine growth. Neonatal antiestrogen exposure caused large area reductions only in the uterine glands and luminal epithelium. Little change in cell density occurred in any cell population exposed to antiestrogen. These data demonstrate that the decreased uterine growth resulting from estrogen exposure during early postnatal development is a consequence of combined hypotrophy and hypoplasia in all cell types except longitudinal muscle while antiestrogen-induced morphological alterations were limited to hypoplasia having epithelial cell specificity.