Modulation of Rat Uterine Progesterone Receptor Levels and Peroxidase Activity by Tamoxifen Citrate, LY117018, and Estradiol*

Abstract

The biochemical and morphological effects on the immature rat uterus of tamoxifen citrate (TAM) and LY117018 were compared with those of estradiol. A single dose of TAM (100 μg) increased uterine wet weight and peroxidase activity 12,24,36,48,60, and 72 h postinjection, while the uterine DNA content was increased after 36 h compared to controls at 72 h. A single sc dose of LY117018 (100 fig) also increased uterine wet weight and peroxidase activity, although to a lesser extent than TAM, 36–72 h postinjection. DNA content was increased to the same extent as that observed after TAM treatment. Coadministration of progesterone (1.0 mg) with 100 μg TAM or LY117018 completely blocked the antiestrogen-induced increase in uterine peroxidase activity and elongation of the luminal epithelium observed at 36 h, while the increase in uterine wet weight was only partially blocked. Cytosol progesterone receptor (PR) levels were increased significantly at 36 h by estradiol (10 μg) or TAM (100 μg), but no increase was observed after LY117018 administration (100 μg). Increasing doses of TAM (10, 25, 100, and 1000 μg) progressively increased uterine wet weight and DNA content at 36 h. Peroxidase activity also increased progressively while eosinophil uptake was observed only at the highest dose of TAM administered. Increasing doses of LY117018 (10, 25, 100, and 1000 μg) increased uterine DNA content to a similar extent as TAM, although the increases in uterine wet weight were not as great. Peroxidase activity also increased in a dose-dependent fashion after LY117018 treatment, but to a lesser degree than after TAM, while eosinophil uptake was observed after the 1000 fig dose of LY117018. The administration of estradiol (0.5 μg/animal) or TAM (25 μgg/animal) daily for 3 days increased uterine wet weight, DNA content, cytosol PR, and peroxidase activity above control values. The luminal epithelium was increased in height by both compounds, but only estradiol significantly increased uterine eosinophilia. Multiple doses of LY117018 (25 μg/animal) daily for 3 days increased uterine wet weight, DNA content, and peroxidase activity to a lesser extent than TAM or estradiol, while the luminal epithelium was increased in height to the same extent. However, unlike estradiol or TAM, multiple doses of LY117018 failed to induce cytosol PR. These results demonstrate that 1) LY117018 is less estrogenic than TAM, since the administration of this new antiestrogen did not increase the uterine cytosol PR concentration, while increases in uterine wet weight and peroxidase activity occurred to a lesser extent; and 2) low doses of TAM or LY117018 stimulate peroxidase activity without an increase in uterine eosinophilia, while estradiol and higher doses of TAM or LY117018 increase peroxidase activity and increase the uptake of eosinophils into the uterus.