Proliferative effects of different hormone regimens on mammary glands in ovariectomized rats

Objective: To compare the proliferative effect of different hormone regimens and estrogen receptor modulation on mammary glands in a rat model of surgical menopause. Design: Experimental animal study. Setting: University Hospital. Intervention: In a rat model of surgical menopause, 78 adult Sprague Dawley female rats were ovariectomized and treated with estrogen, estrogen combined with continuous or intermittent progesterone or the estrogen receptor modulator raloxifene and their respective vehicle controls. Following intraperitoneal drug administration for 20 days, rats were perfused, mammary glands were removed, tissues were processed for immunohistochemical (Ki-67) and hematoxylin-eosin staining, and investigated under light microscope. Main outcome measure: Histopathological examination of mammary glands and Ki-67 positive cells (proliferation index). Results: Histological examination showed dilatation in the duct cysts and vactiolization in the epithelial cells in groups receiving progestin, either intermittent or continuous. Histological findings in the raloxifene group were no different from the control group, and the atrophic terminal ductal lobular unit in adipose tissue rich stroma was similar to postmenopausal breast. In animals with a proliferative response, increased proliferation started and dominated in the terminal ductal lobular unit epithelium. Comparison of Ki-67 proliferation indices between groups revealed that estrogen alone or combined with intermittent progesterone yielded significantly higher Ki-67 indices compared to controls; estrogen combined with continuous progesterone also resulted in increasing the probability of proliferation, but the effect was not as pronounced as the other two groups. Raloxifene treatment, on the other hand, did not cause proliferation. Conclusion: Estrogen alone or combined with progesterone may increase the risk of breast cancer by enhancing proliferation in the TDLU; raloxifen does not induce proliferation and may be a safe estrogen receptor modulator regarding its effects on mammary glands during menopause.