Effects of SERM (selective estrogen receptor modulator) treatment on growth and proliferation in the rat uterus

BACKGROUND: Selective estrogen receptor modulators (SERMs) have been developed in order to create means to control estrogenic effects on different tissues. A major drawback in treatment of estrogen receptor (ER) positive breast cancer with the antagonist tamoxifen (TAM) is its agonistic effect in the endometrium. Raloxifene (RAL) is the next generation of SERMs where the agonistic effect on the endometrium has been reduced. METHODS: The aim of the present study was to determine the effect of SERM treatment on the uterus, as assessed by proliferation markers and several factors involved in uterine growth. Ovariectomized (ovx) rats were treated with estradiol (E(2)), tamoxifen (TAM), RAL, ICI182780 (ICI) or vehicle (OVX-controls). We studied the effects on mRNA levels of the growth hormone (GH) receptor, insulin-like growth factor-I (IGF-I), ERα and ERβ. In addition, by immunohistochemistry the proliferation markers PCNA and Ki-67, as well as ERα and ERβ, were detected. RESULTS: The uterine weight of the rats treated with E(2 )or TAM was increased as compared to OVX-controls. The uterine GH-receptor mRNA level was highest in the E(2 )treated animals. In ICI treated rats no GH-receptor mRNA could be detected. The IGF-I mRNA level increased 16-fold in uteri of the TAM treated group and 9-fold in the E(2 )treated rats as compared to OVX-controls. The ERα mRNA level was increased in the E(2 )treated rats, while the ERβ mRNA level was increased after TAM treatment. The proliferation, as assessed by PCNA, was lowest in ICI treated animals. CONCLUSIONS: The uterine wet weight, the LE height and the GH-receptor mRNA levels showed similar patterns, indicating that GH is involved in the regulation of uterine weight. Tamoxifen, which has been related to increased incidence of endometrial carcinoma in women, dramatically increased IGF-I mRNA levels in rat uterus. Since proliferation was not higher in TAM and E(2 )treated rats than in OVX controls, this assay of simple, early proliferation does not give the full explanation of why TAM should enhance the risk of developing endometrial cancer.