The effects of tamoxifen on uterine gene and protein expression have been examined in both women and mice treated with this drug. In the endometrium of women taking tamoxifen for up to 4 years, analysis of gene expression using cDNA arrays, indicated that tamoxifen increased expression of genes that may be involved in cell proliferation. In the endometrium of post-menopausal women, expression of the paracrine signalling protein nerve growth factor (NGF) was increased, although real time PCR showed no increase in NGF expression. Mouse models were used to compare the long-term effects of tamoxifen, oestradiol and 4-hydroxyoestradiol on uterine pathology and gene expression. In uterotrophic assays, oral dosing of oestradiol, tamoxifen or 4-hydroxyestradiol, administered to immature CD-1 mice on 3 days all led to increases in uterine weight, although not necessarily by cell proliferation. In newborn CD-1 mice the maximal uterotrophic dose of oestradiol (100 microg/kg), 4-hydroxyoestradiol (386 microg/kg) or tamoxifen (250 microg/kg) were given orally on days 1 to 5 after birth and gene and pathological changes examined in the uterus 3 months after dosing. Tamoxifen but not 4-hydroxyoestradiol or oestradiol led to adenomyosis. At this time, the expression of >250 genes were significantly altered by each treatment but changes in only nine genes were common to all three oestrogens. It is concluded that not all oestrogen agonists are the same in this model and while oestrogenicity is needed for the development of adenomyosis additional, unidentified factors, are required.