The effect of tamoxifen on uterine growth and development

The aim of this research is to examine the abnormal features of uterine growth and development associated with tamoxifen use, to determine if this is due to its failure to replicate all the effects of oestradiol; either inducing or repressing the expression of key paracrine acting regulators of uterine cellular populations or their gene expression profiles, and to examine if such abnormal features could be prevented by the administration of a progestagen-containing levonorgestrel intrauterine device (LNG-IUS) from the onset of tamoxifen treatment for breast cancer. Postmenopausal women were assessed by hysteroscope and ultrasound scanning for uterine volume, endometrial thickness and the presence of endometrial polyps or submucous fibroids before insertion of the LNG-IUS system and after 1 year. The same was done on a control group that were not treated with LNG-IUS. Benign changes in the uterus were histologically related to, (1) steroid receptor isoform, (2) proliferation and apoptosis markers, (3) mesenchymal marker expression and (4), gene expression and pathway profiles, when compared to the oestrogen induced changes of the proliferative phase uterus and the oestrogen deficient, atrophic, postmenopausal uterus. The uterotrophic effects and benign changes induced by tamoxifen were confirmed; LNG-IUS prevented both the uterotrophic effects and formation of endometrial polyps. Additionally, ERα, PRA and PRB expression were increased in tamoxifen endometrium similar to that of the proliferative phase endometrium; ERβ expression was also up regulated in the tamoxifen uterus linking it with tamoxifen associated proliferation. Increased Ki67 and Bcl2, but low BAX expression, in the tamoxifen uteri signified increased proliferation and apoptosis failure, coupled with the unique mesenchymal positivity associated with large endometrial cystic glands, suggested a transitional state tissue, undergoing remodelling with significant gene modulation. This was confirmed with microarray analysis where tamoxifen induced not only “oestrogen genes” but also “tamoxifen only genes” and pathways, revealing some of the mechanism(s) whereby tamoxifen causes uterine growth; some of these changes are oestrogen-like and others are brought out through the direct action of tamoxifen itself.