Irregular endometrial bleeding occurs in up to 60% of hormone therapy (HT) users and leads to discontinuation of therapy in up to one-third of these women. Aberrant endometrial angiogenesis has been implicated as a cause of abnormal endometrial bleeding. Vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) are two well-characterized angiogenic modulators that play critical roles in endometrial angiogenesis. We have proposed a hypothesis that alterations in the expression of these two potent angiogenic modulators may be a mechanism involved in endometrial bleeding in HT users. 17beta-Estradiol increased VEGF levels in the endometrial glandular epithelium (Ishikawa cells) in vitro. Progesterone has no effect on VEGF expression. The synthetic progestins in HT preparations were found to increase VEGF expression to a greater extent than 17beta-estradiol. Progesterone increased TSP-1 mRNA in Ishikawa cells. 17beta-Estradiol had no effect on TSP-1 mRNA and the effect of synthetic progestins on TSP-1 expression was lower than that found with progesterone. We propose, based on these data, that progestins used in HT preparations may alter the balance between angiogenic promoters and inhibitors. These alterations could induce a unique pro angiogenic activity in the endometrial capillary plexus, with consequent aberrant vasculogenesis, which may result in irregular endometrial bleeding.