Effects of levonorgestrel-releasing IUS and progesterone receptor modulator PRM CDB-2914 on uterine leiomyomas

We have found that the use of levonorgestrel-releasing IUS results in a remarkable decrease in endometrial proliferation and a remarkable increase in apoptosis in the endometrium; therefore, it is effective for long-term management of menorrhagic women with uterine myomas because of the striking reduction in menorrhagia. This prompted us to characterize the effects of progesterone (P4) and progesterone receptor modulator (PRM) CDB2914 on uterine myoma growth. In vitro studies with cultured uterine leiomyoma cells and normal myometrial cells revealed that P4 stimulated the proliferative activity in leiomyoma cells, but not in normal myometrial cells. P4 increased EGF expression, whereas E2 augmented EGF-R expression in leiomyoma cells, indicating that P4 and E2 act in combination to stimulate leiomyoma cell growth. P4 also increased Bcl-2 expression and decreased TNF-α expression in those cells. Unlike the EGF expression, IGF-I expression in leiomyoma cells was inhibited by P4. These results suggest that P4 has dual actions on leiomyoma growth: one is to stimulate the growth through up-regulating EGF and Bcl-2 expression, and the other is to inhibit the growth through down-regulating IGF-I expression in the cells.By contrast, CDB2914 inhibited proliferation and stimulated apoptosis of leiomyoma cells without affecting normal myometrial cells. Furthermore, CDB2914 inhibited vascular endothelial growth factor and adrenomedullin expression in leiomyoma cells, but not in normal myometrial cells. The cell type-specific action of CDB2914 on leiomyoma cells, without affecting the surrounding normal myometrial cells, is meaningful for understanding the usefulness of CDB2914 in the medical treatment of uterine myomas.