The use of
levonorgestrel-releasing intrauterine system (LNG-IUS) is effective for management of menorrhagic women with uterine
myomas because of reduction in
menorrhagia. However, the size of
myomas during use of LNG-IUS increased in some but decreased in other instances. This prompted us to characterize the effects of
progesterone (P4) on cultured
leiomyoma cell growth. Treatment with P4 resulted in increase in
epidermal growth factor (
EGF) expression in cultured
leiomyoma cells, whereas treatment with E2 augmented
EGF-R expression in those cells. This indicates that P4 and E2 act in combination to stimulate
myoma growth through induction of
EGF/
EGF-R expression. Bcl-2 expression in
leiomyoma cells was up-regulated by P4. Furthermore, P4 augmented
proliferating cell nuclear antigen expression in cultured
leiomyoma cells but not in cultured normal myometrial cells. This fact let us to examine the effects of
progesterone receptor modulator (PRM) on
leiomyoma cell proliferation and apoptosis in comparison with normal myometrial cells. Our studies revealed that
CDB-2914 inhibits the proliferation, stimulates apoptosis of cultured
leiomyoma cells, and inhibits the expression of angiogenic factors (
vascular endothelial growth factor and
adrenomedullin) and their receptors in cultured
leiomyoma cells, without affecting those in cultured normal myometrial cells. We then evaluated the effects of
CDB-2914 on extracellular matrix (ECM) components in cultured
leiomyoma cells.
CDB-2914 increased ECM
metalloproteinase inducer,
matrix metalloproteinase (MMP)-1, MMP-8 contents and decreased tissue inhibitors of
MMP (TIMP)-1,
TIMP-2 contents as well as type I and
type III collagen contents in cultured
leiomyoma cells, without comparable effects on cultured normal myometrial cells. These findings demonstrate that PRM not only inhibits the proliferation and stimulates apoptosis of cultured
leiomyoma cells but also suppresses
collagen synthesis in a cell-type specific manner. This is meaningful for understanding the molecular mechanism of the usefulness of PRM in the treatment of
uterine fibroids.