27 - 30 May 2005

CONTROL OF UTERINE LEIOMYOMA CELL PROLIFERATION AND APOPTOSIS BY PROGESTERONE AND SELECTIVE PROGESTERONE RECEPTOR MODULATOR T. Maruo, H. Matsuo, T. Samoto, Y. Shimomura, O. Kurachi, S. Nakago, T. Yamada, Q. Xu, W. Chen, J. Wang and N. Ohara Department of Obstetrics and Gynecology Kobe University Graduate School of Medicine Kobe JAPAN

Although the clinical observations have supported an important role for estrogen in leiomyoma growth, there is increasing evidence to suggest the involvement of progesterone in leiomyoma growth. We have found that the use of levonorgestrel-releasing infrauterine system (LNg-IUS) is effective for long-term management of menorrhagic women with uterine myomas because of striking reduction in menorrhagia [1,2]. This prompted us to characterize the effects of progestin on the proliferation and apoptosis in cultured leiomyoma cells.

EGF and IGF-I have been shown to play a crucial role in promoting leiomyoma growth through stimulating proliferation and inhibiting apoptosis of leiomyoma cells [3,4]. Treatment with P4 resulted in increase in EGF expression in cultured leiomyoma cells, whereas treatment with E2 augmented EGF-R expression in those cells [5]. This indicates that P4 and E2 act in combination to stimulate leiomyoma growth through the induction of EGF and EGF-R expression in uterine leiomyoma cells. Treatment with E2 down-regulated p53 protein expression in cultured leiomyoma cells6. Bcl-2 was abundantly expressed in leiomyoma, but not in normal myometrium. The abundant expression of Bcl-2 in leiomyoma may be one of the molecular bases for the enhanced growth of leiomyoma in the uterus. The Bcl-2 expression in leiomyoma cells was up-regulated by P47. Treatment with P4 not only augmented EGF and Bcl-2 expression in cultured leiomyoma cells but also inhibited IGF-I and TNFa expression in those cells [8,9]. These results suggest that P4 may have dual actions: one is to stimulate leiomyoma cell growth and survival through up-regulating EGF and Bcl-2 expression as well as down-regulating TNFa expression in those cells, and the other is to inhibit leiomyoma cell growth and survival through down-regulating IGF-I expression in those cells10. This may explain why the size of uterine myoma during use of LNg-IUS increases in some but decreases in other instances.

Taking these findings into account, we evaluated the effects of selective progesterone receptor modulator on uterine leiomyoma cell proliferation and apoptosis. J867 asoprisnil inhibited the proliferative activity and stimulated apoptosis in cultured leiomyoma cells, but not in cultured normal myometrial cells. This is meaningful for understanding the clinical usefulness of J867 asoprisnil in the medical treatment of uterine myomas.

References:

1. Maruo T, et al. (2001) In Maruo T, Barlow D, et al (eds) Cell and Molecular Biology of Endometrium in Health and Disease. Osaka, Japan, pp 193-207.
2. Maruo T, et al. (2001) Hum Reprod 16: 2103-2108.
3. Gao Z, et al. (2001) J Clin Endocrinol Metab 86: 5593-5599.
4. Maruo T, et al. (1996) In Kuramoto H and Gurpide E (eds) In Vitro Biology of Sex Steroid Hormone Action. Churchill Livingstone, Tokyo, Japan, pp 251-263.
5. Shimomura Y, et al. (1998) J Clin Endocrinol Metab 83: 2192-2198.
6. Gao Z, et al. (2002) J Clin Endocrinol Metab 87: 3915-3920.
7. Matuo H, et al. (1997) J Clin Endocrinol Metab 82: 293-299.
8. Kurachi O, et al. (2001) J Clin Endocrinol Metab 86: 2275-2280.

List of abstracts from the 3rd International Conference on the Female Reproductive Tract