Effects of progesterone on growth factor expression in human uterine leiomyoma
Introduction
Uterine leiomyoma is the most common benign tumor originated from uterine smooth muscle cells, occurring in as many as 30% of women over 35 years of age [1]. It is a frequent cause of menorrhagia, dysmenorrhea, pelvic discomfort, infertility, and recurrent pregnancy loss. The growth of uterine leiomyomas has been known to be dependent on the presence of ovarian steroid hormones. Most of the available information about leiomyoma growth points to a vital role for estrogen and progesterone (P4). Actually, Brandon et al. [2], [3] demonstrated increased expression of estrogen receptor and P4 receptor in uterine leiomyomas compared to those in the adjacent normal myometrium. Because leiomyoma growth is closely associated with reproductive years and the vital role of estrogen in uterine growth has been established [4], estrogen has received much attention as the major factor responsible for leiomyoma development. A growing body of evidence suggests that the action of estrogen may be mediated in part by local growth factors, such as epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I), produced by the target cells [4], [5], [6]. The mechanisms of action of P4 in the regulation of leiomyoma growth, however, are not defined as yet. Thus, much attention was paid to evaluate the effects of P4 on the expression of local growth factors and apoptosis-related factors in cultured uterine leiomyoma cells.
Section snippets
EGF
EGF is a 6-kDa polypeptide that is known to be generated by proteolytic processing of a larger molecular precursor, 133-kDa prepro-EGF [7], [8]. EGF is shown to be present in its prepro form in the kidney and other tissues [9]. Nelson et al. [10] demonstrated in murine uterine tissues that the effect of 17β-estradiol (E2) may be mediated by EGF and that EGF is capable of replacing E2 in the stimulation of female genital tract growth. Actually, we have demonstrated that treatment with either E2
Effects on EGF and EGF receptor expression
In monolayer cultures of leiomyoma cells, the addition of either E2 (10 ng/ml) or P4 (100 ng/ml) resulted in an increase in PCNA expression in the cells compared to that in control cultures. The fact that P4 up-regulates PCNA protein expression in cultured leiomyoma cells is in good agreement with the in vivo finding of a higher PCNA labeling index in leiomyoma tissues in the secretory, P4-dominated, phase compared to that in the proliferative phase. Furthermore, we demonstrated that the PCNA
Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific Research no. 12877263 from the Japanese Ministry of Education, Science and Culture, by the Ogyaa-Donation Foundation of the Japan Association of Maternal Welfare, and by the Population Council, New York, USA.
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