Elsevier

Steroids

Volume 68, Issues 10–13, November 2003, Pages 817-824
Steroids

Effects of progesterone on growth factor expression in human uterine leiomyoma

https://doi.org/10.1016/j.steroids.2003.08.017Get rights and content

Abstract

It is now evident that the use of levonorgestrel-releasing intrauterine system (LNg-IUS) is effective for long-term management of menorrhagic women with uterine myomas because of a striking reduction in menorrhagia. This prompted us to characterize the effects of progesterone (P4) on the growth and apoptosis of uterine leiomyoma cells. On the other hand, we have recently noted that epidermal growth factor (EGF) and IGF-I play a crucial role in prompting uterine leiomyoma growth through stimulating the proliferative potential and inhibiting apoptosis of cultured human leiomyoma cells. In the present review, attention was paid to evaluate the effects of P4 on the expression of growth factors (EGF, IGF-I) and apoptosis-related factors (TNFα, Bcl-2 protein) in cultured uterine leiomyoma cells. Treatment with P4 augmented EGF and Bcl-2 protein expression, but inhibited IGF-I and TNFα expression in cultured leiomyoma cells. It is known that TNFα induces apoptosis in a variety of cell types and Bcl-2 protein is an apoptosis-inhibiting gene product. Thus, the results obtained suggest that P4 has dual actions on uterine leiomyoma growth: one is to stimulate leiomyoma cell growth and survival through up-regulating EGF and Bcl-2 protein expression as well as down-regulating TNFα expression in those cells, and the other is to inhibit leiomyoma cell growth through down-regulating IGF-I expression in those cells. This may explain why the size of uterine myomas during use of LNg-IUS increases in some but decreases in other instances. This may also explain why the size of uterine myomas during pregnancy does not increase despite the overwhelming increase in circulating concentrations of sex steroid hormones.

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.

References (47)

  • D.D. Brandon et al.

    Estrogen receptor gene expression in human uterine leiomyomata

    J. Clin. Endocrinol. Metab.

    (1995)
  • L.J. Murphy et al.

    Uterine insulin-like growth factor-1: regulation of expression and its role in estrogen-induced uterine proliferation

    Endocr. Rev.

    (1990)
  • Y.M. Huet-Hudson et al.

    Estrogen regulates synthesis of epidermal growth factor in mouse uterine epithelial cells

    Mol. Endocrinol.

    (1990)
  • K.G. Nelson et al.

    Transforming growth factor is a potential mediator of estrogen action in the mouse uterus

    Endocrinology

    (1992)
  • A. Gray et al.

    Nucleotide sequence of epidermal growth factor cDNA predicts a 128,000-molecular weight protein precursor

    Nature

    (1993)
  • J. Scott et al.

    Structure of a mouse submaxillary messenger RNA encoding epidermal growth factor and seven related proteins

    Science

    (1983)
  • K.G. Nelson et al.

    Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation

    Proc. Natl. Acad. Sci. U.S.A.

    (1991)
  • Maruo T, Samoto T, Matsuo H, Shimomura Y, Mochizuki M. Regulation of proliferative and Bcl-2 oncoprotein expression in...
  • M.J. Rossi et al.

    Presence of epidermal growth factor, platelet-derived growth factor, and their receptors in human myometrial tissue and smooth muscle cells: their action in smooth muscle cells in vitro

    Endocrinology

    (1992)
  • M.A. Lumsden et al.

    The binding of epidermal growth factor to the human uterus and leiomyomat in women rendered hypo-oestrogenic by continuous administration of an LHRH agonist

    Br. J. Obstet. Gynecol.

    (1988)
  • L.T.M. Van Der Ven et al.

    Expression of insulin-like growth factors (IGFs), their receptors and IGF binding protein-3 in normal, benign and malignant smooth muscle tissues

    Br. J. Cancer

    (1997)
  • S.R. Howe et al.

    Presence of an insulin-like growth factor I autocrine loop predicts uterine fibroid responsiveness to tamoxifen

    Cancer Res.

    (1996)
  • L.T.M. Van Der Ven et al.

    Growth advantage of human leiomyoma cells compared to normal smooth-muscle cells due to enhanced sensitivity toward insulin-like growth factor I

    Int. J. Cancer

    (1994)
  • Cited by (0)

    View full text