Sex steroidal regulation of uterine leiomyoma growth and apoptosis

Abstract

Uterine leiomyomas develop during the reproductive years and regress after menopause, indicating ovarian steroid-dependent growth potential. Although the clinical and biochemical observations have traditionally supported an important role for estrogen in the promotion of leiomyoma growth, there is also increasing evidence to suggest the involvement of progesterone in the pathogenesis of leiomyoma. In this review, much attention has been paid to characterizing the molecular mechanisms of sex steroidal regulation of leiomyoma growth and apoptosis by evaluating the effects of sex steroids on the expression of growth factors and apoptosis-related factors. The effects of GnRH agonist on the expression of these factors in leiomyoma are also described. 17beta-Estradiol up-regulates epidermal growth factor (EGF) receptor, but down-regulates p53 protein in leiomyoma cells, whereas progesterone augments EGF and Bcl-2 protein, but inhibits insulin-like growth factor (IGF-I) and tumour necrosis factor (TNFalpha). Since it is now evident that EGF and IGF-I act as local factors which stimulate leiomyoma growth, these findings suggest that progesterone may have dual actions, stimulatory and inhibitory, on leiomyoma cell growth and survival, depending on the local growth factor conditions around each leiomyoma. This may explain why the size of uterine leiomyomas during the use of levonorgestrel-releasing intrauterine system (LNG-IUS) increases in some but decreases in other instances. This may also explain why the size of leiomyomas during pregnancy does not increase despite the overwhelming increase in circulating concentrations of sex steroid hormones. Moreover, there is further evidence to suggest that the interactions between estrogen receptors and progesterone receptors may be involved in the modulation of gene transcription activity in leiomyoma. This review demonstrates that leiomyoma growth is integrally regulated by the complex cross-talk between sex steroid hormones and growth factors.

A Mathematical Model of the Growth of Uterine Myomas

“…Sex hormones, such as oestrogen, are believed to play a major role in the growth of myomas [12,24,28,29]. The presence of oestrogen induces vesodilation leading to an increase in blood flow maintaining nutrient supply to the myoma cells [29].…”

Immunohistochemical Expression of Bcl-2 and Microvessels Density in Uterine Fibroids in Saudi Patients

“…However, another study done on Pakistani patients depicted an up-regulation of Bcl-2 levels in nearly 50% of the leiomyomata. The mean level of Bcl-2 protein in the leiomyomatous tissue was greater than that of the adjacent normal myometrium but showed no statistically significant difference [p = 0.399] (24).…”

“…They presumed that progesterone could cause a reciprocal rise in Bcl-2 protein levels favouring an apoptosis inhibited environment within the tumour area (22,24).…”

Involvement of Bcl-2, Src, and ERα in gossypol-mediated growth inhibition and apoptosis in human uterine leiomyoma and myometrial cells

“…Bcl-2 has already been recognized as an inhibitor of the apoptotic process. Related to sex steroid hormones, Bcl-2 protein expression in leiomyoma cells has been extensively reported [25] . In this study, we noticed that there was no significant difference in Bcl-2 expression in the leiomyoma and myometrial cells, and this is supported by data previously reported by Wu et al [3] .…”