Progesterone and progesterone receptor modulator in uterine leiomyoma growth

Use of the levonorgestrel-releasing intrauterine system (LNG-IUS) results in a remarkable decrease in endometrial proliferation and a remarkable increase in apoptosis in the endometrium; therefore it is effective for the long-term management of menorrhagic women with uterine myomas because of the striking reduction in menorrhagia. Although no significant differences in myoma volume as assessed by magnetic resonance imaging were noted between pretreatment and 12 months of use of LNG-IUS, myoma volume determined during LNG-IUS use showed an increase, no change and a decrease in each one third of cases examined [1-4]. This prompted us to characterize the effects of progesterone (P4) and the progesterone receptor modulator CDB2914 on uterine myoma growth.

Uterine leiomyomas develop during the reproductive years and regress after menopause, indicating ovarian steroids-dependent growth potential. Although 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 P4 in the pathogenesis of leiomyoma. In this context, several growth factors have been demonstrated to play a vital role in leiomyoma cell growth, including epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I), which stimulate cell proliferation and inhibit apoptosis of leiomyoma cells [5]. It becomes clear that a cross-talk between sex steroid hormones, growth factors and apoptosis-related factors exists in the regulation of uterine myoma growth. Thus, much attention has been paid to characterize the molecular mechanisms of sex steroidal regulation of leiomyoma growth and apoptosis by evaluating the effects of P4 and 17β-estradiol (E₂) on the expression of growth factors and apoptosis-related factors.

In vitro studies with cultured uterine leiomyoma cells and normal myometrial cells revealed that P4 stimulated proliferative activity in leiomyoma cells, but not in normal myometrial cells. P4 increased EGF expression in leiomyoma cells, whereas E₂ augmented EGF receptor (EGF-R) expression in leiomyoma cells, indicating that P4 and E₂ act in combination to stimulate leiomyoma cell growth [6]. P4 also increased expression of the antiapoptotic protein Bcl-2 and decreased expression of tumor necrosis factor-α (TNF-α) in these cells [7],[8]. Unlike the EGF expression, IGF-I expression in leiomyoma cells was inhibited by P4. These results suggest that P4 has dual actions on leiomyoma growth: one is to stimulate growth through upregulating EGF and Bcl-2 expression, the other is to inhibit growth through downregulating IGF-I expression. It seems likely that P4 may have dual actions, stimulatory and inhibitory, on leiomyoma cell growth and survival, depending on the local growth factor conditions around each leiomyoma [9-11]. This may explain why the size of uterine leiomyomas during the use of LNG-IUS increases in some instances, but decreases in others. It may also explain why the size of leiomyomas during pregnancy does not increase despite the overwhelming increase in circulating concentrations of sex steroid hormones.

By contrast, a novel progesterone receptor modulator CDB2914 which binds competitively to the progesterone receptor with high affinity inhibited proliferation and stimulated apoptosis of cultured leiomyoma cells without affecting cultured normal myometrial cells [12]. Furthermore, CDB2914 inhibited vascular endothelial growth factor (VEGF) and adrenomedullin expression in cultured leiomyoma cells, but not in cultured normal myometrial cells [13]. Since VEGF and adrenomedullin are involved in the angiogenesis and vascular network in uterine myomas, the cell-type specific action of CDB2914 on leiomyoma cells without affecting the surrounding normal myometrial cells is meaningful for understanding the usefulness of CDB2914 in the medical treatment of uterine myomas.

Three questions to the Editorial's author

Question 1: Does progesterone exert a stimulatory effect on uterine myoma growth?

Although the action of P4 on uterine myoma growth is not simple, its net effect on uterine myoma growth is in favor of increased proliferative activity of leiomyoma cells. P4 contributes to leiomyoma cell growth through stimulating EGF expression and to cell survival through stimulating Bcl-2 expression and inhibiting TNF-α expression in the cells. However, P4 also exerts an inhibitory effect on leiomyoma cell growth and survival by inhibiting IGF-I expression in the cells. This suggests that P4 may have dual actions on uterine myoma growth: one is to stimulate and the other is to inhibit leiomyoma cell growth.

Question 2: What is the relationship in regulating uterine myoma growth between estrogen and progesterone?

Historically, the pathogenesis of uterine myomas has been attributed to E₂. However, it is now evident that P4 and E₂ act in combination to stimulate the EGF/EGF-R system in regulating leiomyoma cell growth. E₂ stimulates EGF-R expression in the cells, while P4 stimulates EGF expression in uterine leiomyoma cells.

Question 3: Do uterine myomas increase in size during pregnancy?

Although until recently it has been described in textbooks that uterine myomas increase in size during pregnancy, this is not necessarily the case despite the increased circulating concentrations of E₂ and P4. The dual actions of P4 may explain, at least in part, why most uterine myomas identified early in pregnancy remain the same size or even shrink over the course of pregnancy.