Cell-Type Specific Actions of Progesterone Receptor Modulators in the Regulation of Uterine Leiomyoma Growth

ABSTRACT

Although the traditional concept supports a crucial role of estrogen in promoting leiomyoma growth, unequivocal evidence has emerged indicating that progesterone also plays a vital role in the regulation of leiomyoma growth. Recent clinical trials have demonstrated the efficacy of asoprisnil, a selective progesterone receptor modulator, and CDB-2914, a novel progesterone receptor modulator, for the treatment of women with symptomatic leiomyomata. These compounds significantly reduced leiomyoma and uterine volume and improved leiomyoma-related symptoms without serious complications. However, the precise mechanism whereby these compounds cause leiomyoma regression remains poorly understood. Our extensive in vitro studies have provided novel evidence for the growth inhibitory effects of asoprisnil and CDB-2914 on cultured leiomyoma cells. Both compounds exhibited antiproliferative, proapoptotic, and antifibrotic actions on cultured leiomyoma cells in the absence of comparable effects on cultured normal myometrial cells. Asoprisnil and/or CDB-2914 modulated the ratio of progesterone receptor isoforms (PR-A and PR-B) in cultured leiomyoma cells; decreased the cell viability; suppressed the expression of growth factors, angiogenic factors, and their receptors in those cells; and induced apoptosis through activating the mitochondrial and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways and eliciting endoplasmic reticulum stress. Furthermore, these compounds suppressed types I and III collagen synthesis by modulating extracellular matrix-remodeling enzymes in cultured leiomyoma cells without affecting those syntheses in cultured normal myometrial cells. These findings indicate that both compounds exert antiproliferative, proapoptotic, and antifibrotic actions on leiomyoma cells in a cell-type specific manner. This supports the notion that asoprisnil and CDB-2914 hold promise for the nonsurgical treatment of uterine leiomyomata.

KEYWORDS

Leiomyoma - myometrium - progesterone receptor modulator - proliferation - growth factor - angiogenic factor - apoptosis - endoplasmic reticulum stress - extracellular matrix - collagen

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