Cellular Biology of Myomas: Interaction of Sex Steroids with Cytokines and Growth Factors

Uterine leiomyomata are the most common benign tumors in women of reproductive age, clinically diagnosed in 20% to 30% of women and established at autopsy in an additional 20% to 30% of women [1]. Growth of these tumors is believed to depend on ovarian hormones; however, in vitro studies in human tissues aiming to demonstrate a direct growth-promoting action of ovarian hormones has shown inconsistent or indirect results. This suggests the presence of intermediate elements, such as cytokines and growth factors, through which the ovarian hormones may be exerting their growth-stimulatory effects on leiomyomas. Estrogen and progesterone may regulate gene expression of these cytokines and growth factors, which in turn modify the transcription of other genes. The result of this abnormal production of cytokines and growth factors may be an increase in cell proliferation, accumulation of extracellular matrix (ECM), or a combination of these phenomena. More recently, another potential mechanism, decreased apoptosis, was proposed by Matsuo and coworkers [2], who found that Bcl-2 protein, an apoptosisinhibiting gene product, was abundantly expressed in leiomyomata relative to that in normal myometrium. In this study, Bcl-2 protein expression in leiomyoma cells was up-regulated by progesterone, but down-regulated by estradiol. The same group reported up-regulation of expression of proliferating cell nuclear antigen (PCNA) in leiomyomas by progesterone and estradiol. They also showed [3] that gonadotropin-releasing hormone antagonist (GnRH-a) cetrorelix downregulates PCNA and up-regulates apoptosis.