Role of hormonal and reproductive factors in the etiology and treatment of uterine leiomyoma.

Uterine leiomyomas are the most common gynecologic neoplasm in reproductive-age women. While it is clear that hormonal factors play a prominent role in this disease, how steroid hormones contribute to disease etiology or may be utilized as targets for intervention are currently areas of active scientific investigation. To study the impact of hormones on uterine leiomyomas, the Eker rat has been developed as an in vivolin vitro animal model system for these tumors. Spontaneous leiomyomas arise in intact Eker rats with a high frequency and leiomyoma-derived cell lines from these animals maintain the biochemical and physiological characteristics of the tumors from which they were obtained. Using this animal model system, it has been established that tumor development is absolutely dependent on steroid hormones and that sensitivity/responsiveness to estrogen is enhanced in tumors and tumor-derived cell lines. Modulation of hormonal milieu, such as that which naturally occurs during pregnancy, can effectively inhibit tumor development. The hormone responsiveness of these tumors makes them good candidates for hormonal therapy. Selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene hold promise as potential therapeutic agents for this disease. SERMs inhibit proliferation of leiomyoma-derived cell lines in vitro, repress the growth of these lines in nude mice, and, when administered over a 2- to 4-month course of treatment to Eker rats, reduce tumor incidence by more than 50%. In addition to endogenous hormones, xenoestrogens in our environment (e.g., phytoestrogens, organochlorine pesticides, pharmacologic compounds) are of potential concern with regards to their impact on this disease. These environmental estrogens have been shown to promote the growth of leiomyoma cells in vitro and in vivo. Further elucidation of the role of these and other hormonal and reproductive factors in the development of uterine leiomyoma will be invaluable for increasing our understanding of the etiology of this disease and developing new therapeutic strategies to help to reduce the negative impact of uterine leiomyomas on women's health.