Theories of Fibroid Information

October 3, 2011

Despite the major public health impact of leiomyomas, little is known about their cause. Until recently, the steroid hormones estrogen and progesterone were considered the most important regulators of leiomyoma growth. There is abundant evidence that estrogen promotes fibroid growth including the clinical observations that fibroids grow in the presence of high levels of estrogen, such as during the reproductive years, and that they regress in the presence of low levels of estrogen, such as following menopause or during gonadotropin releasing hormone (GnRH) agonist therapy.

Reprinted with permission

Despite the major public health impact of leiomyomas, little is known about their cause. Until recently, the steroid hormones estrogen and progestrone were considered the most important regulators of leiomyoma growth. There is abundant evidence that estrogen promotes fibroid growth including the clinical observations that fibroids grow in the presence of high levels of estrogen, such as during the reproductive years, and that they regress in the presence of low levels of estrogen, such as following menopause or during gonadotropin releasing hormone (GnRH) agonist therapy. Furthermore, fibroids have higher estrogen concentrations, bind more estrogen, have more estrogen receptors, and convert estradiol (a more active form of estrogen) to estrone (a less active form of estrogen) more slowly than normal myometrium.

Progesterone is also thought to play a role in fibroid growth. More specifically, clinical studies suggest progesterone facilitates the growth of fibroids. For example, fibroid size increases during treatment with synthetic progesterones. Combination GnRH agonist and progesterone therapy has been shown to have no effect on uterine volume, in contrast to GnRH agonist therapy alone which has been shown to reduce uterine volume. The observation that fibroids regress with the antiprogesterone agent, RU-486, further supports the role of progesterone as a promoter of fibroid growth. Histologically, fibroids from patients treated with progesterone show more cellular growth than those from patients without progesterone therapy. Biochemically, fibroids have higher progesterone receptor concentrations than normal myometrium. Together, these data suggest that progesterone also enhances fibroid growth.

Other hormones such as growth hormone (GH) and prolactin (PRL) are also thought to promote fibroid growth, but their role is even less well defined.

More recently, growth factors, which are small proteins that affect cell growth, have been shown to mediate the growth-promoting effects of estrogen and to play an important role in the development of fibroid tumors. Potentially important factors in fibroid growth include transforming growth factor-beta, basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor, and platelet-derived growth factor. (For more information about this, please see the article, Leiomyoma-related bleeding: A classic hypothesis updated for the molecular era, on the "Publications" page.)

Overall, estrogen, progesterone, and growth factors likely promote tumor growth, but only after the initiation of tumor formation. This initiating event remains unknown, although recent evidence suggests there is a strong inherited component to fibroid development. Indirect evidence for this hypothesis is as follows. First, fibroids are at least twice as common in black women than in white women. Although racial differences in socioeconomic status and access to health care, as well as racial differences in known risk factors for fibroids, may contribute to this finding, two recent studies suggest that these factors do not completely explain the discrepancy. Secondly, another study found a genetic predisposition for hysterectomy as indicated by a two fold higher twin pair correlation for hysterectomy in identical versus fraternal twins. Thirdly, there exists a rare heritable form of uterine fibroids in association with fibroids of the skin called Reed's syndrome. Finally, a recent Russian studies suggest that women with a family history of fibroids are twice as likely to develop fibroids than women with no family history. Unfortunately, few scientific studies directly examine the genetic component of fibroid development.

Recently, researchers at the Center for Uterine Fibroids have identified mutations in two genes, HMGI(C) and HMGI(Y), that appear to be important in the development of some fibroids. (For more information about the genetics of fibroids, please see articles published about these genes on the "Publications" page.) Normally, these genes code for proteins that help control cell growth by indirectly regulating DNA transcription.

However, mutations in these genes are probably secondary changes in already genetically susceptible cells. Therefore, it is likely that other gene(s) crucial for fibroid development exist that have not yet been identified. To this end, the staff at the Center for Uterine Fibroids is studying families with at least one pair of siblings affected by fibroids to search for gene(s) that predispose women to fibroid development. For information about this study, including participation, please see, Finding Genes for Fibroids, on the "Current Studies" page.

Ultimately, understanding the hormones, growth factors, and gene(s) involved in the formation and growth of fibroid tumors may lead to innovative, less invasive treatment options.

References:

*For general information and pictures of the uterus, please go to anatomy and physiology of the uterus.

For more information, visit The Center for Uterine Fibroids

The Center for Uterine Fibroids at Brigham and Women's Hospital in Boston, Massachusetts is starting a study to identify gene(s) involved in uterine fibroids.