Study Background & Design

Fibroid Growth Study

Study Background

The Fibroid Growth Study (FGS) is designed to investigate why some fibroids grow to become health problems while others do not. Funding is provided jointly by the National Institute of Environmental Health Sciences (NIEHS) and the National Center for Research on Minority Health and Health Disparities (NCMHD) (http://ncmhd.nih.gov/). Scientific direction and oversight is provided by NIEHS. Collaborators in this research include University of North Carolina Hospitals, the General Clinical Research Center (GCRC) (http://verne.med.unc.edu/home.html) and Integrated Laboratory Systems, Incorporated (ILS) (http://www.ils-inc.com/).

FGS has the following four specific aims:

• Fibroid growth will be evaluated over time by MRI.
• The relationship between fibroid growth and symptoms or outcome (i.e., surgery/no surgery) will be determined.
• The research team will identify markers that may be related to growth.
• Members of the research group will examine the hormone and lifestyle factors that may be related to fibroid growth.

Uterine fibroids are benign (non-cancerous) tumors that are present in the muscular wall of the uterus in up to 70% of all women (1). They are the leading cause for hysterectomy in the United States and are responsibility for about one-fifth of all gynecological-related hospital admissions. Even though they are benign, fibroids sometimes cause reproductive problems such as heavy bleeding, pelvic pressure, severe cramping, pain, infertility, and miscarriage (2). Recent data suggests that fibroids can also cause pregnancy complications, such as placenta previa and breech presentation (3). Little information is available about why fibroids develop or why they grow. Some evidence suggests that it may be related to a genetic problem. It is also possible that fibroids may grow in response to environmental factors, such as diet, smoking, exercise, or exposure to certain chemicals.

Uterine leiomyomas are a significant health problem for women, but particularly for African-American women (4-7). We recently completed a cross-sectional study of uterine leiomyomas (fibroids) in women age 35 to 49, randomly selected from membership in a prepaid health plan in Washington, DC (4). Sonogram data, with size and location of leiomyomas (if present) were collected for 1083 women, 87% of premenopausal participants. The prevalence of ultrasound-detected fibroids was surprisingly high, especially in the African-American participants; the rates were 72% and 50%, for African-American and Caucasian women, respectively. A substantial percentage of the women with fibroids were not previously diagnosed (44% and 69% for African-Americans and Caucasians, respectively). Extensive studies of uterine leiomyomas in other ethnic groups have not been conducted.

Leiomyomas are found throughout the uterus, including the intramural, subserosal, and submucosal regions. Submucosal fibroids can protrude into the uterine cavity and result in severe bleeding (8). Intramural fibroids can cause pelvic pain, and subserosal fibroids are associated with symptoms of intense pressure. It is thought that only large leiomyomas in the latter two locations cause significant symptoms. However, association of leiomyoma symptoms, location, and growth is not clear. The few studies that attempted to measure the rate of progression of fibroid disease have focused on risk of fibroid-related surgery. They have been conducted in clinical populations of mostly symptomatic women. Among women with leiomyomas and a uterine size greater than or equal than that typical during the 8th week of pregnancy, about 20% had hysterectomies within a year (9). In a more general population of women diagnosed with leiomyomas, only about one-third of the women had surgery within 5 years (10). Among newly diagnosed cases of uterine fibroids in the Nurses' Health Study, about 15% progressed to hysterectomy within 21 months (11). Weber et al. (10) investigated factors associated with increased risk of surgical intervention and identified the following: large uterine size, excessive bleeding, and prior surgery for pelvic adhesions or gall bladder removal.

Although large fibroids are more likely to cause morbidity than small fibroids, few data have been collected on actual growth of fibroids. In one study, 31 asymptomatic women with large uteri (>12 week gestation) were followed for a year. Size of the largest fibroid, as measured by MRI, increased in 50% of the women (20% of the women had an increase of 50% or more) (12). Biopsy samples taken at entry into the study indicated that growth was related to higher tissue levels of progesterone receptor and increased cellularity of the leiomyomas. Another study that measured growth by ultrasound (but did not report eligibility requirements) found that about one-third of the women experienced an increase in leiomyoma volume (increase of greater than 30%) during the one-year follow-up period and growth was related to increased leiomyoma vascularity (13). All other studies to report growth data were clinical trials in which a placebo or no-treatment group was followed for change in uterine size for comparison with a treatment group. These studies usually involved small numbers of women selected from clinical populations and followed for two months to one year. Though actual measures of change in uterine size varied from a 15% decline (14) to a 44% increase (15), most changed less than 10% (16-24), and none were reported as statistically significant changes.

Reproductive hormones stimulate development and growth of uterine leiomyomas. For example, fibroids most commonly develop during the reproductive years and typically regress after menopause. Gonadotropin releasing hormone (GnRH) agonists, which suppress the pituitary-ovarian hormone axis, are sometimes beneficial in therapy to reduce the size of leiomyomas, reduce hemorrhage, and/or inhibit growth. The hormonal responsiveness of these leiomyomas is further demonstrated by in vitro experimental studies. Leiomyomas express estrogen and progesterone receptors (25) and laboratory studies with leiomyoma-derived cell lines indicate that these cells are responsive to steroid hormones (26). Leiomyoma cells proliferate in response to estrogen in culture, and estrogen antagonists such as ICI 18572, tamoxifen and raloxifene, can inhibit this response. Moreover, their well-differentiated phenotype, including hormonal responsiveness, high expression of gap-junction proteins, and limited cytogenetic and molecular alterations, suggest that leiomyomas may actually represent an exaggerated and aberrant hormone responsiveness similar to that of a smooth muscle cell during pregnancy (27). Much of this response is attributed to progesterone and to the high progesterone receptor levels in these cells. Interestingly, studies that report changes in growth of existing leiomyoma during pregnancy are not consistent. Some leiomyomas grow, others shrink, but many show little change (28). Thus, even within the same environment, and under conditions that are generally stimulatory to leiomyoma growth, no clear pattern of response is documented. Given that many women have fibroids, but not all are symptomatic, the clinically relevant question is not what causes fibroids, but what causes fibroids to grow and cause symptoms?

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Study Design

Three hundred women with large and/or multiple fibroids will be recruited for this study. These women will have up to four study-related visits to UNC Hospital over a one-year period. Those visits will include a physical exam, blood and urine collection, and magnetic resonance image (MRI) scans. Participants will also be asked to complete an initial comprehensive telephone questionnaire, followed by monthly telephone update questionnaires. Questions relating to medical, family, menstrual, pregnancy, and sexual histories and lifestyle will be asked. Some women decide with their physician to have surgery to remove their fibroids. If a woman enrolled in this study decides to have surgery (hysterectomy or myomectomy), we will ask her permission to collect and examine post-operative tissues. If the woman is having a myomectomy (removal of fibroids only), we will also ask permission to remove a small piece (about 2 centimeters) of normal uterine tissue for comparison to the fibroid tissue.

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References

1. Schoenmakers EF, Huysmans C, Van de Ven WJ. Allelic knockout of novel splice variants of human recombination repair gene RAD51B in t(12;14) uterine leiomyomas. Cancer Res 59:19-23 (1999).
2. Kjerulff KH, Langenberg P, Seidman JD, Stolley PD, Guzinski GM. Uterine leiomyomas. Racial differences in severity, symptoms, and age at diagnosis. J Reprod Med 41:483-489 (1996).
3. Coronado GD, Marshall LM, Schwartz SM. Complications in pregnancy, labor, and delivery with uterine leiomyomas: A population-based study. Obstet Gynecol 95:764-769 (2000).
4. Baird, D. D., Schectman, J. M., Dixon, D., Sandler, D. P., and Hill, M. C. African-Americans at higher risk than whites for uterine fibroids: Ultrasound evidence. Am.J.Epidemiol. 147, S90. 1998.Ref Type: Abstract
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21. Gregoriou O, Vitoratos N, Papadias C, et al. Effect of tibolone on postmenopausal woman with myomas. Maturitas 27:187-191 (1997).
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24. Ylikorkala O, Tiitinen A, Hulkko S, et al. Decrease in symptoms, blood loss and uterine size in nafarelin acetate before abdominal hysterectomy: A placebo-controlled, double-blind study. Hum Reprod 10:1470-1474 (1995).
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26. Cesen-Cummings K, Copland JA, Barrett JC, Walker CL, Davis BJ. Pregnancy, Parturition, and Prostaglandins: Defining Uterine Leiomyomas. Environ Health Perspect 108 Suppl 5:817-820 (2000).
27. Andersen J, Barbieri RL. Abnormal gene expression in uterine leiomyomas. J Soc Gynecol Investig 2:663-672 (1995).
28. Strobelt N, Ghidini A, Cavallone M, Pensabene I, Ceruti P, Vergani P. Natural history of uterine leiomyomas in pregnancy. J Ultrasound Med 13:399-401 (1994).

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