Etiology of Uterine Leiomyomata ("Fibroids")
Uterine leiomyomata (commonly known as "fibroids") are benign tumors of clonal origin comprised of interlacing smooth muscle and fibrous tissue. Although benign, uterine leiomyomata are a major source of morbidity for women of reproductive age, accounting for between 30 and 40 per cent of the indications for hysterectomy among reproductive-aged U.S. women. Over 180,000 hysterectomies performed annually in the U.S. are attributable to these "benign" neoplasms.
A growing body of evidence from molecular, epidemiologic, and clinical studies has accumulated indicating that ovarian hormones are likely to be key factors in the growth and development of uterine leiomyomata. However, relatively few studies in human populations have tested this hypothesis using rigorous study designs, or have attempted to incorporate molecular and biochemical epidemiologic approaches. In 1995 we received funding from the National Institute of Child Health and Human Development to initiate TULEP (The Uterine Leiomyomata Epidemiology Project), a population-based case-control study. The goal of TULEP is to determine the association between a variety of hormonal and hormonally-mediated factors -- such as oral contraceptive use, estrogen replacement therapy, obesity, reproductive history, exercise, and diet -- and the development of uterine leiomyomata. Cases of newly diagnosed uterine leiomyomata and controls frequency matched on age were identified and recruited from the membership of Group Health Cooperative of Puget Sound (GHC). The primary data collection activity was an in-person interview, but data collection also included a comprehensive food frequency questionnaire, measurements of waist and hip girth, and venous blood specimens. At the close of the first phase of data collection in September 1999, 647 cases and 637 controls had been recruited. Statistical analyses to address the specific aims are underway.
In 1996 we received funding from the National Institute for Environmental Health Sciences for an ancillary study to TULEP. This study -- called BULB (Blood and Urine Leiomyomata Biomarkers) -- aims to determine whether uterine leiomyomata are related to two sources of putative "environmental endocrine disruptors": 1) organochlorine pesticides and polychlorinated biphenyls, and 2) dietary isoflavones and lignans. The participants in this study -- 191 cases and 177 controls -- were premenopausal women recruited from among those participating in the TULEP study. The main activities are a venous blood sample (for pesticide and PCB measurements) and two overnight urine samples (for isoflavone and lignan excretion). Dietary intake histories for the days corresponding to the urine collection are also elicited. While recruitment for BULB has been completed, specimen analyses are still being coducted.
Recently, we have initiated studies to determine whether polymorphisms in genes involved in the synthesis and metabolism of steroid hormones are related to the risk of developing uterine leiomyomata. In vitro studies suggest that the estradiol metabolite 4-OH estradiol may be important in uterine leiomyomata growth. The production of this metabolite is regulated in part by the enzyme catechol O methyl transferase (COMT); higher the COMT activity reduces the level of 4-OH metabolite. The COMT gene is polymorphic, with approximately 25% of whites having a genotype that is associated with reduced enzyme activity. Using DNA extracted from peripheral leukocytes of TULEP cases and controls, we are examining whether the reduced activity variant is associated with an increased risk of uterine leiomyomata. We plan to continue this line of research by determining the relationship between other steroid hormone metabolism genes (e.g., CYP17, CYP11a, UGT1A1) and uterine leiomyomata risk.
Related Publications
Schwartz SM. Epidemiology of uterine leiomoyomata. Clin Obstet Gynecol 2001; 44: 316-326.
Schwartz SM. Studying the epidemiology of uterine leiomyomata: past, present, and future. Am J Epidemiol 2001;153:27-29.
Schwartz SM, Marshall LM, Baird DD. Epidemiologic contributions to understanding the etiology of uterine leiomyomata. Environ Health Perspect 2000;108 (suppl 5):821-27.
Coronado GD, Marshall LM, Schwartz SM. Complications in pregnancy, labor, and delivery in women with uterine leiomyomata: a population-based study. Obstet Gynecol 2000; 95:764-769.
Schwartz SM, Marshall LM. Uterine Leiomyomata. In: Women and Health. Goldman M, Goldman M, eds. Academic Press, NY, 1999.