Uterine Leiomyomas

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

Uterine leiomyomas (fibroids) are the leading indication for hysterectomy in the United States. Despite the morbidity and high medical costs associated with fibroids, there has been little epidemiologic study of this condition. Uterine leiomyomas are histologically identifiable as benign smooth muscle tumors with varying amounts of associated fibrous tissue. Many women have more than one uterine leiomyoma, but each appears to be clonally distinct. MED12 mutations that appear to cause gain of function are found in the majority of tumors and are likely triggers for tumorigenesis. Several specific cytogenetic changes have also been identified in tumor tissue, but most tumors show no chromosomal abnormalities. These benign tumors are hormone-dependent. They develop after puberty and regress after menopause. Both estrogen and progesterone are considered important stimulants, or at least permissive factors for tumor growth. To address the research needs in this field we designed four studies. The first, the NIEHS Uterine Fibroid Study, is a large epidemiologic study of black and white women, aged 35-49, in which the randomly selected participants were screened for fibroids with ultrasound. The second study (Fibroid Growth Study, Shyamal Peddada, PI) is a clinical study of fibroids designed to describe fibroid growth. The third study, Postpartum Uterine Regression, monitored fibroid change with pregnancy and postpartum uterine regression. The fourth study is an ultrasound-based, prospective study of fibroid incidence and growth in African Americans, the U.S. ethnic group at highest risk of fibroids, and this study is the major current focus of our fibroid group. In 2010 2012 we enrolled nearly 1700 African American women, aged 23-34, in the Study of Environment, Lifestyle & Fibroids (SELF), based in the Detroit, Michigan area with collaboration from Henry Ford Health System. Any prior diagnosis of fibroids was an exclusion criterion. The Participants were screened for fibroids with ultrasound at enrollment (detection limit of lesion = 0.5 cm diameter). There were three subsequent clinic visits at approximately 20-month intervals to monitor fibroids by ultrasound examinations in order to identify onset time. Fibroids detected at enrollment (newly detected, not previously clinically diagnosed), as well as those that develop during the study, were followed in the same manner to assess fibroid growth. We collected risk factor and symptom data at enrollment and at each 20-month visit for five years. The study was designed to collect a broad spectrum of exposure data including recognized risk factors for fibroids (age of menarche, pregnancy history, alcohol use, body mass index) and potential risk factors for which there has been only suggestive data. Three primary hypotheses will be tested. (1) Vitamin D deficiency is a risk factor for fibroids, (2) Reproductive tract infections are risk factors for fibroids, and (3) A higher proportion of African ancestry is associated with increased fibroid risk (African ancestry measured by informative SNPs known to have very different frequencies between Europeans and Africans). We have completed participant-visits for the 3rd and final follow-up. Our participation at the 5-year follow-up was 90% of those initially enrolled. We are still collecting data, including relevant medical-record retrieval. We also are conducting quality control checks on the ultrasound data based on archived images. We are in the process of developing data files for both the prospective incidence and the fibroid growth analyses. The enrollment data have been analyzed to examine the associations of the following exposures with prevalent fibroids: keloid scars, being fed soy formula as an infant, Depo Provera use, and reproductive tract infections. Stored biospecimens have been assayed for markers of reproductive tract infections and metals. Current assay work includes 1) 25(OH)D to assess vitamin D status and 2) high sensitivity C-reactive protein to assess chronic inflammation. The genetic analyses will follow. We completed analysis of fibroid incidence and growth during the first 20-month interval of observation. We found that about 10% of fibroid-free women at baseline had developed fibroids by the first follow-up, and incidence increased with age. The incidence finding validates earlier modeled data suggesting that fibroid development is about 10 years earlier in African Americans compared to whites. Growth was based on fibroid volume change over an 18-month interval analyzed on a log scale but converted to percent increase indexed to an 18-month interval. Average growth was nearly a 90% increase in volume per 18 months. The growth-rate estimate for small fibroids (<1cm in diameter) was twice that of the average, while the rate for large fibroids (4+ cm in diameter) was only about half the average. We have just begun to examine risk factors for fibroid incidence. In an examination of oral contraceptive use and cumulative incidence of fibroid at 40 months, we found that this most commonly used contraceptive neither increases nor decreases fibroid risk. Several prior reports showed highly varied results from protective to increasing risk. This first examination using truly prospective data for new fibroid development provides an important reassurance to reproductive-age women that choosing to take oral contraceptives is unlikely to enhance their risk of fibroid development. Our next analyses will investigate associations of Depo Provera use and fibroid development, another commonly-used hormonal contraceptive. As data become available we will begin to address our primary hypotheses. Two research groups have extramural funding for add-on studies with SELF. Lauren Wise, at Boston University, along with Ganesa Wegienka at Henry Ford Health System will be investigating endocrine disrupting chemical exposures and fibroid development. Erica Marsh, at the University of Michigan, is investigating ovarian aging in the SELF population.