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 NIEHS Uterine Fibroid Study, the Fibroid Growth Study, and the Postpartum Uterine Regression Study, and a fourth, 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 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 continue in our efforts to develop longitudinal data files for the prospective fibroid incidence and growth analyses, We have developed survivorship methods we will use to investigate exposure effects on fibroid incidence, and have modified the mixed model regression analyses used in the Fibroid Growth Study to assess exposure effects on fibroid growth. 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, 25(OH)D as the biomarker for vitamin D status, high sensitivity C-reactive protein to assess chronic inflammation, and metals. 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 begun to examine risk factors for fibroid incidence. In an examination of oral contraceptive (OC) use and cumulative incidence of fibroid at 40 months, those who used OCs had reduced incidence compared to those who had used OCs, the great majority of the cohort. However among women who had used OCs there was no increased fibroid incidence for those who used longer rather than shorter times or for those who used recently compared to early in their lives. Infact, the risk of fibroid incidence were somewhat elevated for recent an long-term users among the OC users. An survivorship analysis approach using the full follow-up data will be used to further address this important question. We have completed a detailed investigation of use of the injectable contraceptive, Depo Provera, and fibroid development. Consistent with our previously published cross-sectional findings, there was an inverse association between Depo Provers use and fibroid development. DMPA use for at least 10 months within 2 years of a study visit was associated with a 40% lower fibroid incidence (adjusted hazard ratio 0.6, 95% Confidence Interval (CI) 0.3, 1.0) and 45% lower fibroid growth (95% CI -54, -33) compared to other women. Recent use of DMPA was also associated with increased likelihood of fibroid shrinkage (adjusted relative risk (aRR) 2.1, 95% CI 1.5, 3.0) and increased fibroid loss (aRR 1.5, 95% CI 1.1, 2.2). These beneficial side-effects of a commonly used contraceptive has the potential to limit fibroid progression and delay surgery. are less likely to have incident fibroids. There is also a clear indication of lower growth rates among users. A manuscript describing these results is being drafted. For our analyses of the most common reproductive tract infections and fibroid development, we have used biomarkers of exposures using blood and vaginal swab samples collected at baseline. Serological evidence of genital herpes is based on a type-specific assay to qualitatively detect genital herpes (HSV-2) immunoglobulin G antibodies regardless of the presence of HSV-1. Assessment of Chlamydia infection history was also based on a serological assay, the gold-standard micro-immunofluorescence assay measures titer levels for immunoglobulin G antibodies to Chlamydia trachomatis, the infectious agent. Assessment of bacterial vaginosis was based on the standard research criterion, Nugent scoring of vaginal bacteria, derived from our vaginal swab samples. In our analyses of these exposures with our longitudinal fibroid data, we found no associations with either fibroid incidence or growth for either genital herpes or bacterial vaginosis. The analyses for Chlamydia are ongoing. 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 are investigating endocrine disrupting chemical exposures and fibroid development. The Boston Group has measured several potential endocrine disruptors. At the concentrations observed, the data show no convincing evidence that these chemicals are increasing fibroid incidence.