Uterine Leiomyomas

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

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 somatic mutations, found in the majority of tumors, 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 for tumor development and growth, but progesterone is likely required.. 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. Given the limited research, SELF was designed to collect a broad spectrum of exposure data beyond the few factors generally-accepted to be associated with fibroid development. Detailed data were collected to test three primary hypotheses: (1) Reproductive tract infections are risk factors for fibroids, (2) Vitamin D deficiency is a risk factor 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 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 have developed longitudinal data files for the prospective fibroid incidence and growth analyses. With biostatistical support, we have developed survivorship methods for investigating exposure effects on fibroid incidence and a mixed model regression approach to examine effects on fibroid growth. Using the baseline and first follow-up ultrasound data, we described age-specific measures of ultrasound-detected fibroid incidence (new fibroid detected in a recently documented fibroid-free uterus) for the first time, and found that incidence with increased with age. The relatively high incidence before age 30 supports the previously reported earlier onset of fibroids in Blacks compared to Whites based on estimates modeled from cross-sectional fibroid prevalence data. Unlike incidence, fibroid growth decreases with age, even after adjusting for the demonstrated variation in growth by fibroid size (smaller fibroids have more rapid growth on average than larger fibroids). We have completed a detailed investigation of use of the injectable contraceptive, Depo Provera, and fibroid development. Recent use is associated with reduced incidence and growth with measurable increase in loss of fibroids. These beneficial side-effects of a commonly used contraceptive has the potential to limit fibroid progression and delay (and perhaps even eliminate) the need for invasive surgeries such as hysterectomy. We are currently examining use of the hormonal IUD (another progestin exposure) and its association with fibroid development. We have completed analyses of several reproductive tract exposures (serologically documented Chlamydia and genital herpes infections, as well as bacterial vaginosis as measured by bacterial assessment of vaginal swab samples). None were found to increase fibroid development, suggesting that this long-standing hypothesis is unlikely to explain the increased fibroid burden seen in Black women compared to White women in the U.S. Early life infant formula feeding with it's known high phytoestrogen exposure was found to be associated with increased fibroid incidence. This supports the prior predictions based on laboratory and animal model studies with the primary soy phytoestrogen, genistein. Our findings from our analyses of vitamin D and prospectively monitored fibroid development has been published. Despite the majority of our study sample having insufficient vitamin D, we were able to detect a nearly 10% decrease in fibroid growth and the suggestion of both more fibroid loss and reduced incidence among those with higher concentrations of biomarker for circulating D. To test effects of sufficient vitamin D, a trial with supplementation is warranted. We have carefully analyzed our longitudinal data on BMI and fibroid incidence and growth, and the findings have been presented at recent Epidemiology Society meetings and submitted for publication. We found a non-linear association: compared to those with BMIs <25 (the normal range), those with BMIs of 30-35 had significantly elevated fibroid incidence, but those with BMIs at 40 or above had reduced incidence. Associations with growth were weak, and too imprecise to draw conclusions. This is the first study to examine such a large range of BMIs. The inflammatory effects of BMI on mutations rates and cell survival, known to vary by BMI elevation, may be important drivers of the nonlinear association. In addition, hormonal changes with high BMI may play a role. We completed genotyping the DNA samples from our study sample, and have begun examining both ancestry and mitochondrial haplotypes in relation to fibroid development. Dr. Fasil Tekola-Ayele at NICHD is collaborating on this project. SELF has become a resource for other researchers. NIEHS collaborators, Dr. Jukic and Dr. Jackson, have utilized SELF data for their respective research interests in fertility/ovarian reserve and sleep. Kyla Taylor in the NTP is examining personal care product data from the study. Three research groups have extramural funding for add-on studies with SELF. Lauren Wise, at Boston University, along with Ganesa Wegienka at Henry Ford Health have completed an additional follow-up ultrasound, extending the follow-up time from our 5-year period to a 7-8 year follow-up. The full follow-up data have been used to directly measure age-specific fibroid incidence among women from their early twenties to late 30s. This is a first for fibroid research. Such data are needed for other ethnic groups in the US. The extramural collaborators have measured several endocrine disruptors from stored urine, serum, and whole-blood samples to examine the effects of these exposures on fibroid incidence. Initial analyses were conducted to describe correlates of these exposures in this cohort, given the general lack of such data in this understudied group. The concentrations observed have shown little or no convincing evidence for being important drivers of fibroid development, but further analyses with chemical mixtures is being done. Anissa Vines at the University of North Carolina at Chapel Hill will be examining psychosocial factors and fibroid development.