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 less commonly. These benign tumors are hormone-dependent, with development after puberty and regression after menopause. Both estrogen and progesterone are considered important for tumor development and growth. To address the research needs in this field in 2010-2012 we enrolled nearly 1700 African American women, aged 23-35, in the Study of Environment, Lifestyle & Fibroids (SELF), based in the Detroit, Michigan area with collaboration from Henry Ford Health. Any prior diagnosis of fibroids was an exclusion criterion. Participants were screened for fibroids >= 0.5 cm in diameter at the enrollment ultrasound. There were three subsequent DIR-supported 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. A subsequent follow-up visit with similar data collection has been completed in 2024 with NIEHS extramural funding to collaborators at Henry Ford Health and Boston University. An additional study visit (5th follow-up) has begun (>150 participant visits completed) with 1-year of extramural funding, but further funding is needed for completion of this follow-up. Given the limited existing fibroid 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 developed longitudinal data files for the prospective fibroid incidence and growth analyses through the 4th visit, and 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. Our detailed investigation of use of the injectable contraceptive, Depo Provera, and fibroid development indicated that recent use is associated with reduced incidence and growth as well as increased loss of fibroids. These beneficial side-effects of a commonly used contraceptive have 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 estrogen containing hormonal contraceptive pills and their association with fibroid development over 5 years. 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 its 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. Vitamin D, measured by serum 25(OH)D concentrations, was generally low among SELF participants, yet despite this, we detected a nearly 10% reduction in fibroid growth and the suggestion of both more fibroid loss and reduced incidence among those with higher concentrations. To test effects of sufficient vitamin D, a trial with supplementation is warranted. Longitudinal data on BMI and fibroid incidence and growth, revealed 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 the degree of BMI elevation, may be important drivers of the nonlinear association. In addition, hormonal changes with high BMI may play a role. Family history has been recognized as a risk factor for uterine fibroids. Using data collected from SELF participants mothers (88%) we assessed the association between maternal history of fibroid diagnosis, including age at diagnosis, and fibroid incidence in the participants. We found a 20% increased incidence of fibroids among participants with a maternal history of fibroid diagnosis, which was strongest (50% increase) among those whose mothers were diagnosed before age 30. We completed genotyping the DNA samples from our study sample, and we find little association between degree of African ancestry and fibroid development. Risk alleles that have been reported in the literature are also being examined and we are developing a polygenic risk score to predict early onset of uterine fibroids. Dr. Fasil Tekola-Ayele at NICHD is collaborating on this project. SELF has become a resource for Dr. Jukic’s and Dr. Jackson’s respective research interests in fertility/ovarian reserve and sleep. Dr. Jackson’s group has used SELF data to examine multiple association with sleep health including: psychosocial stressors and coping mechanisms, skin tone as a marker of colorism, and childhood neighborhood safety. Dr Jukic’s group has examined associations between vitamin D concentrations and a marker of ovarian reserve (anti-Müllerin hormone) and is currently analyzing associations between vitamin D and menstrual cycle length. At the most recent visit SELF will be collecting additional sleep data (including chronotype) and will be asking details about use of infertility care and time to pregnancy. These new data will expand the research opportunities for Dr. Jukic and Dr. Jackson who are now co-PIs on SELF. Dr. Kyla Taylor in the DTT is examining personal care product data from the study including patterns of use and associations with measured concentrations of endocrine disrupting chemicals. Kristen Upson, at Michigan State, is examining cadmium exposure and fibroid development. Extramural funding has provided for additional SELF research (Ganesa Wegienka at Henry Ford Health, Lauren Wise at Boston University, Anissa Vines at University of North Carolina at Chapel Hill). Dr. Vines examined associations of psychosocial factors and early life disadvantage with fibroid development. The extended follow-up data have been used by Dr. Wegienka to directly measure age-specific fibroid incidence among women from their early twenties to late 30s, a first for fibroid research. Such data are needed for other ethnic groups in the US. Drs Wise and Wegienka have measured several endocrine disruptors from stored urine, serum, plasma, and whole-blood samples to examine the effects of these exposures on fibroid development. Initial analyses were conducted to describe correlates of these exposures in this cohort, given the general lack of such data in young African American women. PFAS chemicals have been assessed by metabolomic analyses which allow identification of a much broader set of PFAS for examining possible associations with fibroid development.