Uterine Leiomyomas

子宫肌瘤

• 批准号: 10924938
• 负责人: DONNA D. BAIRD
• 金额: $ 135.99万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10924938
• 关键词: Address; African; African American; African ancestry; Age; Animal Model; Area; Bacterial Vaginosis; Benign; Biometry; Black Populations; Blood specimen; Body mass index; Boston; Cell Survival; Chemicals; Chlamydia; Chromosome abnormality; Clinic Visits; Collaborations; Contraceptive Agents; Contraceptive Usage; Cytogenetics; DNA; Data; Data Files; Depo Provera; Development; Diagnosis; Diameter; Endocrine Disruptors; Enrollment; Environment; Epidemiology; Estrogens; Ethnic Population; European; Exclusion Criteria; Extramural Activities; Fertility; Fibroid Tumor; Frequencies; Funding; Genistein; Genotype; Goals; Growth; Growth and Development function; Haplotypes; Health; Health system; Herpesviridae Infections; Histologic; Hormonal; Hormonal Change; Hormones; Hysterectomy; Incidence; Incidence Study; Infant formula; Inflammatory; Injectable; Investigation; Laboratories; Lesion; Life; Life Style; Magnetic Resonance Imaging; Measurable; Measurement; Measures; Medical Care Costs; Methods; Michigan; Mitochondria; Modeling; Monitor; Morbidity - disease rate; Mutation; National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Normal Range; North Carolina; Operative Surgical Procedures; Participant; Phytoestrogens; Postmenopause; Postpartum Period; Prevalence; Progesterone; Progestins; Prospective Studies; Psychosocial Factor; Puberty; Publications; Publishing; Reporting; Reproductive Tract Infections; Research; Research Personnel; Resources; Risk; Risk Factors; Sampling; Sampling Studies; Serology; Serum; Sleep; Smooth Muscle Tumor; Societies; Somatic Mutation; Statistical Data Interpretation; Study models; Suggestion; Supplementation; Swab; Symptoms; Testing; Time; Tissues; Tumor Tissue; United States; Universities; Urine; Uterine Fibroids; Uterus; Vagina; Variant; Visit; Vitamin D; Vitamin D Deficiency; Whole Blood; Woman; aged; black women; circulating biomarkers; clinical diagnosis; cohort; design; detection limit; early onset; epidemiology study; feeding; follow-up; genital herpes; high body mass index; interest; meetings; ovarian reserve; personal care products; prospective; rapid growth; reproductive tract; research study; side effect; soy; survivorship; tumor; tumorigenesis; ultrasound

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.

子宫肌瘤（纤维瘤）是美国子宫切除术的主要适应症。尽管与肌瘤相关的发病率和高昂的医疗费用，但对这种情况的流行病学研究却很少。子宫肌瘤在组织学上可识别为良性平滑肌肿瘤，具有不同数量的相关纤维组织。许多女性患有不止一种子宫肌瘤，但每一种似乎都具有克隆特征。在大多数肿瘤中发现的 MED12 体细胞突变可能是肿瘤发生的触发因素。在肿瘤组织中也发现了几种特定的细胞遗传学变化，但大多数肿瘤没有表现出染色体异常。这些良性肿瘤具有激素依赖性。它们在青春期后发展，并在更年期后消退。雌激素和孕激素都被认为对肿瘤的发育和生长很重要，但孕激素可能是必需的。 为了满足该领域的研究需求，我们设计了四项研究：NIEHS 子宫肌瘤研究、肌瘤生长研究和产后子宫回归研究，以及第四项研究，这是我们肌瘤组当前的主要焦点。 2010 年和 2012 年，我们与亨利·福特医疗系统合作，在密歇根州底特律地区的环境、生活方式和肌瘤研究 (SELF) 中招募了近 1700 名 23-34 岁的非裔美国女性。任何先前的肌瘤诊断都是排除标准。参与者在入组时通过超声筛查肌瘤（病变检测限 = 0.5 厘米直径）。随后每隔大约 20 个月进行 3 次临床就诊，通过超声检查监测肌瘤以确定发病时间。以相同的方式跟踪入组时检测到的肌瘤（新检测到的，以前未临床诊断的）以及研究期间出现的肌瘤，以评估肌瘤的生长。五年来，我们在入组时以及每次 20 个月的访视时收集了风险因素和症状数据。 鉴于研究有限，SELF 旨在收集广泛的暴露数据，而不仅仅是普遍认为与肌瘤发展相关的少数因素。收集详细数据来检验三个主要假设：(1) 生殖道感染是肌瘤的危险因素，(2) 维生素 D 缺乏是肌瘤的危险因素，(3) 较高比例的非洲血统与肌瘤风险增加相关（非洲血统通过已知在欧洲人和非洲人之间具有不同频率的信息丰富的 SNP 来测量）。我们已经完成了第三次也是最后一次后续行动的参与者访问。我们对 5 年随访的参与率为最初入组者的 90%。我们开发了用于前瞻性肌瘤发病率和生长分析的纵向数据文件。在生物统计学的支持下，我们开发了生存方法来研究暴露对肌瘤发病率的影响，并开发了混合模型回归方法来检查对肌瘤生长的影响。 使用基线和首次随访超声数据，我们首次描述了超声检测到的肌瘤发病率（在最近记录的无肌瘤子宫中检测到的新肌瘤）的年龄特异性测量，并发现发病率随着年龄的增长而增加。根据横截面肌瘤患病率数据建模的估计，30 岁之前的发病率相对较高，这支持了之前报道的黑人比白人更早发生肌瘤的观点。与发病率不同，肌瘤的生长会随着年龄的增长而减少，即使在调整了肌瘤大小的生长变化后（较小的肌瘤平均比较大的肌瘤生长更快）。 我们已经完成了对注射避孕药 Depo Provera 的使用和肌瘤发展的详细调查。最近的使用与减少发病率和生长以及肌瘤损失的显着增加有关。常用避孕药的这些有益副作用有可能限制子宫肌瘤的进展并延迟（甚至可能消除）子宫切除术等侵入性手术的需要。我们目前正在研究激素宫内节育器（另一种孕激素暴露）的使用及其与肌瘤发展的关系。 我们已经完成了对几种生殖道暴露的分析（血清学记录的衣原体和生殖器疱疹感染，以及通过阴道拭子样本的细菌评估测量的细菌性阴道病）。没有发现任何一种会增加肌瘤的发展，这表明这一长期存在的假设不太可能解释美国黑人女性与白人女性相比肌瘤负担增加的原因。 研究发现，婴儿早期配方奶粉喂养中含有大量植物雌激素，与子宫肌瘤发病率增加有关。这支持了先前基于主要大豆植物雌激素金雀异黄酮的实验室和动物模型研究的预测。 我们对维生素 D 的分析和对肌瘤发展的前瞻性监测的结果已经发表。尽管我们的大多数研究样本维生素 D 不足，但我们能够检测到肌瘤生长减少了近 10%，并且表明循环 D 生物标志物浓度较高的人群中肌瘤减少更多，发病率降低。为了测试充足维生素 D 的效果，有必要进行补充试验。 我们仔细分析了 BMI 和肌瘤发病率和生长的纵向数据，研究结果已在最近的流行病学协会会议上提出并提交出版。我们发现了一种非线性关联：与BMI<25（正常范围）的人相比，BMI为30-35的人肌瘤发病率显着升高，但BMI为40或以上的人肌瘤发病率降低。与增长的关联很弱，而且太不精确，无法得出结论。这是第一项研究如此大范围的体重指数的研究。 BMI 对突变率和细胞存活的炎症影响（已知随 BMI 升高而变化）可能是非线性关联的重要驱动因素。此外，高体重指数导致的荷尔蒙变化也可能起到一定作用。 我们完成了研究样本中 DNA 样本的基因分型，并开始检查与肌瘤发育相关的祖先和线粒体单倍型。 NICHD 的 Fasil Tekola-Ayele 博士正在合作开展该项目。 SELF 已成为其他研究人员的资源。 NIEHS 的合作者 Jukic 博士和 Jackson 博士利用 SELF 数据来研究他们各自在生育/卵巢储备和睡眠方面的研究兴趣。 NTP 的凯拉·泰勒 (Kyla Taylor) 正在检查该研究中的个人护理产品数据。三个研究小组拥有外部资金，用于与 SELF 进行附加研究。波士顿大学的 Lauren Wise 和 Henry Ford Health 的 Ganesa Wegienka 完成了额外的超声随访，将随访时间从 5 年延长到 7-8 年。完整的随访数据已用于直接测量二十岁出头至三十岁末女性的特定年龄肌瘤发病率。这是肌瘤研究的首次。美国其他族裔群体也需要此类数据。校外合作者从储存的尿液、血清和全血样本中测量了几种内分泌干扰物，以检查这些暴露对子宫肌瘤发病率的影响。鉴于该研究组普遍缺乏此类数据，因此进行了初步分析以描述该队列中这些暴露的相关性。观察到的浓度几乎没有或没有令人信服的证据表明是纤维瘤发展的重要驱动因素，但正在对化学混合物进行进一步分析。北卡罗来纳大学教堂山分校的 Anissa Vines 将研究心理社会因素和子宫肌瘤的发展。

项目成果

IGF-I and IGFBP-3 polymorphisms in relation to circulating levels among African American and Caucasian women.

• DOI: 10.1158/1055-9965.epi-08-0856
• 发表时间: 2009-03
• 期刊: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
• 作者: D'Aloisio AA;Schroeder JC;North KE;Poole C;West SL;Travlos GS;Baird DD
• 通讯作者: Baird DD

Genital Chlamydia trachomatis Seroprevalence and Uterine Fibroid Development: Cohort Study of Young African-American Women.

• DOI: 10.3390/microorganisms10010010
• 发表时间: 2021-12-22
• 期刊: Microorganisms
• 影响因子: 4.5
• 作者: Moore K;Baird D
• 通讯作者: Baird D

Disparities by Skin Color Among Young African-American Women.

• DOI: 10.1007/s40615-020-00856-x
• 发表时间: 2021-08
• 期刊: Journal of racial and ethnic health disparities
• 影响因子: 3.9
• 作者: Moore KR;Williams DR;Baird DD
• 通讯作者: Baird DD

Genome-wide analysis of loss of heterozygosity and copy number amplification in uterine leiomyomas using the 100K single nucleotide polymorphism array.

• DOI: 10.1016/j.yexmp.2011.03.007
• 发表时间: 2011-08
• 期刊: EXPERIMENTAL AND MOLECULAR PATHOLOGY
• 影响因子: 3.6
• 作者: Meadows, Kellen L.;Andrews, Danica M. K.;Xu, Zongli;Carswell, Gleta K.;Laughlin, Shannon K.;Baird, Donna D.;Taylor, Jack A.
• 通讯作者: Taylor, Jack A.

Vitamin d and the risk of uterine fibroids.

维生素 D 和子宫肌瘤的风险。

• DOI: 10.1097/ede.0b013e31828acca0
• 发表时间: 2013-05
• 期刊: Epidemiology (Cambridge, Mass.)
• 作者: Baird DD;Hill MC;Schectman JM;Hollis BW
• 通讯作者: Hollis BW