Epidemiology of Uterine Fibroids: From Menarche to Menopause.
ABSTRACT: Uterine leiomyomata (UL) have a substantial impact on women's health, but relatively few studies have identified opportunities for primary prevention of these neoplasms. Most established risk factors are not modifiable, including premenopausal age, African ancestry, age at menarche, and childbearing history. The main challenge in studying UL is that a large proportion of tumors are asymptomatic. Herein, we review the epidemiology of UL from published studies to date. We highlight the advantages of ultrasound screening studies and the ways in which their innovative methods have helped clarify the etiology of disease. We conclude with a discussion of promising new hypotheses.
Project description:Uterine leiomyomata (UL) are the most common female pelvic tumors and the primary indication for hysterectomy in the United States. We assessed genetic liability for UL by a known embryonic proliferation modulator, HMGA2, in 248 families ascertained through medical record-confirmed affected sister-pairs. Using a (TC)( n ) repeat in the 5' UTR and 17 SNPs spanning HMGA2, permutation-based association tests identified a significant increase in transmission of a single TC repeat allele (TC227) with UL (allele-specific P = 0.00005, multiple testing corrected min-P = 0.0049). The hypothesis that TC227 is a pathogenic variant is supported by a trend towards higher HMGA2 expression in TC227 allele-positive compared with non-TC227 UL tissue as well as by absence of culpable exonic sequence variants. HMGA2 has also been suggested recently by three genome-wide SNP studies to influence human height variation, and our examination of the affected sister-pair families revealed a significant association of TC227 with decreased height (allele-specific P = 0.00033, multiple testing corrected min-P = 0.016). Diminished stature and elevated risk of UL development have both been correlated with an earlier age of menarche, which may be the biological mechanism for TC227 effects as a tendency of women with TC227 to have an earlier onset of menarche was identified in our study population. These results indicate HMGA2 has a role in two growth-related phenotypes, UL predisposition and height, of which the former may affect future medical management decisions for many women.
Project description:To investigate uterine leiomyomata (UL) incidence in relation to polymorphisms in genes involved in vitamin D metabolism and skin pigmentation. Rates of UL are 2-3 times higher in African Americans than in European Americans. Recent studies suggest that vitamin D deficiency is associated with an increased risk of UL.Nested case-control study.Not applicable.Two thousand two hundred thirty-two premenopausal women first diagnosed with UL confirmed by ultrasound or surgery during 1997-2011 (cases) and 2,432 premenopausal women never diagnosed with UL through 2011 (controls).None.Self-reported UL. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between each polymorphism and UL, controlling for age, geographic region, and ancestry.Three of 12 polymorphisms were associated with UL at the nominal significance level: rs4944957 and rs12800438 near DHCR7 and rs6058017 in ASIP. After correction for multiple hypothesis testing, two single nucleotide polymorphisms remained significantly associated with UL (rs12800438 and rs6058017). Compared with the AA genotype for rs12800438 (correlated with higher serum 25[OH]D levels), ORs were 1.09 (95% CI, 0.92, 1.29) and 1.23 (95% CI, 1.03, 1.47) for the GA and GG genotypes, respectively. Compared with the AA genotype for rs6058017 (correlated with lighter skin pigmentation), ORs were 1.01 (95% CI, 0.83, 1.22) and 1.18 (95% CI, 0.97, 1.44) for the GA and GG genotypes, respectively.Our data support the hypothesis that vitamin D deficiency is involved in UL etiology.
Project description:Age at menarche (AAM) is an important marker of the pubertal development and function of the hypothalamic-pituitary-ovarian system. It was reported as a possible factor for a risk of uterine leiomyoma (UL). However, while more than 350 loci for AAM have been determined by genome-wide association studies (GWASs) to date, no studies of these loci for their association with UL have been conducted so far. In this study, we analyzed 52 candidate loci for AAM for possible association with UL in a sample of 569 patients and 981 controls. The results of the study suggested that 23 out of the 52 studied polymorphisms had association with UL. Locus rs7759938 <i>LIN28B</i> was individually associated with the disease according to the dominant model. Twenty loci were associated with UL within 11 most significant models of intergenic interactions. Nine loci involved in 16 most significant models of interactions between single-nucleotide polymorphism (SNP), induced abortions, and chronic endometritis were associated with UL. Among the 23 loci associated with UL, 16 manifested association also with either AAM (7 SNPs) or height and/or body mass index (BMI) (13 SNPs). The above 23 SNPs and 514 SNPs linked to them have non-synonymous, regulatory, and expression quantitative trait locus (eQTL) significance for 35 genes, which play roles in the pathways related to development of the female reproductive organs and hormone-mediated signaling [false discovery rate (FDR) ? 0.05]. This is the first study reporting associations of candidate genes for AAM with UL.
Project description:Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.Breast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons).The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.Cancer Research UK.
Project description:The plexiform variant of uterine leiomyomata (UL) is named for its ribbons or nests of smooth muscle cells that have a rounded, epithelioid shape caused by their entrapment in abundant extracellular matrix. Plexiform UL are currently classified as epithelioid smooth muscle tumors alongside the less predictable, "true" epithelioid tumors (ie, leiomyoblastomas). Karyotypes of six plexiform UL cases were studied, and their abnormalities were found to differ from those of leiomyoblastomas. Analyses using real-time polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization demonstrated elevated mRNA and protein levels of the architectural factor HMGA2 and, in some cases, increased DNA copy number. Four of these plexiform UL were profiled with Affymetrix human U133 plus 2.0 expression arrays. Cluster analysis using genes previously shown to discriminate benign and malignant uterine smooth muscle tissues revealed that the plexiform tumors form an isolated group in the benign branch. This is in contrast to an earlier finding in which another variant, cellular UL characterized by loss of a portion of the short arm of chromosome 1, clustered with malignant leiomyosarcomas. These results provide additional evidence of genetic heterogeneity underlying UL of various histological types. We further suggest that plexiform UL should be classified among tumors with extensive hyalinization rather than with "true" epithelioid smooth muscle neoplasms.
Project description:Uterine leiomyomata (UL) are associated with severe reproductive morbidity and are the primary indication for hysterectomy in the United States. A recent prospective cohort study of Black women reported positive associations between intakes of marine-sourced ?-3 fatty acids and UL risk. We examined whether intakes of dietary fat were associated with UL incidence in a 5-year prospective study of premenopausal Black women living in Detroit who underwent serial ultrasound. At baseline (2010-2012) and 20, 40, and 60 months of follow-up, participants underwent transvaginal ultrasound. Among 1,171 UL-free women at baseline, incident UL were detected in 277 women. Cox regression was used to estimate hazard ratios and 95% confidence intervals for the association of dietary fat and UL incidence. Intakes of total fat and saturated, monounsaturated, polyunsaturated, and trans-fat were not appreciably associated with UL incidence. Intake of the marine ?-3 polyunsaturated fatty acid, docosahexaenoic acid, was associated with 49% higher UL incidence (quartile 4 vs. 1: hazard ratio = 1.49, 95% confidence interval: 1.04, 2.14; P for trend = 0.01). Intakes of total marine ?-3 polyunsaturated fatty acids were similarly associated with elevated UL incidence (hazard ratio = 1.35, 95% confidence interval: 0.94, 1.93; P for trend = 0.03). It remains unclear whether the fatty acids or persistent environmental pollutants drive the association.
Project description:Uterine fibroids (UFs) are benign tumors that arise from a single genetically altered mesenchymal stem cell under the influence of gonadal hormones. UFs are the most common benign gynecologic tumors in premenopausal women worldwide. It is estimated that nearly 70% to 80% of women will develop UFs at some point during their lifetime. UFs often present with abnormal uterine bleeding (AUB), pelvic fullness, and may have deleterious effects on fertility. The natural regression of UFs begins in menopause. This is, however, a generality as this pathology may still be present in this age group. Many clinicians are concerned about hormone therapy (HT) because of UFs regrowth; nevertheless, research of this subject remains inconclusive. If UFs are present in perimenopause or menopause, they typically manifest as AUB, which represents up to 70% of all gynecological consultations in perimenopausal and postmenopausal women. As AUB is a broad symptom and may not be specific to UFs, a thorough evaluation is required for correct diagnosis and proper treatment accordingly. Understanding the unique characteristics of the available treatment modalities is crucial in deciding the appropriate treatment approach. Decision on treatment modality should be made based on selection of the least morbidity and lowest risk for each patient. Multiple modalities are available; however, surgery remains the method of choice, with the best cure rates. Various attempts to create an inexpensive, safe, and effective drug for the treatments of UFs are still in the early stages of the clinical trials with some showing great promise. Treatment options include tibolone, aromatase inhibitors, selective estrogen receptor modulators, uterine artery embolization, and selective progesterone receptor modulators.
Project description:To replicate results from a previous genome-wide association study of European ancestry women, in which a positive association was found between uterine leiomyomata (UL) and rs4247357, a single-nucleotide polymorphism located near the fatty acid synthase (FASN) gene.Prospective cohort study.Not applicable.African-American women aged 23-50 years, who were premenopausal and had an intact uterus in 1997.None.We genotyped rs4247357 among 2,301 incident UL cases and 3,005 controls from the Black Women's Health Study (1997-2011). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression with control for age, geographic region of residence, and percent European ancestry using a panel of validated ancestry informative markers.Overall, rs4247357 was not associated with UL risk. Relative to the CC genotype, ORs were 1.04 (95% CI 0.92-1.19) for the AC genotype and 1.09 (95% CI 0.93-1.29) for the AA genotype. A positive association was found, however, among those with higher European ancestry (?40%). Relative to the CC genotype, ORs were 2.03 (95% CI 1.12-3.69) for the AC genotype and 2.44 (95% CI 1.20-4.96) for the AA genotype. Dietary fat intake also appeared to modify the FASN-UL association.Although there was little overall association between rs4247357 and UL risk, a positive association was observed among women with ?40% European ancestry. Direct sequencing of this genomic region might be warranted to determine whether rs4247357, or some other variant, is causally related to UL.
Project description:Uterine leiomyomata (ULs) represent the most common tumor in women and can cause abnormal uterine bleeding, large pelvic masses, and recurrent pregnancy loss. Although the dependency of UL growth on ovarian steroids is well established, the relative contributions of 17beta-estradiol and progesterone are yet to be clarified. Conventionally, estradiol has been considered the primary stimulus for UL growth, and studies with cell culture and animal models support this concept. In contrast, no research model has clearly demonstrated a requirement of progesterone in UL growth despite accumulating clinical evidence for the essential role of progesterone in this tumor. To elucidate the functions of ovarian steroids in UL, we established a xenograft model reflecting characteristics of these tumors by grafting human UL tissue beneath the renal capsule of immunodeficient mice. Leiomyoma xenografts increased in size in response to estradiol plus progesterone through cell proliferation and volume increase in cellular and extracellular components. The xenograft growth induced by estradiol plus progesterone was blocked by the antiprogestin RU486. Furthermore, the volume of established UL xenografts decreased significantly after progesterone withdrawal. Surprisingly, treatment with estradiol alone neither increased nor maintained the tumor size. Although not mitogenic by itself, estradiol induced expression of progesterone receptor and supported progesterone action on leiomyoma xenografts. Taken together, our findings define that volume maintenance and growth of human UL are progesterone dependent.
Project description:Previous studies have found an association between uterine leiomyomata (UL) and uterine malignancies. This relation has not been studied in black women, who are disproportionately affected by UL.We investigated prospectively the association between self-reported physician-diagnosed UL and endometrial cancer in the Black Women's Health Study. During 1995-2013, 47,267 participants with intact uteri completed biennial health questionnaires. Reports of endometrial cancer were confirmed by pathology data from medical records and cancer registries. Cox regression was used to derive incidence rate ratios (IRR) and 95% confidence intervals (CI).There were 300 incident endometrial cancer cases during 689,546 person-years of follow-up. In multivariable models, UL history was associated with a 42% greater incidence of endometrial cancer compared with no such history (95% CI 1.12-1.80). IRRs for cancer diagnosed 0-2, 3-9, and ?10 years after UL diagnosis were 3.20 (95% CI 2.06-4.98), 0.95 (95% CI 0.60-1.52), and 1.35 (95% CI 1.03-1.77), respectively. Stronger overall associations between UL history and endometrial cancer were observed for later stages at cancer diagnosis (IRR = 2.25, 95% CI 1.09-4.63) and type II/III cancers (IRR = 3.13, 95% CI 1.64-5.99).In this large cohort of black women, a history of UL was positively associated with endometrial cancer, particularly type II/III tumors. The strongest association was observed for cancer diagnosed within 2 years of UL diagnosis, a finding that might be explained by greater surveillance of women with UL or misdiagnosis of cancer as UL. However, an association was also observed for cancer reported ?10 years after UL diagnosis.