Risk Of Uterine Leiomyoma Research Articles

Polymorphism of catechol-o-methyltransferase and uterine leiomyoma

Uterine leiomyoma (ULM) is the most common gynecological benign tumor that is affecting around 20-50 % of women over the age of 30. Although its molecular pathogenesis is still unknown, ULM has a multifactorial etiology determined by both genetics and environmental factors. The present study was designed to find out whether Val158Met polymorphism in the catechol-o-methyltransferase (COMT) gene is associated with the risk of ULM. We analyzed COMT Val158Met polymorphism in 105 ULMs patients and 105 healthy subjects using a polymerase chain reaction-based restriction fragment length polymorphism assay. We found remarkably similar frequencies in ULM compared with controls for COMT Val158Met genotypes and alleles, and no association was found between ULM and this polymorphism (p = 0.46). The COMT 158 Met allele in patients with large (≥5 cm) fibroids was higher than in patients with small (<5 cm) fibroids, and significant association was found between fibroid size and COMT 158 Met allele (p = 0.011, OR 0.50, 95 %CI 0.28-0.90). Our results reflect that COMT Val158Met polymorphism is not associated with an increased risk of ULMs, but Val158Met polymorphism may be a risk factor for development of large fibroids in Turkish patients with ULM.

Genetic Testing by Cancer Site

This review article discusses hereditary cancer predisposition syndromes with uterine manifestations. Lynch syndrome accounts for 2% to 3% of endometrial cancers. The identification of endometrial cancer patients at risk for Lynch syndrome is discussed, as are the characteristics of Lynch syndrome-associated endometrial cancer and the screening and prevention options for women at risk for Lynch syndrome-associated endometrial cancer. Endometrial cancer associated with PTEN hamartoma tumor syndrome (also known as Cowden syndrome) is also discussed. HLRCC (hereditary leiomyomatosis and renal cell carcinoma), which has an associated high risk of symptomatic uterine leiomyomas, is reviewed.

Polymorphisms in genes HSD17B1 and HSD17B2 and uterine leiomyoma risk in Chinese women

To evaluate the association of HSD17B1 and HSD17B2 gene polymorphisms with uterine leiomyoma in Chinese women. 121 Chinese women with clinically diagnosed uterine leiomyoma and 217 healthy normal Chinese women were investigated to compare three single nucleotide polymorphisms (SNPs) (rs605059 and rs676387 of HSD17B1 gene and rs8191246 of HSD17B2 gene) by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing method. All the SNPs were polymorphisms in Chinese women. Frequencies of rs605059 AA genotype and A allele were significantly increased in patients with uterine leiomyoma compared to healthy controls (GG vs. AA, OR 0.40, 95% CI 0.20-0.82; G vs. A, OR 0.68, 95% CI 0.50-0.94). The results suggest that the genotype of HSD17B1 rs605059 may play a role in the tumourgenesis of uterine leiomyoma.

P1-417 Does life-course socioeconomic position explain colour/race inequalities in the prevalence of self-reported uterine leiomyomas? Evidence from the prÓ-saÚde study, Brazil

IntroductionUSA studies showed that uterine leiomyomas (UL) occur more frequently among black women, but the nature of this association remains largely unexplained. Because black women are disproportionately disadvantaged in social...

Abuse in Childhood and Risk of Uterine Leiomyoma

Childhood adversities are associated with adult health. We hypothesize that exposure to physical and sexual abuse in childhood and adolescence will be associated with incidence of clinically symptomatic uterine leiomyomas (fibroids) through influences on health behaviors and reproductive hormone regulation. Participants included 68,505 women enrolled in the Nurses' Health Study II, an ongoing prospective cohort study of premenopausal women from 14 US states aged 25-42 years at enrollment (1989), who completed a retrospective questionnaire on childhood violence exposure (2001). A cumulative indicator of severity and chronicity of child/teen violence exposure was derived using factor analysis. We used a Cox proportional-hazards model to estimate the incidence rate ratios (IRRs) and 95% confidence intervals (CIs). During the 728,865 woman-years of follow-up (1989-2005), 9823 incident diagnoses of ultrasound- or hysterectomy-confirmed uterine leiomyomas were reported; 65% reported any physical or sexual abuse. A dose-response association between cumulative abuse and fibroid risk was found. Compared with those who reported no abuse, multivariable IRRs for ultrasound or hysterectomy-confirmed uterine leiomyomas were 1.08 (95% CI = 1.03-1.13), 1.17 (1.10-1.24), 1.23 (1.14-1.33), 1.24 (1.10-1.39), and 1.36 (1.18-1.54), for cumulative exposures ranging from mildest to most severe. Increased emotional support in childhood also attenuated associations. Severity and chronicity of child/teen sexual and physical abuse was associated with increasing risk of clinically detected fibroids among premenopausal women.

Is genetic polymorphism of ER-α, CYP1A1, and CYP1B1 a risk factor for uterine leiomyoma?

Uterine leiomyoma is the most common benign smooth muscle tumor. This study was carried out to evaluate the association of ER-α, CYP1A1, and CYP1B1 polymorphisms with uterine leiomyoma in Egyptian women. The study population consisted of 160 patients with uterine leiomyoma and 100 healthy women as control. The genetic polymorphisms for ER-α MSP1 exon 1, CYP1B1 Leu432Val, and CYP1A1 Ile462Val were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods. There were no statistically significant differences in the overall associations between the ER-α exon I CT genotypes and uterine leiomyoma (P = 0.47). However, an elevated risk of uterine leiomyoma was observed among women with the CYP1A1 Ile462Val AG genotype (P = 0.07) and CYP1B1 Leu 432Val C/C genotype (P = 0.08). We concluded that the carriage of CYP1A1 Ile462Val AG and CYP1B1 Leu 432Val CC genotypes predict the susceptibility to leiomyoma in Egyptian women and they are likely to contribute in the pathogenesis of leiomyoma.

Dietary glycemic index and load in relation to risk of uterine leiomyomata in the Black Women’s Health Study

High dietary glycemic index (GI) and glycemic load (GL) may promote tumorigenesis by increasing endogenous concentrations of insulin-like growth factor I (IGF-I) or the bioavailability of estradiol. In vitro studies have shown that uterine leiomyoma (UL) cells proliferate in response to IGF-I and display increased IGF-I gene expression and protein synthesis. Previous epidemiologic studies suggest that a high GL is a risk factor for endometrial and ovarian cancers, which, like UL, are hormone-responsive tumors. We investigated the relation of dietary GI and GL with UL risk in the Black Women's Health Study. In this prospective cohort study, we followed 21,861 premenopausal women for incident UL from 1997 to 2007. Diet was assessed in 1995 and 2001 with food-frequency questionnaires. We used Cox regression to estimate incidence rate ratios (IRRs) and 95% CIs, controlled for potential confounders. During 162,604 person-years of follow-up, there were 5800 cases of UL diagnosed by ultrasound or surgery. Dietary GI was weakly associated with UL risk overall (IRR for highest compared with lowest quintile: 1.09; 95% CI: 0.99, 1.19; P for trend = 0.04). Positive associations were observed between GL and UL in women aged <35 y (IRR for highest compared with lowest quintile: 1.18; 95% CI: 1.02, 1.37; P for trend = 0.15) and between GI and UL in college-educated women (IRR for highest compared with lowest quintile: 1.17; 95% CI: 1.03, 1.34; P for trend = 0.004). Our results suggest that high dietary GI and GL may be associated with an increased UL risk in some women. The observed associations warrant investigation in future studies.

Genetic polymorphisms of DNA repair gene XRCC1 and risk of uterine leiomyoma

The objective was to study the relationship between the polymorphisms of the DNA repair gene XRCC1 Arg399Gln, Arg194Trp, and Arg280His uterine leiomyoma in a Chinese population. In the case-control study, we compared the XRCC1 gene polymorphism of 136 uterine leiomyoma patients and 140 healthy controls by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results suggested that the genotype Arg/Arg of codon 280 was significantly different from its heterozygote (odds ratio [OR] = 3.633, 95% confidence interval [CI]: 2.147-6.148). In conclusion, the results suggest that polymorphism of XRCC1 Arg280His was associated with the increased risk of uterine leiomyoma in a Chinese population.

No Association Between Estrogen Receptor Beta Polymorphisms and Uterine Leiomyoma

Numerous candidate genes have been proposed as susceptibility factors for the development of uterine leiomyoma. Interaction of estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2) plays a pivotal role in tunica muscularis uteri cell proliferation, differentiation, and tumorigenesis of myometrium. To our knowledge, no study has examined the relationship between the ESR2 and uterine leiomyoma. The aim of the study was to evaluate the association of ESR2 polymorphisms with uterine leiomyoma in Chinese women. We investigated two common ESR2 polymorphisms, rs1256049 (G1082A) and rs928554 (Cx + 56 A --> G), to find their association with uterine leiomyoma risk by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing method. A total of 150 Chinese women with clinically diagnosed uterine leiomyoma and 150 healthy, normal Chinese women were included in the study. The results suggest that there were no significant differences in the genotype and allele frequencies of ESR2 polymorphisms between uterine leiomyoma patients and controls in Chinese women (p > 0.05). Further studies are still needed to explore the complicated interaction between environmental factors and ESR2 polymorphisms in the risk of uterine leiomyoma, particularly in ethnically different populations.

CYP1A1 and CYP1B1 genetic polymorphisms and uterine leiomyoma risk in Chinese women

The aim of the study was to evaluate the association of CYP1A1 and CYP1B1 polymorphisms with uterine leiomyoma in Chinese women. We investigated 100 women with clinically diagnosed uterine leiomyoma and 110 healthy normal subjects from Chinese women. The genetic distribution of two CYP1A1 polymorphisms at MspI, Ile462Val and four CYP1B1 polymorphisms at Arg48Gly, Ala119Ser, Leu432Val, Asp449Asp were analyzed by polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing method. All the SNPs showed polymorphisms in Chinese women. The genotype A/G and the allele G on Ile462Val was significantly different between uterine leiomyoma patients and controls (P < 0.05). These results suggest that the genotype of CYP1A1 Ile462Val was associated with the increased risk of uterine leiomyomas in Chinese women.

Lycopene and other carotenoid intake in relation to risk of uterine leiomyomata

Carotenoids have antioxidant properties and have been associated with reduced risks of some cancers. We hypothesized that carotenoid intake may reduce the risk of diagnosed uterine leiomyoma (UL). We evaluated the associations between dietary carotenoids and risk of diagnosed UL in 82,512 premenopausal women aged 26-46 years in 1991 in the Nurses' Health Study II over 10 years of follow-up. Diet was assessed every 4 years with a validated food frequency questionnaire, and incidence of UL was assessed biennially by questionnaire. Total lycopene intake was not associated with diagnosed UL risk. Intake of beta-carotene was associated with slightly increased risks of diagnosed UL; this association was restricted to current smokers (for highest vs lowest quintile, relative risk = 1.36, 95% confidence interval 1.05 to 1.76; P(trend) = .003). Overall, our findings do not suggest that carotenoids reduce the risk of diagnosed UL. Among current smokers, high intake of beta-carotene may slightly increase risk of diagnosed UL.

Anthropometric Characteristics and Risk of Uterine Leiomyoma

The etiology of uterine leiomyoma (or fibroids) is poorly understood. Sex steroid hormones and growth factors have been hypothesized to play a role in their development, and anthropometric characteristics may influence uterine leiomyoma risk. We analyzed prospectively-collected data from the Nurses' Health Study II, a cohort of 116,609 female registered nurses age 25 to 42 years at baseline. Incidence of uterine leiomyoma and anthropometric characteristics were assessed every 2 years. We calculated hazard ratios and 95% confidence intervals adjusted for known and suspected risk factors for uterine leiomyoma. Uterine leiomyomas were associated with current body mass index, change in weight since age 18, and waist-to-hip ratio. However, there was little evidence of their association with body mass index at age 18, childhood or adolescent body size, or adult height. Body mass and weight gain in adulthood may increase the risk of uterine leiomyoma, but body mass in early life does not.

Serum Dioxin Concentrations and Risk of Uterine Leiomyoma in the Seveso Women's Health Study

Uterine leiomyomata (fibroids), benign neoplasms of the smooth muscle, are a major cause of hysterectomy. Exposure to hormonally active chemicals may play an etiologic role. The authors investigated the risk of uterine leiomyoma associated with exposure to 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) for women who resided near Seveso, Italy, in 1976 at the time of a chemical explosion. Twenty years later, women enrolled in the Seveso Women's Health Study were asked about history of fibroids, medical records were obtained, and vaginal ultrasonography was performed for a subset. Serum collected soon after the explosion was analyzed for TCDD. A likelihood-based method that combines both historical and current status (ultrasound) data was adapted to estimate the hazard ratio. Of 956 eligible women, 251 (26.3%) had fibroids. Compared with that for women with TCDD levels of < or = 20 parts per trillion, the age-adjusted hazard ratios were 0.58 (95% confidence interval: 0.41, 0.81) for women with levels of 20.1-75.0 parts per trillion and 0.62 (95% confidence interval: 0.44, 0.89) for women with levels of >75.0 parts per trillion. This finding suggests that TCDD may have antiestrogenic effects in the uterine myometrium, in contrast to apparently estrogenic effects previously found in the breast of Seveso Women's Health Study women.

Ethnic distribution of estrogen receptor-α polymorphism is associated with a higher prevalence of uterine leiomyomas in black Americans

To investigate whether polymorphisms in the estrogen receptor alpha (ERalpha) gene are associated with an increased risk of uterine leiomyomas (ULMs). Genomic DNA was isolated from normal myometrium samples collected at the time of the hysterectomy. Volunteers in an academic research environment. One hundred ninety-eight women with surgically confirmed ULMs and 229 matched controls with nonfibroid uteri. Hysterectomy samples were collected from volunteers. The two PvuII and XbaI intronic polymorphisms in the ERalpha gene using polymerase chain reaction and restriction fragment length polymorphism. The ERalpha PP genotype was associated with a significantly increased risk of ULM in black and white women, but not in Hispanic women. Women with the ERalpha PP genotype were 6.42 times (confidence limits 2.04-20.16) more likely to have ULMs than other genotypes. The ERalpha PP genotype was also significantly associated with larger tumor burden (>400 g). The overall prevalence of the PP genotype was significantly higher in black women (35%) than white (13%) or Hispanic (16%) women. Myometrial cell lines expressing the PP genotype exhibited enhanced proliferative response to estrogen in vitro compared with their pp counterparts. The ERalpha PP genotype is a genetic risk factor for ULM development among surgically treated women. The higher prevalence of this genotype in blacks might explain the increased occurrence of this tumor among black women.

Matrix Metalloproteinase-1 and -9 Promoter Polymorphisms Are Not Associated With an Increased Risk of Uterine Leiomyomas in a Japanese Population

Matrix metalloproteinases (MMPs) play an important role in modeling and remodeling the extracellular matrix in leiomyomas. Hence, we investigated whether associations exist between leiomyomas and promoter polymorphisms in the MMP-1 and MMP-9 genes in a Japanese population. We compared the distribution of polymorphisms in the promoter regions of MMP-1 (-1607 1G/2G) and MMP-9 (-1562 C/T) in 267 leiomyoma patients and 184 control patients using polymerase chain reaction-fragment-length polymorphism (PCR-RFLP) analysis. The allele frequencies of the MMP-1 -1607 2G and MMP-9 -1562 T polymorphisms were 74.6% and 18.6% in leiomyoma patients, and 71.3% and 18.6% in control patients, respectively. No significant differences in allele frequencies or genotype distributions were found between leiomyoma and control patients. Moreover, no associations were found between MMP-1 and MMP-9 genotypes and leiomyoma size or a family history of the condition. These findings suggest that MMP-1 and MMP-9 promoter polymorphisms are unlikely to be associated with an increased risk of uterine leiomyomas in Japanese women.

Catechol-O-Methyltransferase Polymorphism Is Associated With Increased Uterine Leiomyoma Risk in Different Ethnic Groups

Uterine leiomyomas (ULMs) are estrogen-dependent tumors that are more common in African American women. The etiology for such ethnic disparity is currently unknown. Catechol-O-methyltransferase (COMT) is an essential enzyme in estrogen metabolism. In the current study, we investigated the association of the functional COMT Val158Met polymorphism with ULM in different ethnic groups. We also studied the biologic role of COMT in tumor formation in human and rat leiomyoma cell lines and the potential therapeutic utility of COMT inhibitors. The genotype frequencies of the functional COMT Val158Met polymorphism among participants with (186 women) or without (142 women) ULMs were compared, as was the differential ethnic distribution of that polymorphism using polymerase chain reaction (PCR) and restriction-fragment linkage polymorphism. Proliferation, Western blot, and reporter transactivation analyses were applied to myometrial and leiomyoma cells representative of different COMT genotypes. Women with the high-activity COMT Val/Val genotype are 2.5 times more likely to develop ULMs than women with other genotypes (confidence interval, 1.017 to 6.151; P <.001). The prevalence of this genotype was significantly higher in African American women (47%) compared with white (19%) or Hispanic (30%) women (P = .003). Myometrial cell lines expressing the Val/Val genotype exhibited significantly enhanced responses to estrogen in proliferation and in estrogen-responsive element reporter assays. COMT-specific inhibitors reversed such a response and induced apoptosis. Myometrial specimens from Val/Val women demonstrated distinct estrogen-regulated gene expression that was consistent with enhanced proliferation and decreased apoptosis. The high-activity COMT Val/Val genotype is associated with increased risk of ULM. Our results provide a possible explanation for the higher prevalence of ULMs among African American women and offer a potential new target for nonsurgical treatment using COMT inhibitors.

The CYP17 MspA1 polymorphism is not associated with an increased risk of uterine leiomyomas in a Japanese population

The CYP17 gene is thought to be a candidate gene for susceptibility to hormone-related diseases. A single (T→C) nucleotide polymorphism in the promoter region of CYP17 is speculated to influence its transcription. The present study was conducted to investigate the possible association between uterine leiomyomas and CYP17 gene polymorphism in a Japanese population. Genotyping analysis of the CYP17 gene was performed in 138 leiomyoma cases, 183 unaffected controls and 179 population controls using polymerase chain reaction and restriction fragment length polymorphism analysis. No significant difference in CYP17 genotype distribution was noted between leiomyoma cases and controls. Women carrying the A2 allele were not at an increased risk of uterine leiomyoma compared with those carrying the A1 allele in unaffected controls (odds ratio, 1.26; 95% confidence interval, 0.92–1.72) and those carrying the A1 allele in population controls (odds ratio, 0.99; 95% confidence interval, 0.72–1.36). No significant difference in allele frequencies were found between leiomyoma cases and controls. These findings suggest that CYP17 gene polymorphism is unlikely to be associated with an increased risk of uterine leiomyomas in a Japanese population.

DNA repair gene XRCC1 Arg399Gln polymorphism is associated with increased risk of uterine leiomyoma

DNA repair gene XRCC1 Arg399Gln polymorphism has been associated with the risk of several human tumours. In the present study we investigated whether the XRCC1 polymorphism is related to the risk of uterine leiomyoma, the most common neoplasm of the female genital tract. Three hundred and twenty-seven patients with uterine leiomyoma and 197 normal controls were enrolled, and XRCC1 genotyping was determined by PCR and restriction fragment length polymorphism. The proportions of individuals homozygous for 399Arg allele, heterozygous and homozygous for the 399Gln allele were 85.8%, 13.7% and 0.5% among the control group, and 46.2%, 53.2% and 0.6% in those with leiomyoma (P < 0.001), respectively. Logistic regression analysis (after adjusting for age, parity, menarche age and body mass index) showed a significant increased risk of uterine leiomyoma in women with the Arg/Gln genotype versus the Arg/Arg genotype (odds ratio 6.79; 95% confidence interval 4.20-10.99; P < 0.001). In Korean women, the 399Gln polymorphism of XRCC1 is associated with an increased risk of uterine leiomyoma.

Postmenopausal estrogen and progestogen therapy and the risk of uterine leiomyomas.

Leiomyomas are common benign neoplasms. Although hormone therapy is the most common and effective treatment for menopausal symptoms, little is known about its effect on leiomyomas. We examined the risk of a first diagnosis of leiomyomas in peri- and postmenopausal women associated with prior use of estrogen and progestogen therapy (EPT). A case-control study was conducted among enrollees from a nonprofit health plan. Cases had a first diagnosis of leiomyomas confirmed by surgery or ultrasound. Controls were women of the same age range without a diagnosis of leiomyomas selected at random from membership and outpatient files. Participants were interviewed regarding prior use of exogenous hormones, medical history, and reproductive history. This analysis was restricted to cases (n = 256) and controls (n = 276) who were peri- or postmenopausal and more than 40 years of age. Adjusted odds ratios (OR) and 95% CIs were estimated using logistic regression models. EPT use for more than 5 years was associated with a 1.7-fold increased risk of leiomyomas (95% CI, 0.9-3.3). Associations with EPT use were only present among women with a body mass index less than 24 kg/m; OR (ever-use), 2.3 (95% CI, 1.2-4.3); and OR (>or= 5 years use), 4.0 (95% CI, 1.6-10.3). Among peri- and postmenopausal women, prior EPT use was associated with an increased risk of a subsequent leiomyomas. This association seemed limited to the subset of women with low body mass index. Exogenous sources of estrogen and progestin in the setting of low adiposity may contribute to the development of leiomyomas.

Risk of benign gynaecological diseases and hormonal disorders according to responsiveness to ovarian stimulation in IVF: a follow-up study of 8714 women.

Over the past decade, attention has been focused increasingly on the long-term health effects of IVF in women. Assuming that hormonal changes due to stimulation regimens for IVF are strongest among 'high' responders, we evaluated whether responsiveness to ovarian stimulation in IVF is predictive of the risk of benign gynaecological disorders >12 months after the last IVF cycle. A nationwide historical cohort study of women who underwent IVF treatment was conducted. After a median time of 4.6 years following the last IVF treatment cycle, 8714 cohort members completed a health survey questionnaire that inquired about reproductive variables and the occurrence and age at onset of specific medical conditions including uterine leiomyoma, surgically removed ovarian cysts and thyroid disorders. Detailed data on cause of subfertility and IVF treatment were collected from the medical records. Women were included in the 'high responders' group when on average >/=14 oocytes were retrieved per IVF cycle (n = 1562), in the 'normal responders' group when they had a mean number of 4-13 retrieved oocytes (n = 6033), and in the 'low responders' group when they had a mean number of 0-3 retrieved oocytes per cycle (n = 1119). Among women with a high response to ovarian stimulation, we found a borderline significantly decreased risk of uterine leiomyoma [relative risk (RR) = 0.6; 95% confidence interval (CI) 0.4-1.0] and surgically removed ovarian cysts (RR = 0.6; 95% CI 0.3-1.0) in comparison with 'normal responders'. After OHSS, the age-adjusted RRs were 1.8 (95% CI 0.9-3.8) for having surgically removed ovarian cysts and 1.0 (95% CI 0.4-2.2) for uterine leiomyoma (both not significant). Despite the small number of events observed, highly elevated risks of gynaecological disorders and hormonal diseases in women undergoing IVF treatment can be excluded based on the present data and this follow-up period. Women with a low response to ovarian stimulation tended to have higher risks of benign gynaecological diseases than high responders.