Genetic contribution of reproductive traits to risk of uterine leiomyomata: a large-scale, genome-wide, cross-trait analysis.

BACKGROUND: Although phenotypic associations between female reproductive characteristics and uterine leiomyomata have long been observed in epidemiologic investigations, the shared genetic architecture underlying these complex phenotypes remains unclear. OBJECTIVE: We aimed to investigate the shared genetic basis, pleiotropic effects, and potential causal relationships underlying reproductive traits (age at menarche, age at natural menopause, and age at first birth) and uterine leiomyomata. STUDY DESIGN: With the use of large-scale, genome-wide association studies conducted among women of European ancestry for age at menarche (n=329,345), age at natural menopause (n=201,323), age at first birth (n=418,758), and uterine leiomyomata (ncases/ncontrols=35,474/267,505), we performed a comprehensive, genome-wide, cross-trait analysis to examine systematically the common genetic influences between reproductive traits and uterine leiomyomata. RESULTS: Significant global genetic correlations were identified between uterine leiomyomata and age at menarche (rg, -0.17; P=3.65×10-10), age at natural menopause (rg, 0.23; P=3.26×10-07), and age at first birth (rg, -0.16; P=1.96×10-06). Thirteen genomic regions were further revealed as contributing significant local correlations (P<.05/2353) to age at natural menopause and uterine leiomyomata. A cross-trait meta-analysis identified 23 shared loci, 3 of which were novel. A transcriptome-wide association study found 15 shared genes that target tissues of the digestive, exo- or endocrine, nervous, and cardiovascular systems. Mendelian randomization suggested causal relationships between a genetically predicted older age at menarche (odds ratio, 0.88; 95% confidence interval, 0.85-0.92; P=1.50×10-10) or older age at first birth (odds ratio, 0.95; 95% confidence interval, 0.90-0.99; P=.02) and a reduced risk for uterine leiomyomata and between a genetically predicted older age at natural menopause and an increased risk for uterine leiomyomata (odds ratio, 1.08; 95% confidence interval, 1.06-1.09; P=2.30×10-27). No causal association in the reverse direction was found. CONCLUSION: Our work highlights that there are substantial shared genetic influences and putative causal links that underlie reproductive traits and uterine leiomyomata. The findings suggest that early identification of female reproductive risk factors may facilitate the initiation of strategies to modify potential uterine leiomyomata risk.

Uterine leiomyomata claim rate estimates and demographic characteristics by county. Florida, 2010-2019.

To describe the demographic characteristics and estimate the uterine leiomyomata claim rates (ULCRs) by women 18 years and older in Florida, we conducted a cross-sectional analysis of the 2010-2019 administrative claims for uterine leiomyomata and associated study variables (age, race, ethnicity, county of residence, anatomic site, length of stay, and additional diagnoses). ULCR ratios were estimated by race and ethnicity, using ULCR for non-Hispanic White women as the reference group. We identified 232,475 claims, most of which were among non-Hispanic White women in their forties. The overall ULCR estimate [95 percent CI] was 284.8 [284.21, 285.39] per 100,000 women 18 years and older, with a small, nonsignificant trend to increase over time (R2 = .310; p = .094). Black, Hispanic, and other women of color presented with higher ULCR ratios (4.84, 1.87, and 1.58, respectively). Urban counties had significantly higher ULCRs than suburban and rural counties. While non-Hispanic White women had the highest frequency of ULCRs, women of color-especially Black women-presented with significantly higher ULCR ratios. The epidemiologic profile of uterine leiomyomata in terms of age, race, ethnicity, and geographic location points to unmet healthcare needs among specific demographic and geographic groups of women in Florida.

A prospective ultrasound study of cigarette smoking and uterine leiomyomata incidence and growth.

BACKGROUND: Uterine leiomyomata (fibroids) are common, benign neoplasms that contribute substantially to gynecologic morbidity. Some existing epidemiologic studies indicate that cigarette smoking is associated with lower uterine leiomyomata risk. However, no prospective studies have systematically screened an entire study population for uterine leiomyomata using transvaginal ultrasound or evaluated the association between cigarette smoking and uterine leiomyomata growth. OBJECTIVE: This study aimed to examine the association between cigarette smoking and uterine leiomyomata incidence and growth in a prospective ultrasound study. STUDY DESIGN: We enrolled 1693 residents from the Detroit metropolitan area into the Study of Environment, Lifestyle, and Fibroids during 2010 to 2012. Eligible participants were aged 23 to 34 years, had an intact uterus but no previous diagnosis of uterine leiomyomata, and self-identified as Black or African American. We invited participants to complete a baseline visit and 4 follow-up visits over approximately 10 years. At each visit, we used transvaginal ultrasound to assess uterine leiomyomata incidence and growth. Participants provided extensive self-reported data throughout follow-up including exposures to active and passive cigarette smoking in adulthood. We excluded participants who did not return for any follow-up visits (n=76; 4%). We fit Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals for the association between time-varying smoking history and incidence rates of uterine leiomyomata. We fit linear mixed models to estimate the percentage difference and 95% confidence intervals for the association between smoking history and uterine leiomyomata growth. We adjusted for sociodemographic, lifestyle, and reproductive factors. We interpreted our results based on magnitude and precision rather than binary significance testing. RESULTS: Among 1252 participants without ultrasound evidence of uterine leiomyomata at baseline, uterine leiomyomata were detected in 394 participants (31%) during follow-up. Current cigarette smoking was associated with a lower uterine leiomyomata incidence rate (hazard ratio, 0.67; 95% confidence interval, 0.49-0.92). Associations were stronger among participants who had smoked for longer durations (≥15 years vs never: hazard ratio, 0.49; 95% confidence interval, 0.25-0.95). The hazard ratio for former smokers was 0.78 (95% confidence interval, 0.50-1.20). Among never smokers, the hazard ratio for current passive smoke exposure was 0.84 (95% confidence interval, 0.65-1.07). Uterine leiomyomata growth was not appreciably associated with current (percent difference, -3%; 95% confidence interval, -13% to 8%) or former (percent difference, -9%; 95% confidence interval, -22% to 6%) smoking. CONCLUSION: We provide evidence from a prospective ultrasound study that cigarette smoking is associated with lower uterine leiomyomata incidence.

Urinary phytoestrogens and the risk of uterine leiomyomata in US women.

BACKGROUND: Uterine leiomyomata (UL) is a common gynecological disease in women. Studied on the relationship between single metabolites of urinary phytoestrogens and UL, especially for the combined effects of mixed metabolites on UL still are insufficient. METHODS: In this cross-sectional study, we included 1,579 participants from the National Health and Nutrition Examination Survey. Urinary phytoestrogens were assessed by measuring urinary excretion of daidzein, genistein, equol, O-desmethylangolensin, enterodiol and enterolactone. The outcome was defined as UL. Weighted logistic regression was used to analyze the association between single metabolites of urinary phytoestrogens and UL. Notably, we adopted the weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and quantile g-computation (qgcomp) models, to investigate the combined effects of six mixed metabolites on UL. RESULTS: The prevalence of UL was approximately 12.92%. After adjusting age, race/ethnicity, marital status, drinking status, body mass index, waist circumference, menopausal status, ovary removed status, use of female hormones, hormones/hormone modifiers, total energy, daidzein, genistein, O-desmethylangolensin, enterodiol, and enterolactone, the association of equol with UL was significant [Odds ratio (OR) = 1.92, 95% confidence interval (CI): 1.09-3.38]. In the WQS model, mixed metabolites of urinary phytoestrogen had a positive association with UL (OR = 1.68, 95%CI: 1.12-2.51), with the highest weighted chemical of equol. In the gpcomp model, equol had the largest positive weight, followed by genistein and enterodiol. In the BKMR model, equol and enterodiol have positive correlation on UL risk, while enterolactone has negative correlation. CONCLUSION: Our results implied a positive association between the mixed metabolites of urinary phytoestrogen and UL. This study provides evidence that urinary phytoestrogen-metabolite mixture was closely related to the risk of female UL.

Risk of uterine leiomyomata with menstrual and reproductive factors in premenopausal women: Korea nurses' health study.

BACKGROUND: Uterine leiomyomata (UL) are benign smooth muscle tumors that may cause significant morbidity in women of reproductive age. This study aimed to investigate the relationship of menstrual and reproductive factors with the risk of UL in premenopausal women. METHODS: This prospective study included 7,360 premenopausal women aged 22-48 years who were part of the Korea Nurses' Health Study. Information on the menstrual cycle and reproductive history was assessed between 2014 and 2016, and self-reported cases of UL were obtained through 2021. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During 32,072 person-years of follow-up, 447 incident cases of UL were reported. After adjusting for other risk factors, women with late age at menarche had a lower incidence of UL (≥ 16 vs. 12-13 years: HR 0.68; 95% CI 0.47-0.99; p for trend = 0.026). The risk of UL was inversely associated with current menstrual cycle length (≥ 40 or too irregular to estimate vs. 26-31 days: HR 0.40; 95% CI 0.24-0.66) and cycle length at ages 18-22 years (HR 0.45; 95% CI 0.31-0.67; p for trend < 0.001, each). Parous women had lower risk of UL than nulliparous women (HR 0.40; 95% CI 0.30-0.53) and women who were aged 29-30 years at first birth had a lower risk of UL than those who were aged ≤ 28 years at first birth (HR 0.58; 95% CI 0.34-0.98). There was no significant association of the number of births or breastfeeding with the risk of UL among parous women. Neither a history of infertility nor oral contraceptive use was associated with the risk of UL. CONCLUSIONS: Our results suggest that age at menarche, menstrual cycle length, parity, and age at first birth are inversely associated with the risk of UL in premenopausal Korean women. Future studies are warranted to confirm the long-term effects of menstrual and reproductive factors on women's health.

Intrauterine Fetal Demise Associated with Vascular Malperfusion and Multiple Uterine Leiomyomata: A Report of Two Cases.

BACKGROUND: Uterine leiomyomata have been loosely associated with intrauterine fetal demise (IUFD), largely attributed to fetal growth restriction from cavitary distortion. We present two cases of IUFD in patients with non-distorting leiomyomata and pathologic placental findings of maternal vascular malperfusion (MVM) and fetal vascular malperfusion (FVM). CASE REPORT: Case 1 details a 28w3d IUFD associated with large leiomyomata (largest 11.9 × 7.6 × 9.7 cm), post-partum deep vein thrombosis, and severe pre-eclampsia histologic features. Case 2 details a 25w2d IUFD associated with smaller leiomyomata (largest 3.1 × 3.0 × 3.3 cm). Both placentas demonstrated MVM, including parenchymal thrombi and accelerated villous maturity, and FVM, including avascular stem villi. DISCUSSION: As the placentas in both cases demonstrated findings consistent with altered placental perfusion, we posit that leiomyomata in these cases may have been associated with both maternal and fetal vascular malperfusion, ultimately contributing to fetal demise.

A prospective cohort study of ambient air pollution exposure and risk of uterine leiomyomata.

STUDY QUESTION: To what extent are ambient concentrations of particulate matter <2.5 microns (PM2.5), nitrogen dioxide (NO2) and ozone (O3) associated with risk of self-reported physician-diagnosed uterine leiomyomata (UL)? SUMMARY ANSWER: In this large prospective cohort study of Black women, ambient concentrations of O3, but not PM2.5 or NO2, were associated with increased risk of UL. WHAT IS KNOWN ALREADY: UL are benign tumors of the myometrium that are the leading cause of gynecologic inpatient care among reproductive-aged women. Black women are clinically diagnosed at two to three times the rate of white women and tend to exhibit earlier onset and more severe disease. Two epidemiologic studies have found positive associations between air pollution exposure and UL risk, but neither included large numbers of Black women. STUDY DESIGN, SIZE, DURATION: We conducted a prospective cohort study of 21 998 premenopausal Black women residing in 56 US metropolitan areas from 1997 to 2011. PARTICIPANTS/MATERIAL, SETTING, METHODS: Women reported incident UL diagnosis and method of confirmation (i.e. ultrasound, surgery) on biennial follow-up questionnaires. We modeled annual residential concentrations of PM2.5, NO2 and O3 throughout the study period. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for a one-interquartile range (IQR) increase in air pollutant concentrations, adjusting for confounders and co-pollutants. MAIN RESULTS AND THE ROLE OF CHANCE: During 196 685 person-years of follow-up, 6238 participants (28.4%) reported physician-diagnosed UL confirmed by ultrasound or surgery. Although concentrations of PM2.5 and NO2 were not appreciably associated with UL (HRs for a one-IQR increase: 1.01 (95% CI: 0.93, 1.10) and 1.05 (95% CI: 0.95, 1.16), respectively), O3 concentrations were associated with increased UL risk (HR for a one-IQR increase: 1.19, 95% CI: 1.07, 1.32). The association was stronger among women age <35 years (HR: 1.26, 95% CI: 0.98, 1.62) and parous women (HR: 1.28, 95% CI: 1.11, 1.48). LIMITATIONS, REASONS FOR CAUTION: Our measurement of air pollution is subject to misclassification, as monitoring data are not equally spatially distributed and we did not account for time-activity patterns. Our outcome measure was based on self-report of a physician diagnosis, likely resulting in under-ascertainment of UL. Although we controlled for several individual- and neighborhood-level confounding variables, residual confounding remains a possibility. WIDER IMPLICATIONS OF THE FINDINGS: Inequitable burden of air pollution exposure has important implications for racial health disparities, and may be related to disparities in UL. Our results emphasize the need for additional research focused on environmental causes of UL. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the National Cancer Institute (U01-CAA164974) and the National Institute of Environmental Health Sciences (R01-ES019573). L.A.W. is a fibroid consultant for AbbVie, Inc. and accepts in-kind donations from Swiss Precision Diagnostics, Sandstone Diagnostics, FertilityFriend.com and Kindara.com for primary data collection in Pregnancy Study Online (PRESTO). M.J. declares consultancy fees from the Health Effects Institute (as a member of the review committee). The remaining authors declare they have no actual or potential competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Uterine fibroid incidence and growth in an ultrasound-based, prospective study of young African Americans.

BACKGROUND: Uterine fibroids are common. Symptoms are debilitating for many, leading to high medical and societal costs. Indirect data suggest that compared with white women, African Americans develop fibroids at least 10 years earlier on average, and their higher health burden has been well documented. OBJECTIVE: The objective of the study was to directly measure fibroid incidence and growth in a large, community-based cohort of young African-American women. STUDY DESIGN: This observational, community-based, prospective study enrolled 1693 African-American women, aged 23-35 years with no prior diagnosis of fibroids. Standardized transvaginal ultrasound examinations at enrollment and after approximately 18 months were conducted to identify and measure fibroids ≥0.5 cm in diameter. Fibroid growth (change in natural log volume per 18 months) was analyzed with mixed-model regression (n = 344 fibroids from 251 women whose baseline ultrasound revealed already existing fibroids). RESULTS: Among the 1123 fibroid-free women with follow-up data (88% were followed up), incidence was 9.4% (95% confidence interval, 7.7-11.2) and increased with age (Ptrend < .0001), from 6% (confidence interval, 3-9) for 23-25 year olds to 13% (confidence interval, 9-17) for 32-35 year olds. The chance of any new fibroid development was greater than twice as high for women with existing fibroids compared with women who were fibroid free at baseline (age-adjusted relative risk = 2.3 (confidence interval, 1.7-3.0). The uterine position of most incident fibroids (60%) was intramural corpus. Average fibroid growth was 89% per 18 months (confidence interval, 74-104%) but varied by baseline fibroid size (P < .0001). Fibroids ≥2 cm in diameter had average growth rates well under 100%. In contrast, small fibroids (<1 cm diameter) had an average growth rate of nearly 200% (188%, confidence interval, 145-238%). However, these small fibroids also had a high estimated rate of disappearance (23%). CONCLUSION: This is the first study to directly measure age-specific fibroid incidence with a standardized ultrasound protocol and to measure fibroid growth in a large community-based sample. Findings indicate that very small fibroids are very dynamic in their growth, with rapid growth, but a high chance of loss. Larger fibroids grow more slowly. For example, a 2-cm fibroid is likely to take 4-5 years to double its diameter. Detailed data on fibroid incidence confirm an early onset in African-American women.

Safety and efficacy of the selective progesterone receptor modulator asoprisnil for heavy menstrual bleeding with uterine fibroids: pooled analysis of two 12-month, placebo-controlled, randomized trials.

STUDY QUESTION: Can asoprisnil, a selective progesterone receptor modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile? SUMMARY ANSWER: Uninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events. WHAT IS KNOWN ALREADY: In a 3-month study, asoprisnil (5, 10 and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dose-dependent manner. STUDY DESIGN, SIZE, DURATION: In two Phase 3, double-blind, randomized, placebo-controlled, multicentre studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg or placebo (2:2:1) once daily for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N = 907). The primary efficacy endpoint was the percentage of women who met all three predefined criteria at 12 months or the final month for patients who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume and health-related quality of life (HRQL). MAIN RESULTS AND THE ROLE OF CHANCE: In all, 90% and 93% of women in the asoprisnil 10-mg and 25-mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P < 0.001). Similar results were observed at month 6 (P < 0.001). The percentage of women who achieved amenorrhea in any specified month ranged from 66-78% in the asoprisnil 10-mg group and 83-93% in the asoprisnil 25-mg group, significantly higher than with placebo (3-12%, P < 0.001). Hemoglobin increased rapidly (by month 2) with asoprisnil treatment and was significantly higher versus placebo throughout treatment. The primary fibroid and uterine volumes were significantly reduced from baseline through month 12 with asoprisnil 10 mg (median changes up to -48% and -28%, respectively) and 25 mg (median changes up to -63% and -39%, respectively) versus placebo (median changes up to +16% and +13%, respectively; all P < 0.001). Dose-dependent, significant improvements in HRQL (Uterine Fibroid Symptom and Quality of Life instrument) were observed with asoprisnil treatment. Asoprisnil was generally well tolerated. Endometrial biopsies indicated dose- and time-dependent decreases in proliferative patterns and increases in quiescent or minimally stimulated endometrium at month 12 of treatment. Although not statistically significantly different at month 6, mean endometrial thickness at month 12 increased by ~2 mm in both asoprisnil groups compared with placebo (P < 0.01). This effect was associated with cystic changes in the endometrium on MRI and ultrasonography, which led to invasive diagnostic and therapeutic procedures in some asoprisnil-treated women. LIMITATIONS, REASONS FOR CAUTION: Most study participants were black; few Asian and Hispanic women participated. The study duration may have been insufficient to fully characterize the endometrial effects. WIDER IMPLICATIONS OF THE FINDINGS: Daily uninterrupted treatment with asoprisnil was highly effective in controlling menstrual bleeding, improving anemia, reducing fibroid and uterine volume, and increasing HRQL in women with HMB associated with uterine fibroids. However, this treatment led to an increase in endometrial thickness and invasive diagnostic and therapeutic procedures, with potential unknown consequences. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by AbbVie Inc. (prior sponsors: TAP Pharmaceutical Products Inc., Abbott Laboratories). E.A. Stewart was a site investigator in the Phase 2 study of asoprisnil and consulted for TAP during the design and conduct of these studies while at Harvard Medical School and Brigham and Women's Hospital. She received support from National Institutes of Health grants HD063312, HS023418 and HD074711 and research funding, paid to Mayo Clinic for patient care costs related to an NIH-funded trial from InSightec Ltd. She consulted for AbbVie, Allergan, Bayer HealthCare AG, Gynesonics, and Welltwigs. She received royalties from UpToDate and the Med Learning Group. M.P. Diamond received research funding for the conduct of the studies paid to the institution and consulted for AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution from Bayer and ObsEva. A.R.W. Williams consulted for TAP and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr consulted for and received research funding from AbbVie. E.R. Myers consulted for AbbVie, Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie and may own AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie and may own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER: NCT00152269, NCT00160381 (clinicaltrials.gov). TRIAL REGISTRATION DATE: 7 September 2005; 8 September 2005. DATE OF FIRST PATIENT'S ENROLMENT: 12 September 2002; 6 September 2002.

A US population-based study of uterine fibroid diagnosis incidence, trends, and prevalence: 2005 through 2014.

BACKGROUND: Despite considerable public health burden, uterine fibroid population-based incidence estimates are few. Secular trends over time are even more limited. OBJECTIVE: We sought to evaluate the incidence, 10-year secular trends, and prevalence of uterine fibroid diagnoses and describe the proportion of symptomatic women. STUDY DESIGN: We performed a retrospective population-based cohort study of women, aged 18-65 years, enrolled 2005 through 2014 in Kaiser Permanente Washington. Uterine fibroid diagnoses identified by International Classification of Diseases, Ninth Revision codes and potential covariates were extracted from computerized databases. Women with prior hysterectomy and, for incidence estimates, women with prior fibroid diagnoses were excluded. Linear trends in incidence rates over the 10-year study period were evaluated using Poisson regression models. Rates and trend tests were examined for all women, by age groups, and by race/ethnicity. RESULTS: Associated International Classification of Diseases, Ninth Revision symptom-related codes were observed in 90% of incident cases. Incidence rates for fibroid diagnoses were highest for the age group 45-49 years, 240.3 per 10,000 woman-years in 2014, and for black women across all years. Overall age-adjusted estimated incidence rates declined during the 10-year study interval, from 139.4 per 10,000 woman-years in 2005 to 101.4 in 2014 (P value trend .0008). Overall prevalence in 2014 was 9.6%, and was highest among women aged 50-54 years (15.9%). Black women had higher prevalence (18.5%) than other racial/ethnic groups. CONCLUSION: We found a decreasing trend of new uterine fibroid diagnoses among predominantly symptomatic women ages 18-65 years in a recent 10-year interval. This finding was due, perhaps in part, to secular trends of decreasing hysterectomies. Nonetheless, uterine fibroids remain a common health burden, with a prevalence of nearly 10%. Rates are disproportionately high and occur at younger ages for black women, and possibly for other non-white racial/ethnic groups. These findings are of concern, as current available long-term medical therapies remain limited.

Uterine leiomyomata: a retrospective study of correlations with hypertension and diabetes mellitus from the Japan Nurses' Health Study.

We performed a scrutiny survey of self-reported uterine leiomyomata (UL) to investigate the associations of parental history with hypertension and personal history of hypertension in the UL cases in Japanese women. Questionnaires that included items on the sites of UL determined by imaging techniques and surgical procedure were mailed to 2015 women with a self-reported UL at a baseline survey of the Japan Nurses' Health Study (n = 15,019). We found that women with a past history and a maternal history of hypertension had an increase in their risk of UL. A maternal history of hypertension was significantly associated with an increase in the risk of UL in women without a past history of hypertension but not in the women with a past history of hypertension. A past history and a parental history of diabetes mellitus were not associated with an increase in the risk of UL. Women of reproductive age with a maternal history of hypertension may be at a higher risk for hypertension and UL. Impact Statement What is already known on this subject? A positive association of uterine leiomyomata (UL) with a past history of hypertension has been found but the association of a parental history of hypertension with UL has not yet been clarified. What do the results of this study add? Maternal hypertension, as well as a personal history of hypertension, was associated with an increased risk of UL and a past history and a parental history of diabetes mellitus were not associated with an increase in the risk of UL. What are the implications of these findings for clinical practice and/or further research? Women of a reproductive age with a maternal history of hypertension may be at a higher risk for hypertension and UL.

Facteurs génétiques à prendre en considération dans le cadre de l'examen gynécologique annuel.

OBJECTIF: Offrir aux médecins un survol des troubles génétiques courants qui devraient être pris en considération dans le cadre de l'examen gynécologique annuel d'une patiente, et ce, afin de déterminer le risque que court celle-ci ou d'en venir à procéder à des examens particuliers ou à orienter la patiente vers un autre service de sous-spécialité, en fonction de ses antécédents personnels ou familiaux. OPTIONS: Ces renseignements d'ordre génétique peuvent être utilisés aux fins de la sensibilisation des patientes et du dépistage ou du diagnostic de possibles maladies et/ou mutations. ISSUES: L'utilisation de ces renseignements d'ordre génétique pourrait mener à l'amélioration de l'évaluation des risques et des avantages et à celle de la prise en charge dans le cadre de l'examen gynécologique annuel. RéSULTATS: Les études publiées en anglais, jusques et y compris en mai 2010, ont été récupérées par l'intermédiaire de recherches menées dans PubMed et la Cochrane Library au moyen d'un vocabulaire contrôlé (« gynaecological diagnosis ¼, « genetic inheritance ¼) et de mots clés (« genetic risk ¼, « genetic mutation ¼, « inheritance ¼, « family history ¼, « uterus ¼, « ovary ¼, « endometrial ¼, « vagina ¼, « colon ¼, « gastric ¼, « renal ¼, « breast ¼, « cardiac ¼, « thrombophilia ¼, « diabetes ¼, « epilepsy ¼, « leiomyomata uteri ¼) appropriés. D'autres sources ont été identifiées par l'intermédiaire de recherches menées dans les sites Web d'organismes s'intéressant à l'évaluation des technologies dans le domaine de la santé et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques et auprès de sociétés de spécialité médicale nationales et internationales. VALEURS: Le niveau des résultats ne permet pas la formulation de recommandations factuelles. AVANTAGES, DéSAVANTAGES ET COûTS: La présente opinion de comité améliorera l'utilisation de nouvelles connaissances génétiques et leur application aux soins gynécologiques offerts annuellement aux femmes. Les occasions de gestion du risque et de diagnostic, pour ce qui est des troubles gynécologiques génétiques, s'en trouveront améliorées. Une compréhension plus exhaustive des troubles génétiques pourrait entraîner une hausse de l'anxiété et du stress psychologique chez les femmes et les membres de leur famille. COMMANDITAIRE: Société des obstétriciens et gynécologues du Canada. RECOMMANDATIONS: Le niveau des résultats ne permet pas la formulation de recommandations factuelles.

Phthalate monoesters in association with uterine leiomyomata in Shanghai.

Phthalates are ubiquitous environmental pollutants because of the broad use of plastics. We conducted a case-control study to determine whether uterine leiomyomata were related to exposure to phthalates. Urine specimens and questionnaires were collected from 61 cases and 61 age-matched controls. Nine phthalate monoesters were determined by ultra performance liquid chromatography coupled with tandem mass spectroscopy. Cases had significantly higher levels of creatinine-adjusted mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate, mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), total di(2-ethylhexyl) phthalate metabolites (∑DEHPmet), and total dibutyl phthalate metabolites (∑DBP(met)) than controls. After adjusting for potential confounders, logistic regression analyses demonstrated that leiomyomata were positively associated with MiBP, MnBP, MEHP, MEHHP, MECPP, ∑DEHP(met), and ∑DBP(met). In summary, our data support the hypothesis that uterine leiomyomata are related to phthalate exposure.

Angiogenesis and pro-angiogenic factors in uterine fibroids - facts and myths.

Uterine leiomyomata present major problem for females. Although they are benign tumors their frequency is associated with many symptoms like infertility, abdominal pain, menorrhagia. Authors based on their own morphological studies and review of the literature try to indicate main factors causing angiogenesis within leiomyomata and its influence on tumor growth. The strongest proangiogenic factor seems to be hypoxia, which stimulates up- and down-regulation of numerous genetically determined substances. Also mechanical pressure acting upon newly growing vessels is one of the factors which may determine formation of so called "vascular pseudocapsule" around the lesion.

Uterine cellular leiomyomata with chromosome 1p deletions represent a distinct entity.

OBJECTIVE: This study aimed to determine whether 1p deletion defines a subset of cellular leiomyomata (CL), which is a hypercellular variant of uterine leiomyomata that may have delayed malignant potential, and to correlate this genetic change with clinical and pathologic characteristics including those present in uterine sarcomas. STUDY DESIGN: Available CL cases at the Mayo Clinic (n = 101) and variant cases reported in another article (n = 16) were identified. Each case with sufficient tissue that met histologic criteria for CL when reviewed by a single pathologist underwent interphase fluorescence in situ hybridization to determine the presence of 1p deletion. Clinical characteristics of women with confirmed CL were compared on the basis of 1p deletion status using univariate analysis. RESULTS: Of the Mayo Clinic cohort of histologically confirmed CL, 23% had deletion of 1p. Women with this subset of CL, when compared to those without 1p deletion, were more likely to be postmenopausal (P = .049) and their uteri tended to be heavier (P = .039) with a larger dominant leiomyoma (P = .030). The pathologic features associated with 1p deletion were high cellularity (P = .036) and hyaline necrosis (P = .047), which remained significant after inclusion of the CL cases from a previously published series. CONCLUSION: Deletion of 1p occurs in approximately one-quarter of CL cases. This genetic alteration is potentially associated with clinicopathologic features that are present in uterine sarcomas, which suggests a distinct clinical entity that may have malignant potential. Our findings are particularly pertinent considering the increased preference for uterine-sparing options in leiomyoma treatment, suggesting assessment of 1p deletion status in CL may influence clinical surveillance decisions.

Fumarate Hydratase-Deficient Abdominal Wall Leiomyoma Presenting a Decade Post-Fumarate Hydratase-Deficient Uterine Leiomyoma Excision: An Incidental or Syndromic Association?

Background. The occurrence of fumarate hydratase-deficient leiomyoma of the abdominal wall is exceptionally rare. Case Presentation. A 50-year-old female patient with a past medical history of fumarate hydratase-deficient uterine leiomyoma presented with a left lower quadrant abdominal mass that has been present for the past 2 years. An ultrasound revealed a 3.5 cm oval hypoechoic mass. A subsequent CT scan showed a 3.5 cm hyperdense mass within the left internal oblique musculature. No family history is noted. A biopsy of the mass exhibited bundles of spindle cell neoplasm exhibiting bizarre ovoid nuclei and eosinophilic cytoplasm. No evidence of mitotic figures or tumor necrosis was noted. Immunohistochemical staining showed positive staining for desmin and smooth muscle actin (SMA), but negative staining for MART-1, S100, and CD34. Lesional cells showed expression of 2-succinocysteine and loss of fumarate hydratase expression. A diagnosis of fumarate hydratase-deficient leiomyoma was rendered. Conclusion. This report reinforces the importance of considering genetic testing for fumarate hydratase mutations in the evaluation of extra-uterine leiomyomatous lesions. Comprehensive follow-up and clinical screening in individuals with new lesions and a known history of fumarate hydratase-deficient neoplasms is mandatory. Recent recommendations support the integration of morphology-based evaluation along with immunohistochemical staining and genetic testing as a part of the standard evaluation for all uterine leiomyomas.

Urinary concentrations of phenols, parabens, and triclocarban in relation to uterine leiomyomata incidence and growth.

OBJECTIVE: To examine the association of urinary concentrations of phenols, parabens, and triclocarban with incidence and growth of uterine leiomyomata (UL; fibroids). DESIGN: Case-cohort study, nested within the Study of Environment, Lifestyle, and Fibroids, a prospective cohort study. SETTING: Clinic visits at baseline and every 20 months for 60 months. PATIENT(S): 754 Black women aged 23-35 years residing in the Detroit, Michigan area (enrolled during 2010-2012). INTERVENTION: None. MAIN OUTCOME MEASURE(S): At each study visit, women underwent transvaginal ultrasound for measurement of UL incidence and growth and provided urine specimens in which we quantified concentrations of seven phenols, four parabens, and triclocarban. We used Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs) characterizing the relation of urinary biomarker concentrations with UL incidence during the 60 months of follow-up. In a subset of UL detected and measured at multiple time points, we used linear regression to assess the associations between biomarker concentrations and UL growth. RESULT(S): Urinary biomarker concentrations were generally inversely associated with UL incidence, but the associations were weak and nonmonotonic. For example, hazard ratios comparing concentrations ≥90th with <50th percentile were 0.77 (95% CI: 0.46, 1.27) for bisphenol A, 0.72 (95% CI: 0.40, 1.28) for bisphenol S, and 0.76 (95% CI: 0.43, 1.33) for methylparaben. Biomarker concentrations were not strongly associated with UL growth. CONCLUSION(S): In this study of reproductive-aged Black women, urinary phenols, parabens, and triclocarban biomarkers were neither strongly nor consistently associated with UL incidence and growth.

Combined Exposure to Multiple Endocrine Disruptors and Uterine Leiomyomata and Endometriosis in US Women.

Background: Uterine leiomyomata (UL) and endometriosis (EM) are common gynecological diseases damaging the reproductive health of fertile women. Among all the potential factors, environmental endocrine-disrupting chemicals are insufficiently addressed considering the multiple pollutants and mixture exposure. Methods: Women aged 20 to 54 years old in the National Health and Nutrition Examination Survey (NHANES) 2001-2006, having a complete measurement of ten commonly exposed endocrine-disrupting chemicals (including urinary phthalate metabolites, equol, and whole blood heavy metals) and answered questions about UL and EM were included (N=1204). Multivariable logistic regression model, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models were implemented to analyze the combined effect of chemicals on the overall association with UL and EM. Results: In single chemical analysis, equol (OR: 1.90, 95% CI: 1.11, 3.27) and mercury (Hg) (OR: 1.91, 95% CI: 1.14, 3.25) were found positively associated with UL in tertile 3 vs. tertile 1. In WQS regression and BKMR models, the significant positive association between WQS index and UL (OR: 2.54, 95% CI: 1.52, 4.29) was identified and the positive relationship between equol and Hg exposure and UL were further verified. Besides, the mixture evaluation models (WQS and BKMR) also found MEHP negatively associated with UL. Although none of the single chemicals in tertile 3 were significantly associated with EM, the WQS index had a marginally positive association with EM (OR: 2.01, 95% CI: 0.98, 4.15), and a significant positive association was identified in subanalysis with participants restricted to premenopausal women (OR: 2.18, 95% CI: 1.03, 4.70). MIBP and MBzP weighted high in model of EM and MEHP weighted the lowest. Conclusion: Comparing results from these three statistical models, the associations between equol, Hg, and MEHP exposure with UL as well as the associations of MIBP, MBzP, and MEHP exposure with EM warrant further research.

Randomized trial of a patient education tool about leiomyoma.

OBJECTIVE: Uterine leiomyomata are a frequent indication for women seeking gynecologic care [1]. The objective of our study was to assess whether patient knowledge about leiomyomata, anxiety, or satisfaction with counseling differed in patients who received multimedia counseling versus standard counseling. METHODS: Women with leiomyomata who presented to the gynecology clinic at a single institution were randomized to standard counseling or multimedia counseling using the drawMD OB/GYN iPad™ application. Participants completed a pre-counseling questionnaire, received the designated method of counseling, and completed a post-counseling questionnaire. Outcomes of the study included assessment of patient knowledge, satisfaction, and anxiety. RESULTS: Seventy-two participants were randomized. There was no significant difference in post-counseling anxiety between the groups (p = 0.86). For both groups, anxiety significantly improved after counseling. Both groups were satisfied with the counseling they received, however, there was no difference between groups. Participants in both groups significantly improved their knowledge about fibroids post-counseling. CONCLUSION: Counseling of patients with leiomyomata improves patient satisfaction and knowledge. The addition of a multimedia tool may or may not enhance patient counseling. PRACTICE IMPLICATIONS: This is the first prospective, randomized controlled trial evaluating the impact of a multimedia tool on patient education and counseling for patients with leiomyomata.

The association between chronic psychological stress and uterine fibroids risk: A meta-analysis of observational studies.

The association between chronic psychological stress and uterine fibroids (UFs) risk remains unclear. In this study, a meta-analysis of observational studies was performed to explore the reported association between them. A literature search was performed in PubMed, EMBASE, and Web of Science to identify relevant published articles. A random-effect model was used to examine pooled odds ratio (OR) and 95% confidence interval (CI). Additionally, subgroup analyses and two-stage random-effect dose-response meta-analysis were performed. A total of six articles with seven studies were included in this meta-analysis. For the highest versus lowest category of chronic psychological stress, the pooled OR was 1.24 (95% CI [1.15, 1.34]; p = .000). Through subgroup analyses, we found a positive association between chronic psychological stress and UFs risk especially in non-Hispanic Blacks studies (OR, 1.24, 95% CI [1.14, 1.34], p = .000). When evaluating for a dose-response, we found a weak correlation between chronic psychological stress and UFs risk, especially for the severe (OR, 1.17, 95% CI [1.07, 1.29]) and very severe (OR, 1.23, 95% CI [1.07, 1.41]) categories. Our meta-analysis shows a statistically significant association between chronic psychological stress and UFs risk particularly for non-Hispanic Blacks. Interventions aiming to reduce chronic psychological stress may be useful to decrease the prevalence of UFs.