Association of forkhead box P3 gene polymorphisms with premature ovarian insufficiency in Chinese women.

OBJECTIVE: Forkhead box P3 (FOXP3), a transcription factor, is regarding critical regulator of the function of regulatory T (Treg) cells and plays a crucial role in the development of autoimmune diseases. Premature ovarian insufficiency (POI) is an autoimmune disease; however, little is known about the association between FOXP3 variants and the susceptibility to POI. METHODS: Long-range polymerase chain reaction was used to analyze complete FOXP3 gene sequences from 153 patients with POI. The frequencies of genotypes and alleles of the FOXP3 gene were compared between patients with POI and 269 East Asian women from the Genome Aggregation (gnomAD) database. RESULTS: Forty-three single-nucleotide polymorphisms (SNPs) were detected, including 25 known SNPs and 18 novel SNPs. The genotype distributions and allele frequencies of two known SNPs (rs17847094 and rs76798919) and three novel SNPs (NC_000023.11:g.49112832G > A, NC_000023.11:g.49112833G > A, and NC_000023.11:g.49120479CT > C) were significantly different between the two groups. Linkage disequilibrium and haplotype analyses of the rs57734889, rs2232365, rs3761548, and rs34629506 SNPs in FOXP3 were performed and compared, and the high D' (standardized disequilibrium coefficients) value indicated that these polymorphisms may contribute to the risk of POI. CONCLUSIONS: This study is the first to show that genetic variants in the regulatory regions of FOXP3 play a vital role in idiopathic POI in the Chinese population.

Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility.

Ovarian deficiency, including diminished ovarian reserve and premature ovarian insufficiency, represents one of the main causes of female infertility. Little is known of the genetic basis of diminished ovarian reserve, while premature ovarian insufficiency often has a genetic basis, with genes affecting various processes. NR5A1 is a key gene required for gonadal function, and variants are associated with a wide phenotypic spectrum of disorders of sexual development, and are found in 0.26-8% of patients with premature ovarian insufficiency. As there is some debate about the extent of involvement of NR5A1 in the pathogenesis of ovarian deficiency, we performed an in-depth analysis of NR5A1 variants detected in a cohort of 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility associated with normal ovarian function. We identified rare non-synonymous protein-altering variants in 2.8 % of women with ovarian deficiency and no such variants in our small cohort of women with infertility but normal ovarian function. We observed previously reported variants associated with premature ovarian insufficiency in patients with diminished ovarian reserve, highlighting a genetic relationship between these conditions. We confirmed functional impairment resulting from a p.Val15Met variant, detected for the first time in a patient with premature ovarian insufficiency. The remaining variants were associated with preserved transcriptional activity and localization of NR5A1, indicating that rare NR5A1 variants may be incorrectly curated if functional studies are not undertaken, and/or that NR5A1 variants may have only a subtle impact on protein function and/or confer risk of ovarian deficiency via oligogenic inheritance.

Association of menopause age and N-terminal pro brain natriuretic peptide: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: Menopause age can affect the risk of developing cardiovascular disease (CVD). The purpose of this study was to investigate the associations of early menopause (menopause occurring before age 45 y) and menopause age with N-terminal pro brain natriuretic peptide (NT-proBNP), a potential risk marker of CVD and heart failure. METHODS: Our cross-sectional study included 2,275 postmenopausal women, aged 45 to 85 years and without clinical CVD (2000-2002), from the Multi-Ethnic Study of Atherosclerosis. Participants were classified as having or not having early menopause. NT-proBNP was log-transformed. Multivariable linear regression was used for analysis. RESULTS: Five hundred sixty-one women had early menopause. The median (25th-75th percentiles) NT-proBNP value was 79.0 (41.1-151.6) pg/mL for all participants, 83.4 (41.4-164.9) pg/mL for women with early menopause, and 78.0 (40.8-148.3) pg/mL for women without early menopause. The mean (SD) age was 65 (10.1) and 65 (8.9) years for women with and without early menopause, respectively. No significant interactions between menopause age and ethnicity were observed. In multivariable analysis, early menopause was associated with a 10.7% increase in NT-proBNP levels, whereas each 1-year increase in menopause age was associated with a 0.7% decrease in NT-proBNP levels. CONCLUSIONS: Early menopause is associated with greater NT-proBNP levels, whereas each 1-year increase in menopause age is associated with lower NT-proBNP levels, in postmenopausal women.

An interpretive description of chemotherapy-induced premature menopause among Latinas with breast cancer.

PURPOSE/OBJECTIVES: To describe the experience of chemotherapy-induced premature menopause (CIPM) among Latinas, explore how CIPM was assimilated into the breast cancer experience, and relate measured acculturation levels to the CIPM experience. RESEARCH APPROACH: Interpretive descriptive method from a feminist inquiry lens. SETTING: Telephone interviews with participants from 12 states in the United States. PARTICIPANTS: 20 Latinas who experienced CIPM after treatment for breast cancer. METHODOLOGIC APPROACH: In-depth interviews and the Brief Acculturation Scale for Hispanics were used to elicit data, with interpreter assistance as needed. FINDINGS: One overarching theme, Bigger Than Menopause, and three subthemes, Experiencing Menopause, Ever-Changing Landscape, and Working Through the Experience, were found. PARTICIPANTS' ability to assimilate CIPM into the breast cancer experience was affected by the magnitude of physiologic and psychosocial effects, access to health care, information and support, sense of control, and acculturation level. CONCLUSIONS: The CIPM experience for Latinas with breast cancer is multifaceted, with less acculturated Latinas facing multiple barriers in accessing health care, treatment, information, and support. INTERPRETATION: PARTICIPANTS described CIPM as part of a larger context that included physiologic and psychosocial effects and affected participants' ability to assimilate CIPM into the breast cancer experience. The impact of low acculturation and barriers experienced were elucidated as factors associated with assimilating CIPM into the breast cancer experience.

Ethnic specificity of variants of the ESR1, HK3, BRSK1 genes and the 8q22.3 locus: no association with premature ovarian failure (POF) in Serbian women.

OBJECTIVE: To identify whether variants found in a large Han Chinese cohort - 8q22.3 SNPs rs3847153 and rs3108910; and one SNP each in HK3 (rs2278493), ESR1 (rs2234693) and BRSK1 (rs12611091) - are associated with premature ovarian failure (POF) in a different ethnic group (Serbian). DESIGN: Case-control genetic association study in 197 Serbian POF cases and 552 matched controls. RESULTS: None of the SNPs found associated with POF in Chinese cohort were found to be associated in the Serbian sample. CONCLUSIONS: In contrast to Han Chinese, no association was found between POF in Serbian women and any of the four tested loci: 8q22.3, HK3, ESR1 and BRSK1. This indicates that ethnically distinct populations may show differences in gene-regulating pathways and genes causing POF.

Factors associated with menopausal age in Iranian women: Tehran Lipid and Glucose Study.

AIM: Menopause, considered a special event in a woman's life, has a wide age range, 40-60 years, and there is no consensus regarding the factors influencing it. We aimed to assess factors affecting the menopausal age in a population of women participants of the Tehran Lipid and Glucose Study. MATERIAL AND METHODS: For the present study, 1114 women were selected from among participants of the Tehran Lipid and Glucose Study. Following implementation of our inclusion criteria, their reproductive histories and demographic background as well as anthropometric parameters were assessed, and ordinal regression analysis was conducted using spss version 15. RESULTS: The mean estimated age at menopause ± standard deviation was 49.6 ± 4.5 years. Menopausal age was considerably lower among women with a history of smoking (P = 0.05), and it increased with increasing age of menarche (P = 0.04) and number of children (P = 0.05). There was no significant correlation between the mean age of menopause and the educational level and anthropometric parameters. CONCLUSION: The smoking status, parity and the age of menarche are the influencing factors of age at menopause among the Iranian population.

Blepharophimosis, ptosis, epicanthus inversus syndrome with translocation and deletion at chromosome 3q23 in a black African female.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disorder whose main features are the abnormal shape, position and alignment of the eyelids. Type I refers to BPES with female infertility from premature ovarian failure while type II is limited to the ocular features. A causative gene, FOXL2, has been localized to 3q23. We report a black female who carried a de novo chromosomal translocation and 3.13 Mb deletion at 3q23, 1.2 Mb 5' to FOXL2. This suggests the presence of distant cis regulatory elements at the extended FOXL2 locus. In spite of 21 protein coding genes in the 3.13 Mb deleted segment, the patient had no other malformation and a strictly normal psychomotor development at age 2.5 years. Our observation confirms panethnicity of BPES and adds to the knowledge of the complex cis regulation of human FOXL2 gene expression.

Genetic analysis of the FOXL2 gene using quantitative real-time PCR in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

PURPOSE: The purpose of this study was to identify the mutation(s) or deletion(s) of the forkhead box protein L2 (FOXL2) gene in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). METHODS: Genomic DNA extracted from peripheral blood was collected from two Chinese families and from one sporadic case. PCR direct sequencing and quantitative real-time PCR-based copy number screening for the whole exon of FOXL2 were performed. RESULTS: Direct sequencing revealed an indel mutation c.50C→TA in the sporadic case which resulted in a frameshift generating 78 novel amino acids and terminating prematurely at codon 95. Deletions in the FOXL2 gene were confirmed by quantitative real-time PCR (q-real-time PCR) in two families in which intragenic mutations were excluded by direct sequencing. These changes containing deletions and a de novo mutation were not detected either in the non-carrier relatives or in 100 normal controls. CONCLUSIONS: This study identified two deletions and a de novo mutation in the FOXL2 gene in Chinese BPES patients. This is the first study to report FOXL2 gene deletions detected by q-real-time PCR in this ethnic group. This technique enriches the diagnostic methods of molecular genetics in BPES patients. The de novo mutation expands the mutation spectrum of FOXL2.

Early menopause association with employment, smoking, divorced marital status and low leptin levels.

AIMS: The aims of this study were (1) to investigate the determining risk factors related to early menopause and (2) to compare the relationships between demographic characteristics and hormonal status and leptin levels in subjects with early (no surgical) and natural menopause. STUDY DESIGN: The prospective study was conducted on 500 women with early and 2700 women with natural menopause. Detailed information was collected about their employment status, past and present smoking habits, coffee and alcohol use, educational level and other factors relevant to health. Thirty participants with early menopause and 30 participants with natural menopause were evaluated for hormone and leptin levels. RESULTS: Employment status (OR: 1.94), current smoking (OR: 1.80) and divorced marital status (OR: 1.79) were found to be significant risk factors for early menopause. Mean levels of leptin in natural and early menopause were measured 11.40 ± 4.1 ng/ml and 8.01 ± 3.9 ng/ml, respectively (p = 0001). Leptin levels in the early (r = 0.765, p = 0.001) and natural (r = 0.750, p = 0.001) menopause subjects correlated positively with oestradiol (E2) levels. CONCLUSION: This study shows that early onset of menopause is correlated with smoking, employment status, divorced marital status and lower leptin levels.

Predictors of premature gonadal failure in patients with systemic lupus erythematosus. Results from LUMINA, a multiethnic US cohort (LUMINA LVIII).

OBJECTIVE: To examine the predictors of time to premature gonadal failure (PGF) in patients with systemic lupus erythematosus from LUMINA, a multiethnic US cohort. METHODS: PGF was defined according to the SLICC Damage Index (SDI). Factors associated with time to PGF occurrence were examined by univariable and multivariable Cox proportional hazards regression analyses: three models according to cyclophosphamide use, at T0 (model 1), over time (model 2) and the total number of intravenous pulses (model 3). RESULTS: Thirty-seven of 316 women (11.7%) developed PGF (19 Texan-Hispanics, 14 African-Americans, four Caucasians and no Puerto Rican-Hispanics). By multivariable analyses, older age at T0 (hazards ratio (HR) = 1.10-1.14; 95% CI 1.02-1.05 to 1.19-1.23) and disease activity (Systemic Lupus Activity Measure-Revised) in all models (HR = 1.22-1.24; 95% CI 1.10-1.12 to 1.35-1.37), Texan-Hispanic ethnicity in models 2 and 3 (HR = 4.06-5.07; 95% CI 1.03-1.25 to 15.94-20.47) and cyclophosphamide use in models 1 and 3 (1-6 pulses) (HR = 4.01-4.65; 95% CI 1.55-1.68 to 9.56-13.94) were predictors of a shorter time to PGF. CONCLUSIONS: Disease activity and Texan-Hispanic ethnicity emerged as predictors of a shorter time to PGF while the associations with cyclophosphamide use and older age were confirmed. Furthermore, cyclophosphamide induction therapy emerged as an important determinant of PGF.

Regional differences in age at menopause between Korean-Korean and Korean-Chinese.

OBJECTIVE: To evaluate the difference in age at menopause between Korean-Korean (KK) women and Korean-Chinese (KC) women. DESIGN: A total of 1,972 participants were recruited: 961 postmenopausal women living in Korea, and 1,011 second- or third-generation emigrants to China. A structured questionnaire was used that included current age (at interview), age at menopause, weight, height, duration of education, socioeconomic status (SES), smoking, alcohol intake, number of children and abortions, etc. For every independent variable, the effect of regional difference (ie, living in Korea or China) on age at menopause was analyzed. Student's t test and chi2 test were applied as appropriate, and multiple regression analyses were performed for significant variables. RESULTS: Age at menopause was significantly higher in KK than KC (49.3 +/- 3.5 y vs 48.9 +/- 3.1 y, P = 0.011). Body mass index (BMI) and number of abortions were also higher in KK (23.3 +/- 2.7 vs 23.1 +/- 2.6, P = 0.021; 1.3 +/- 1.7 vs 0.2 +/- 0.7, P = 0.0001). Duration of education was significantly longer in KK. Smokers showed a significantly earlier menopause onset. BMI was significantly and positively correlated with age at menopause, whereas current SES was negatively correlated. When regional differences were assessed in each categorized subgroup, age at menopause showed a significant difference, too. After adjusting for age, SES, BMI, smoking, and number of children, onset of menopause was still earlier in KC (P = 0.0001, R = 0.037). CONCLUSION: KK women were found to have a later onset of menopause than KC women, and our results suggest that, apart from the well-known genetic influence, environmental effects play a significant role in determining age at menopause.

Onset of natural menopause in African American women.

OBJECTIVES: This study assessed predictors of the onset of natural menopause in African American women. METHODS: We used mailed questionnaires to collect data at baseline in 1995 and during follow-up from Black Women's Health Study participants. Cox proportional hazards regression was used to assess potential predictors-including experiences of racism-of the onset of natural menopause among 17 070 women aged 35 to 55 years and premenopausal in 1995. RESULTS: The hazard ratio (HR) was 1.43 for current smokers (95% confidence interval [CI] = 1.24, 1.66) and 1.21 (95% CI = 1.06, 1.38) for ex-smokers and significantly less for obese women and oral contraceptive users. Hazard ratios for most questions about racism were elevated by 10% to 30% but were not statistically significant. CONCLUSIONS: Earlier onset of natural menopause among African American women is strongly associated with smoking and inversely associated with body mass index and oral contraceptive use.

Premature menopause in a multi-ethnic population study of the menopause transition.

BACKGROUND: Premature menopause, also termed premature ovarian failure (POF), is characterized by cessation of menstruation before the age of 40 years. Little information is available on the general prevalence of POF or on the prevalence by ethnic group. There is also a lack of information on the association of POF with health indicators. METHODS: A cross-sectional survey of women aged 40-55 years was conducted at seven sites in the USA to determine eligibility for a community-based, multi-ethnic longitudinal study of the peri-menopause (The Study of Women Across the Nation, SWAN). Interview data were used to (i). determine the prevalence of self-reported POF overall and by ethnic group, and (ii). assess the association of POF with selected self-reported variables related to health. Cases of POF included only women with no discernible cause for POF. RESULTS: POF was reported by 1.1% (126/11 652) of women. By ethnicity, 1.0% (95% CI, 0.7-1.4) of Caucasian, 1.4% (95% CI, 1.0-2.1) of African American, 1.4% (95% CI, 0.8-2.5) of Hispanic, 0.5% (95% CI, 0.1-1.9) of Chinese and 0.1% (95% CI, 0.02-1.1) of Japanese women experienced POF. The differences in frequency across ethnic groups were statistically significant (P = 0.01). Only Caucasian, African American and Hispanic women were included in further analyses since too few Asian women had POF. In a multivariate model, POF was independently associated with osteoporosis, female hormone use (excluding oral contraceptives), higher body mass index (BMI) and current smoking after adjustment for education level, ability to pay for basics, site and age at interview. In Caucasian women, use of female hormones, osteoporosis, severe disability and smoking were significantly associated with POF. In contrast, POF in African American women was associated with higher BMI and female hormone use, but not osteoporosis. CONCLUSIONS: The prevalence of POF appears to vary by ethnicity. Health factors associated with POF also vary by ethnicity but because of the cross-sectional study design, it is not possible to determine cause and effect relationships. Health risks of POF would benefit from further study.

Age at menopause and prevalence of its different types in contemporary Greek women.

OBJECTIVE: This study attempted to estimate the mean age at menopause and also characterize and quantify its types and frequencies in Greek women who have recently become postmenopausal. DESIGN: A retrospective analysis of hospital records was used to record the frequency of natural, spontaneous or induced premature, and delayed natural menopause; the mean age at menopause of each group; and their possible interrelationships with major events of reproductive history in 1,747 women visiting an endocrine clinic 1 to 5 years after menopause. A group of 438 postmenopausal women drawn from 4,000 cases from the nongynecological clinics of this hospital comprised the control group. RESULTS: Natural menopause was found in 1,333 (76.3%) women with a median age of 51 (95% CI, 50.8-51.2) and mean +/- SD of 48.7 +/- 3.8 years. Medically induced menopause after the age of 40 was recorded in 204 women (11.7%), spontaneous premature in 127 (7.1%), medically induced premature in 60 (3.7%), and delayed menopause in 26 (1.5%), with mean ages of 43.6 +/- 1.7, 35.1 +/- 3.3, 37.2 +/- 1.6, and 59.6 +/- 2.1 years, respectively. No significant differences in mean age at menopause or its types were noted between the two groups. Furthermore, no significant correlations among the parameters examined could be demonstrated except between smoking and age at menopause in the spontaneous premature menopause subgroup (P < 0.05). Finally, ovarian autoantibodies were found in 6.7% of the tested women with premature menopause. CONCLUSIONS: Natural menopause occurred at a mean age of 48.7 years in Greek women, who displayed an unexpectedly high prevalence of spontaneous or induced premature cessation of menstruation.