Genetic insights into the age-specific biological mechanisms governing human ovarian aging.

There is currently little evidence that the genetic basis of human phenotype varies significantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural menopause (ANM) in the UK Biobank show a form of age-specific effect. Nineteen of these replicated discoveries are identified only by our modeling framework, which determines the time dependency of DNA-variant age-at-onset associations without a significant multiple-testing burden. Across the range of early to late menopause, we find evidence for significantly different underlying biological pathways, changes in the signs of genetic correlations of ANM to health indicators and outcomes, and differences in inferred causal relationships. We find that DNA damage response processes only act to shape ovarian reserve and depletion for women of early ANM. Genetically mediated delays in ANM were associated with increased relative risk of breast cancer and leiomyoma at all ages and with high cholesterol and heart failure for late-ANM women. These findings suggest that a better understanding of the age dependency of genetic risk factor relationships among health indicators and outcomes is achievable through appropriate statistical modeling of large-scale biobank data.

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.

Reproductive factors and cardiovascular health in post-menopausal women: a special focus on natural menopause.

Female-specific reproductive factors might contribute to increased risk of cardiovascular disease, and the American Heart Association (AHA) recently proposed Life's Essential 8 (LE8) score to quantify cardiovascular health (CVH). The study aimed to examine the relationships between reproductive factors and the LE8 score among post-menopause women in the United States. We enrolled 3223 post-menopause women from National Health and Nutrition Examination Survey (NHANES). CVH groups based on LE8 score were low (0-49), moderate (50-79), and high good CVH levels (80-100). Multivariate ordinal logistic regressions were applied to estimate the associations between reproductive factors and the LE8 score. In multivariate model, early menarche (OR: 0.69, 95 percent CI: 0.51-0.93) and early menopause (OR: 0.57, 95 percent CI: 0.43-0.77) were associated with LE8 score compared with normal menarche and menopause; Meanwhile, ages at menarche and menopause were positively correlated with LE8 score. The number of pregnancies and full-term pregnancies were negatively associated with LE8 (OR for per pregnancy increase and 95 percent CI, 0.93 (0.88, 0.98), 0.93 (0.87, 0.99), separately). Overall, natural menopausal women with early age at menarche and menopause, and a higher number of pregnancies may have a high risk of lower CVH, and need to focus on their CVH.

Age at menopause and all-cause and cause-specific dementia: a prospective analysis of the UK Biobank cohort.

STUDY QUESTION: Are there associations between natural or surgical menopause and incident dementia by age at menopause? SUMMARY ANSWER: Compared to age at menopause of 46-50 years, earlier natural menopause (≤40 and 41-45 years) was related to higher risk of all-cause dementia, while a U-shape relationship was observed between age at surgical menopause and risk of dementia. WHAT IS KNOWN ALREADY: Menopause marks the end of female reproductive period. Age at menopause reflects the length of exposure to endogenous estrogen. Evidence on the association between age at natural, surgical menopause, and risk of dementia has been inconsistent. STUDY DESIGN, SIZE, DURATION: A population-based cohort study involving 160 080 women who participated in the UK Biobank study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with no dementia at baseline, and had no missing data on key exposure variables and covariates were included. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs on the association of categorical menopause age with incident all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VD). Restricted cubic splines were used to model the non-linear relationship between continuous age at natural, surgical menopause, and risk of dementia. In addition, we analyzed the interaction effect of ever-used menopausal hormone therapy (MHT) at baseline, income level, leisure activities, and age at menopause on risk of dementia. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to women with age at menopause of 46-50 years, women with earlier natural menopause younger than 40 years (1.36, 1.01-1.83) and 41-45 years (1.19, 1.03-1.39) had a higher risk of all-cause dementia, while late natural menopause >55 years was linked to lower risk of dementia (0.83, 0.71-0.98). Compared to natural menopause, surgical menopause was associated with 10% higher risk of dementia (1.10, 0.98-1.24). A U-shape relationship was observed between surgical menopause and risk of dementia. Women with surgical menopause before age 40 years (1.94, 1.38-2.73) and after age 55 years (1.65, 1.21-2.24) were both linked to increased risk of all-cause dementia. Women with early natural menopause without ever taking MHT at baseline had an increased risk of AD. Also, in each categorized age at the menopause level, higher income level or higher number of leisure activities was linked to a lowers risk of dementia. LIMITATIONS, REASONS FOR CAUTION: Menopausal age was based on women's self-report, which might cause recall bias. WIDER IMPLICATION OF THE FINDINGS: Women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures to delay the development of dementia. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Start-up Foundation for Scientific Research in Shandong University (202099000066), Science Fund Program for Excellent Young Scholars of Shandong Provence (Overseas) (2022HWYQ-030), and the National Natural Science Foundation of China (82273702). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Association between ovarian reserve and spontaneous miscarriage and their shared genetic architecture.

STUDY QUESTION: Can potential mechanisms involved in the likely concurrence of diminished ovarian reserve (DOR) and miscarriage be identified using genetic data? SUMMARY ANSWER: Concurrence between ovarian reserve and spontaneous miscarriage was observed, and may be attributed to shared genetic risk loci enriched in antigen processing and presentation and autoimmune disease pathways. WHAT IS KNOWN ALREADY: Previous studies have shown that lower serum anti-Müllerian hormone (AMH) levels are associated with increased risk of embryo aneuploidy and spontaneous miscarriage, although findings have not been consistent across all studies. A recent meta-analysis suggested that the association between DOR and miscarriage may not be causal, but rather a result of shared underlying causes such as clinical conditions or past exposure. Motivated by this hypothesis, we conducted the present analysis to explore the concurrence between DOR and miscarriage, and to investigate potential mechanisms using genetic data. STUDY DESIGN, SIZE, DURATION: Three data sources were used in the study: the clinical IVF data were retrospectively collected from an academically affiliated Reproductive Medicine Center (17 786 cycles included); the epidemiological data from the UK Biobank (UKB), which is a large-scale, population-based, prospective cohort study (35 316 white women included), were analyzed; and individual-level genotype data from the UKB were extracted for further analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were three modules of analysis. First, clinical IVF data were used to test the association between ovarian reserve biomarkers and the subsequent early spontaneous miscarriage risk. Second, the UKB data were used to test the association of spontaneous miscarriage history and early menopause. Third, individual-level genotype data from the UKB were analyzed to identify specific pleiotropic genes which affect the development of miscarriage and menopause. MAIN RESULTS AND THE ROLE OF CHANCE: In the analysis of clinical IVF data, the risk of early spontaneous miscarriage was 1.57 times higher in the group with AMH < 1.1 ng/ml group (P < 0.001), 1.62 times for antral follicular count <5 (P < 0.001), and 1.39 times for FSH ≥10 mIU/ml (P < 0.001) in comparison with normal ovarian reserve groups. In the analysis of UKB data, participants with a history of three or more miscarriages had a one-third higher risk of experiencing early menopause (odds ratio: 1.30, 95% CI 1.13-1.49, P < 0.001), compared with participants without spontaneous miscarriage history. We identified 158 shared genetic risk loci that affect both miscarriage and menopause, which enrichment analysis showed were involved in antigen processing and presentation and autoimmune disease pathways. LIMITATIONS, REASONS FOR CAUTION: The analyses of the UKB data were restricted to participants of European ancestry, as 94.6% of the cohort were of white ethnicity. Further studies are needed in non-white populations. Additionally, maternal age at the time of spontaneous miscarriage was not available in the UKB cohort, therefore we adjusted for age at baseline assessment in the models instead. It is known that miscarriage rate in IVF is higher compared to natural conception, highlighting a need for caution when generalizing our findings from the IVF cohort to the general population. WIDER IMPLICATIONS OF THE FINDINGS: Our findings have implications for IVF clinicians in terms of patient counseling on the prognosis of IVF treatment, as well as for genetic counseling regarding miscarriage. Our results highlight the importance of further research on the shared genetic architecture and common pathophysiological basis of DOR and miscarriage, which may lead to new therapeutic opportunities. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Hunan Youth Science and Technology Innovation Talent Project (2020RC3060), the International Postdoctoral Exchange Fellowship Program (Talent-Introduction Program, YJ20220220), the fellowship of China Postdoctoral Science Foundation (2022M723564), and the Natural Science Foundation of Hunan Province, China (2023JJ41016). This work has been accepted for poster presentation at the 39th Annual Meeting of ESHRE, Copenhagen, Denmark, 25-28 June 2023 (Poster number: P-477). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Progress in genome-wide association studies of age at natural menopause.

Menopause is not only the end of reproductive life, it is also related to diseases such as hyperlipidaemia, atherosclerotic cardiovascular disease, osteoporosis and breast cancer. Traditional epidemiological studies have found that heredity is the main determinant of age at natural menopause (ANM). Early studies on genetic factors were limited to candidate gene studies. Menopause age is not inherited by a single gene, but is the result of multiple gene effects. With the development of genomic technology, the Reproductive Genetics Consortium conducted several genome-wide association studies on ANM in people of European descent, and found that defects in DNA damage repair pathways were the main genetic mechanism. In recent years, due to the ethnic heterogeneity of ANM, there has been further development of global studies into multi-ethnic and trans-ethnic genome-wide association studies. Further genetic and epidemiological studies, including polygenetic score and genetic mechanism research, should be conducted to investigate the pathogenesis and mechanism with respect to menopause and its related diseases.

Is there a link between infertility, miscarriage, stillbirth, and premature or early menopause? Results from pooled analyses of 9 cohort studies.

BACKGROUND: Some reproductive factors (such as age at menarche and parity) have been shown to be associated with age at natural menopause, but there has been little quantitative analysis of the association between infertility, miscarriage, stillbirth, and premature (<40 years) or early menopause (40-44 years). In addition, it has been unknown whether the association differs between Asian and non-Asian women, although the age at natural menopause is younger among Asian women. OBJECTIVE: This study aimed to investigate the association of infertility, miscarriage, and stillbirth with age at natural menopause, and whether the association differed by race (Asian and non-Asian). STUDY DESIGN: This was a pooled individual participant data analysis from 9 observational studies contributing to the InterLACE consortium. Naturally postmenopausal women with data on at least 1 of the reproductive factors (ie, infertility, miscarriage, and stillbirth), age at menopause, and confounders (ie, race, education level, age at menarche, body mass index, and smoking status) were included. A multinomial logistic regression model was used to estimate relative risk ratios and 95% confidence intervals for the association of infertility, miscarriage, and stillbirth with premature or early menopause, adjusting for confounders. Between-study difference and within-study correlation were taken into account by including study as a fixed effect and indicating study as a cluster variable. We also examined the association with number of miscarriages (0, 1, 2, ≥3) and stillbirths (0, 1, ≥2), and tested whether the strength of association differed between Asian and non-Asian women. RESULTS: A total of 303,594 postmenopausal women were included. Their median age at natural menopause was 50.0 years (interquartile range, 47.0-52.0). The percentages of women with premature and early menopause were 2.1% and 8.4%, respectively. The relative risk ratios (95% confidence intervals) of premature and early menopause were 2.72 (1.77-4.17) and 1.42 (1.15-1.74) for women with infertility; 1.31 (1.08-1.59) and 1.37 (1.14-1.65) for women with recurrent miscarriages; and 1.54 (1.52-1.56) and 1.39 (1.35-1.43) for women with recurrent stillbirths. Asian women with infertility, recurrent miscarriages (≥3), or recurrent stillbirths (≥2) had higher risk of premature and early menopause compared with non-Asian women with the same reproductive history. CONCLUSION: Histories of infertility and recurrent miscarriages and stillbirths were associated with higher risk of premature and early menopause, and the associations differed by race, with stronger associations for Asian women with such reproductive history.

Genetic prediction of age at menarche, age at natural menopause and type 2 diabetes: A Mendelian randomization study.

BACKGROUND AND AIMS: The relationship between reproductive factors and type 2 diabetes (T2D) is controversial; therefore, we explored the causal relationship of age at menarche (AAM), age at natural menopause (ANM), with the risk of T2D and glycemic traits using two-sample Mendelian randomization. METHODS AND RESULTS: We used publicly available data at the summary level of genome-wide association studies, where AAM (N = 329,345), ANM (N = 69,360), T2D (N = 464,389). The inverse variance weighting (IVW) method was employed as the primary method. To demonstrate the robustness of the results, we also conducted various sensitivity analysis methods including the MR-Egger regression, the weighted median (WM) and the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. After excluding IVs associated with confounders, we found a causal association between later AAM and reduced risk of T2D (OR 0.81 [95% CI 0.75, 0.87]; P = 2.20 × 10-8), lower levels of FI (ß -0.04 [95% CI -0.06, -0.01]; P = 2.19 × 10-3), FPG (ß -0.03 [95% CI -0.05, -0.007]; P = 9.67 × 10-5) and HOMA-IR (ß -0.04 [95% CI -0.06, -0.01]; P = 4,95 × 10-3). As for ANM, we only found a causal effect with HOMA-IR (ß -0.01 [95% CI -0.02, -0.005]; P = 1.77 × 10-3), but not with T2D. CONCLUSIONS: Our MR study showed a causal relationship between later AAM and lower risk of developing T2D, lower FI, FPG and HOMA-IR levels. This may provide new insights into the prevention of T2D in women.

Association of weight, smoking, and alcohol consumption with age at natural menopause.

In South Korea, rapid economic growth and modernization have led to changes in lifestyle factors that may affect age at natural menopause. Data from 4,793 women aged ≥55 years, who had a natural menopause, were analyzed from the Korea National Health and Nutrition Examination Survey (2013-2017). Multinomial logistic regression was used to examine the association between lifestyle factors and age at natural menopause after adjusting for birth cohort (Model 1) and sociodemographic and reproductive factors (Model 2). Overall, 3.1% of women experienced premature menopause (<40 years), 7.6% early menopause (40-44 years), and 12.8% late menopause (≥55 years). Women born in the 1940s or earlier among the birth cohorts had the highest prevalence of premature (70.0%), early (58.5%), and late (43.1%) menopause. In Model 2, current smoking (odds ratio = 3.99 and 95% confidence interval = 1.35-11.81) was associated with premature menopause. Low (<18.5 kg/m2) and high (≥25 kg/m2) body mass index were associated with early (odds ratio = 2.30 and 95% confidence interval = 1.01-5.22) and late (odds ratio = 1.38 and 95% confidence interval = 1.10-1.72) menopause respectively. Conversely, there was no association between age at natural menopause and alcohol consumption. The results suggest that healthy lifestyle factors, such as not smoking and proper weight maintenance, are significant factors affecting age at natural menopause. Our findings may help develop health policies and provide targeted care to improve women's health after midlife.

Menopause, hysterectomy, menopausal hormone therapy and cause-specific mortality: cohort study of UK Biobank participants.

STUDY QUESTION: What is the association between menopausal hormone therapy (MHT) and cause-specific mortality? SUMMARY ANSWER: Self-reported MHT use following early natural menopause, surgical menopause or premenopausal hysterectomy is associated with a lower risk of breast cancer mortality and is not consistently associated with the risk of mortality from cardiovascular disease or other causes. WHAT IS KNOWN ALREADY: Evidence from the Women's Health Initiative randomized controlled trials showed that the use of estrogen alone is not associated with the risk of cardiovascular mortality and is associated with a lower risk of breast cancer mortality, but evidence from the Million Women Study showed that use of estrogen alone is associated with a higher risk of breast cancer mortality. STUDY DESIGN, SIZE, DURATION: Cohort study (the UK Biobank), 178 379 women, recruited in 2006-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Postmenopausal women who had reported age at menopause (natural or surgical) or hysterectomy, and information on MHT and cause-specific mortality. Age at natural menopause, age at surgical menopause, age at hysterectomy and MHT were exposures of interest. Natural menopause was defined as spontaneous cessation of menstruation for 12 months with no previous hysterectomy or oophorectomy. Surgical menopause was defined as the removal of both ovaries prior to natural menopause. Hysterectomy was defined as removal of the uterus before natural menopause without bilateral oophorectomy. The study outcome was cause-specific mortality. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 178 379 women included, 136 790 had natural menopause, 17 569 had surgical menopause and 24 020 had hysterectomy alone. Compared with women with natural menopause at the age of 50-52 years, women with natural menopause before 40 years (hazard ratio (HR): 2.38, 95% CI: 1.64, 3.45) or hysterectomy before 40 years (HR: 1.60, 95% CI: 1.23, 2.07) had a higher risk of cardiovascular mortality but not cancer mortality. MHT use was associated with a lower risk of breast cancer mortality following surgical menopause before 45 years (HR: 0.17, 95% CI: 0.08, 0.36), at 45-49 years (HR: 0.15, 95% CI: 0.07, 0.35) or at ≥50 years (HR: 0.28, 95% CI: 0.13, 0.63), and the association between MHT use and the risk of breast cancer mortality did not differ by MHT use duration (<6 or 6-20 years). MHT use was also associated with a lower risk of breast cancer mortality following natural menopause before 45 years (HR: 0.59, 95% CI: 0.36, 0.95) or hysterectomy before 45 years (HR: 0.49, 95% CI: 0.32, 0.74). LIMITATIONS, REASONS FOR CAUTION: Self-reported data on age at natural menopause, age at surgical menopause, age at hysterectomy and MHT. WIDER IMPLICATIONS OF THE FINDINGS: The current international guidelines recommend women with early menopause to use MHT until the average age at menopause. Our findings support this recommendation. STUDY FUNDING/COMPETING INTEREST(S): This project is funded by the Australian National Health and Medical Research Council (NHMRC) (grant numbers APP1027196 and APP1153420). G.D.M. is supported by NHMRC Principal Research Fellowship (APP1121844), and M.H. is supported by an NHMRC Investigator Grant (APP1193838). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Is there any difference in hearing function between surgical and natural menopause?

This study was designed to examine cochlear function in surgical postmenopausal women and natural menopause. Three groups, each including 20 patients, were formed: surgical menopause (SM), natural menopause (NM), and healthy controls who had not yet gone through menopause. Conventional audiometry (0.125-8 kHz), ultra-high frequency audiometry (10-16 kHz), and otoacoustic emission (OAE) tests were used in the evaluation of the patients. Almost all the hearing thresholds were significantly poorer in the menopause groups than in the control group (p < .05). However, the amplitudes of the healthy controls were higher in transient evoked otoacoustic emissions (TEOAEs), especially in many frequencies of distortion product otoacoustic emissions (DPOAEs) (p < .05). In the SM group, all the frequencies between 0.125 and 10 kHz for the right ear, and 1, 2, 6 and 8 kHz air-conduction hearing thresholds for the left ear were significantly poorer compared to the NM group (p < .05). There was also a significant decrease in the 4, 6, and 8 kHz DPOAE amplitudes of the SM group compared to the NM group (p < .05). This study showed that postmenopausal women, in particular those with SM had significantly poorer hearing thresholds and lower OAE amplitudes. Menopause may be a potential risk factor for the development of hearing loss in women.

The relevance of the endocrine condition in microglia morphology and dendrite complexity of doublecortin-associated neurons in young adult and middle-aged female rats exposed to acute stress.

Menopause, natural or surgical, might facilitate the onset of psychiatric pathologies. Some reports suggest that their severity could increase if the decline of ovarian hormones occurs abruptly and before natural endocrine senescence. Therefore, we compared the effects of ovariectomy on microglia's morphological alterations, the complexity of newborn neurons, and the animal's ability to cope with stress. Young adult (3 months) and middle-aged (15 months) female Wistar rats were subjected to an ovariectomy (OVX) or were sham-operated. After 3 weeks, animals were assigned to one of the following independent groups: (1) young adult OVX + no stress; (2) young adult sham + no stress; (3) young adult OVX + stress; (4) young adult sham + stress; (5) middle-aged OVX + no stress; (6) middle-aged sham + no stress; (7) middle-aged OVX + stress; (8) middle-aged sham + stress. Acute stress was induced by forced swimming test (FST) exposure. Immobility behavior was scored during FST and 30 min after; animals were euthanized, their brains collected and prepared for immunohistochemical detection of Iba-1 to analyze morphological alterations in microglia, and doublecortin (DCX) detection to evaluate the dendrite complexity of newborn neurons. OVX increased immobility behavior, induced microglia morphological alterations, and reduced dendrite complexity of newborn neurons in young adult rats. FST further increased this effect. In middle-aged rats, the main effects were related to the aging process without OVX or stress exposure. In conclusion, surgical menopause favors in young adult rats, but not in middle-aged, the vulnerability to develop immobility behavior, retracted morphology of microglial cells, and decreased dendrite complexity of newborn neurons.

Association of oral contraceptives and tubal ligation with risk of early natural menopause.

STUDY QUESTION: What is the association of oral contraceptives (OCs) and tubal ligation (TL) with early natural menopause? SUMMARY ANSWER: We did not observe an association of OC use with risk of early natural menopause; however, TL was associated with a modestly higher risk. WHAT IS KNOWN ALREADY: OCs manipulate hormone levels, prevent ovulation, and may modify the rate of follicular atresia, while TL may disrupt the blood supply to the ovaries. These mechanisms may be associated with risk of early menopause, a condition associated with increased risk of cardiovascular disease and other adverse health outcomes. STUDY DESIGN, SIZE, DURATION: We examined the association of OC use and TL with natural menopause before the age of 45 years in a population-based study within the prospective Nurses' Health Study II (NHSII) cohort. Participants were followed from 1989 to 2017 and response rates were 85-90% for each cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants included 106 633 NHSII members who were premenopausal and aged 25-42 years at baseline. Use, duration and type of OC, and TL were measured at baseline and every 2 years. Menopause status and age were assessed every 2 years. Follow-up continued until early menopause, age 45 years, hysterectomy, oophorectomy, death, cancer diagnosis, or loss to follow-up. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs adjusted for lifestyle, dietary, and reproductive factors. MAIN RESULTS AND THE ROLE OF CHANCE: Over 1.6 million person-years, 2579 members of the analytic cohort experienced early natural menopause. In multivariable models, the duration, timing, and type of OC use were not associated with risk of early menopause. For example, compared with women who never used OCs, those reporting 120+ months of OC use had an HR for early menopause of 1.01 (95% CI, 0.87-1.17; P for trend=0.71). TL was associated with increased risk of early menopause (HR = 1.17, 95% CI, 1.06-1.28). LIMITATIONS, REASONS FOR CAUTION: Our study population is homogenous with respect to race and ethnicity. Additional evaluation of these relations in more diverse populations is important. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the largest study examining the association of OC use and TL with early natural menopause to date. While TL was associated with a modest higher risk of early menopause, our findings do not support any material hazard or benefit for the use of OCs. STUDY FUNDING/COMPETING INTEREST(S): The study was sponsored by UO1CA176726 and R01HD078517 from the National Institutes of Health and Department of Health and Human Services. The work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The authors have no competing interests to report. TRIAL REGISTRATION NUMBER: N/A.

Associations of age at natural menopause and occupations in Chinese female workers: A cross-sectional study.

AIMS: To investigate the impact of occupation types on age at natural menopause. METHODS: This is a nation-wide cross-sectional study based on 17,948 female workers aged over 40, who come from different industries or organizations. A face-to-face standardized questionnaire was conducted in all participants with the help of occupational hygienists. Occupational titles were coded according to the International Standard Classification of Occupations (2008) (ISCO08). Cox regression model was used to assess the association between each independent occupation and menopausal timing. Models were adjusted for marriage, education, average annual family income, parity, cigarette smoking, alcohol consumption. RESULTS: Higher risks of earlier age at natural menopause was found among legislators and senior officials (ISCO Minor group:111, HR = 2.328, P < 0.001), among other health associated professionals (ISCO Minor group: 325, HR = 1.477, P = 0.003), the workers involved in mining and mineral processing (ISCO Minor group: 811, HR = 1.515, P = 0.048) and metal processing and finishing (ISCO Minor group: 812, HR = 1.722, P < 0.001). Reduced risks of earlier age at natural menopause, including: finance professionals (ISCO Minor group: 241, HR = 0.751, P = 0.021), manufacturing and construction supervisors (ISCO Minor group: 312, HR = 0.477, P = 0.002), administrative and specialized secretaries (ISCO Minor group: 334, HR = 0.788, P = 0.045), cleaners and helpers (ISCO Minor group: 911, HR = 0.633, P = 0.01). CONCLUSIONS: This is the first study to address the influence of occupation types on reproductive aging, showing some specific occupations could be associated with age at natural menopause. Further investigations are necessary to clarify whether it is chance finding or a true association.

Cognitive function and associated factors among postmenopausal women with hypertension and natural menopause in Taiwan.

Hypertension is prevalent among postmenopausal women worldwide and is a risk factor for cognitive impairment. This study examined the cognitive differences between Taiwanese postmenopausal women with and without hypertension after natural menopause and identified factors associated with cognitive function in hypertensive postmenopausal women. A two-group comparative design study of 171 Taiwanese postmenopausal participants (mean age = 64.8±6.6) was conducted in southern Taiwan. Cognitive performance on neuropsychological tests was evaluated, and demographic, health, menopausal, and disease related variables were assessed. Compared to the non-hypertensive group, women with hypertension showed significantly worse performance and a higher percentage of impairment in global cognitive functioning and memory. Fewer years of education and longer duration of hypertension were associated with lower global cognitive function, and increased age was associated with lower scores in delayed memory. Cognitive screening as well as training on global cognitive functioning and memory are needed for postmenopausal hypertensive women. (148 words).

Age at natural menopause and development of chronic conditions and multimorbidity: results from an Australian prospective cohort.

STUDY QUESTION: Is age at natural menopause (ANM) associated with the development of multiple chronic conditions (multimorbidity) in postmenopausal life? SUMMARY ANSWER: Women with premature menopause experience increased odds of developing individual chronic conditions and multimorbidity. WHAT IS KNOWN ALREADY: ANM is considered as a marker of age-related morbidity and mortality in postmenopausal life. Multimorbidity affects more than 60% of older women and has been recognized as the most common 'chronic condition'. Few studies have examined the association between ANM and the development of multimorbidity. STUDY DESIGN, SIZE, DURATION: A prospective national cohort study of 11 258 Australian women, aged 45-50 years in 1996. Women were followed from 1996 to 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Information about ANM and 11 chronic conditions (diabetes, hypertension, heart disease, stroke, arthritis, osteoporosis, asthma, chronic obstructive pulmonary disease, depression, anxiety and breast cancer) were estimated approximately every 3 years. Multimorbidity is defined as 2 or more of these 11 conditions. Generalized estimating equations were used to link the categorical ANM with individual chronic conditions and multimorbidity. MAIN RESULTS AND THE ROLE OF CHANCE: Among 5107 women reporting ANM, 2.3% experienced premature menopause (≤40 years) and 55.1% developed multimorbidity. Compared with women who experienced menopause at age 50-51 years, women with premature menopause had twice the odds of experiencing multimorbidity by age 60 (OR = 1.98, 95% CI 1.31 to 2.98) and three times the odds of developing multimorbidity in their 60s (OR = 3.03, 95% CI 1.62 to 5.64). Women with premature menopause also experienced higher incidence of most individual chronic conditions. LIMITATIONS, REASONS FOR CAUTION: The main limitation of this study was the use of self-reported data, but with repeated assessments from prospective study design and the validity of most of the chronic conditions from hospital data, the potential for non-differential misclassification is minimized. WIDE IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study to assess the association of premature menopause and development of multimorbidity in a larger national cohort of mid-aged women. Health professionals should consider comprehensive screening and assessment of risk factors for multimorbidity when treating women who experienced premature menopause. STUDY FUNDING/COMPETING INTEREST(S): The Australian Longitudinal Study on Women's Health was supported by the Australian Government Department of Health. X.X. is funded by an International Postgraduate Research Scholarship from the Australian government and a UQ Centennial Scholarship from The University of Queensland. G.D.M. is supported by the National Health and Medical Research Council Principal Research Fellowship (APP1121844). None of the authors has any conflicts of interest to declare.

Type of menopause, age of menopause and variations in the risk of incident cardiovascular disease: pooled analysis of individual data from 10 international studies.

STUDY QUESTION: How does the risk of cardiovascular disease (CVD) vary with type and age of menopause? SUMMARY ANSWER: Earlier surgical menopause (e.g. <45 years) poses additional increased risk of incident CVD events, compared to women with natural menopause at the same age, and HRT use reduced the risk of CVD in women with early surgical menopause. WHAT IS KNOWN ALREADY: Earlier age at menopause has been linked to an increased risk of CVD mortality and all-cause mortality, but the extent that this risk of CVD varies by type of menopause and the role of postmenopausal HRT use in reducing this risk is unclear. STUDY DESIGN, SIZE, DURATION: Pooled individual-level data of 203 767 postmenopausal women from 10 observational studies that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Postmenopausal women who had reported menopause (type and age of menopause) and information on non-fatal CVD events were included. Type of menopause (natural menopause and surgical menopause) and age at menopause (categorised as <35, 35-39, 40-44, 45-49, 50-54 and ≥55 years) were exposures of interest. Natural menopause was defined as absence of menstruation over a period of 12 months (no hysterectomy and/or oophorectomy) and surgical menopause as removal of both ovaries. The study outcome was the first non-fatal CVD (defined as either incident coronary heart disease (CHD) or stroke) event ascertained from hospital medical records or self-reported. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CI for non-fatal CVD events associated with natural menopause and surgical menopause. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with natural menopause, surgical menopause was associated with over 20% higher risk of CVD (HR 1.22, 95% CI 1.16-1.28). After the stratified analysis by age at menopause, a graded relationship for incident CVD was observed with lower age at menopause in both types of natural and surgical menopause. There was also a significant interaction between type of menopause and age at menopause (P < 0.001). Compared with natural menopause at 50-54 years, women with surgical menopause before 35 (2.55, 2.22-2.94) and 35-39 years (1.91, 1.71-2.14) had higher risk of CVD than those with natural menopause (1.59, 1.23-2.05 and 1.51, 1.33-1.72, respectively). Women who experienced surgical menopause at earlier age (<50 years) and took HRT had lower risk of incident CHD than those who were not users of HRT. LIMITATIONS, REASONS FOR CAUTION: Self-reported data on type and age of menopause, no information on indication for the surgery (e.g. endometriosis and fibroids) and the exclusion of fatal CVD events may bias our results. WIDER IMPLICATIONS OF THE FINDINGS: In clinical practice, women who experienced natural menopause or had surgical menopause at an earlier age need close monitoring and engagement for preventive health measures and early diagnosis of CVD. Our findings also suggested that timing of menopause should be considered as an important factor in risk assessment of CVD for women. The findings on CVD lend some support to the position that elective bilateral oophorectomy (surgical menopause) at hysterectomy for benign diseases should be discouraged based on an increased risk of CVD. STUDY FUNDING/COMPETING INTEREST(S): InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). GDM is supported by Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844). There are no competing interests.

Chinese women with 29-30 FMR1 CGG repeats have an earlier menopause.

Purpose: A strong, well-established non-linear relationship exists between fragile X mental retardation (FMR1) premutation and menopausal age. The aim of this study is to evaluate whether this relationship continues into the normal CGG repeat range.Methods:FMR1 CGG repeats of 111 Chinese postmenopausal women from a prospective cohort and the relationship with age at menopause were analyzed. Associations of FMR1 genotypes with annually measured estradiol and follicle stimulating hormone (FSH) levels were also assessed.Results: One premutation and two intermediate carriers were identified, with a prevalence of 0.90% and 1.80%, respectively. The age at menopause differed with statistical significance (p = 0.007) between women carrying bi-allelic 29-30 repeats (49.66 ± 3.26 years) and those carrying a different number of repeats (51.26 ± 2.74 years). Age at menopause among subgroups (≤28, 29-30, and ≥31 repeats) of alleles 1 and 2 were also different (p = 0.014, p = 0.044). FSH trajectories to final menstrual period differed between women with the bi-allelic 29-30 repeats and others (p = 0.019).Conclusions: Women with 29-30 FMR1 CGG repeats may experience menopause approximately 2 years earlier than those carrying ≤28 or ≥31 CGG repeats, and have a longer FSH fluctuant period.

Premature natural menopause and cognitive function among older women in Indonesia.

We examine the association between premature natural menopause and cognitive function among older women in Indonesia. Data come from Indonesia Family Life Survey (IFLS) 2014 (N = 1,031 menopausal women). Multilevel ordered logistic regression was used to take into account unobserved factors in the women's communities, also considering a range of potential confounding factors including their reproductive histories, lifestyles, and sociodemographic characteristics. The findings show that premature natural menopause was significantly associated with lower cognitive function in later life (ß = -0.97, P< .01, CI -1.61-(-0.33)). The findings were robust against potential confounding factors including reproductive history, lifestyle, and sociodemographic characteristics.

Association of gene polymorphisms in the anti-Müllerian hormone signalling pathway with ovarian function: a systematic review and meta-analysis.

This systematic review evaluated whether single nucleotide polymorphisms of AMH and AMHRII genes are associated with ovarian function. A literature search of PubMed and Embase was complemented by hand searches in the reference lists. Eight studies involving 3155 participants were included in a meta-analysis and 10 studies included for description. For AMH c.146T>G polymorphism, no significant difference in serum anti-Müllerian hormone (AMH) levels was found between participants with different genotypes (weighted mean difference [WMD] 0.42, 95% confidence interval [CI] -0.16 to 0.99). Subgroup analyses showed similar results for the European region and in healthy and infertile populations. Regarding AMHRII -482 A>G, there was no significant difference in serum AMH levels between participants with A/A genotype and G/A or G/G genotype carriers (WMD -0.04, 95% CI -0.31 to 0.23). In subgroup analysis, an interesting trend was confirmed in healthy women and polycystic ovary syndrome (PCOS) patients (WMD -0.36, 95% CI -0.63 to -0.09, P = 0.009; WMD 0.46, 95% CI 0.15 to 0.77, P = 0.004). The review suggests that AMH c.146T>G is not associated with AMH levels, while AMHRII -482 A>G may be related to AMH levels in PCOS and healthy subgroups. However, the impact of polymorphisms in the AMH signalling pathway on ovarian function still requires further investigation.