Dissecting the shared genetic architecture between anti-Müllerian hormone and age at menopause based on genome-wide association study.

BACKGROUND: While the phenotypic association between anti-Müllerian hormoneand age at menopause has been widely studied, the role of anti-Müllerian hormone in predicting the age at menopause is currently controversial, and the genetic architecture or causal relationships underlying these 2 traits is not well understood. AIM: We aimed to explore the shared genetic architecture between anti-Müllerian hormone and age at menopause, to identify shared pleiotropic loci and genes, and to investigate causal association and potential causal mediators. STUDY DESIGN: Using summary statistics from publicly available genome-wide association studies on anti-Müllerian hormone (N=7049) and age at menopause (N=201,323) in Europeans, we investigated the global genetic architecture between anti-Müllerian hormone and age at menopause through linkage disequilibrium score regression. We employed pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation of Genetic Associations, multimarker analysis of GenoMic annotation, and colocalization analysis to identify loci and genes with pleiotropic effects. Tissue enrichment analysis based on Genotype-Tissue Expression data was conducted using the Linkage Disequilibrium Score for the specific expression of genes analysis. Functional genes that were shared were additionally identified through summary data-based Mendelian randomization. The relationship between anti-Müllerian hormone and age at menopause was examined through 2-sample Mendelian randomization, and potential mediators were further explored using colocalization and metabolite-mediated analysis. RESULTS: A positive genetic association (correlation coefficient=0.88, P=1.33×10-5) was observed between anti-Müllerian hormone and age at menopause. By using pleiotropic analysis under composite null hypothesis and Functional Mapping and Annotation of Genetic Associations, 42 significant pleiotropic loci were identified that were associated with anti-Müllerian hormone and age at menopause, and 10 of these (rs10734411, rs61913600, rs2277339, rs75770066, rs28416520, rs9796, rs11668344, rs403727, rs6011452, and rs62237617) had colocalized loci. Additionally, 245 significant pleiotropic genes were identified by multimarker analysis of GenoMic annotation. Genetic associations between anti-Müllerian hormone and age at menopause were markedly concentrated in various tissues including whole blood, brain, heart, liver, muscle, pancreas, and kidneys. Further, summary data-based Mendelian randomization analysis revealed 9 genes that may have a causative effect on both anti-Müllerian hormone and age at menopause. A potential causal effect of age at menopause on anti-Müllerian hormone was suggested by 2-sample Mendelian randomization analysis, with very-low-density lipoprotein identified as a potential mediator. CONCLUSION: Our study revealed a shared genetic architecture between anti-Müllerian hormone and age at menopause, providing a basis for experimental investigations and individual therapies to enhance reproductive outcomes. Furthermore, our findings emphasized that relying solely on anti-Müllerian hormone is not sufficient for accurately predicting the age at menopause, and a combination of other factors needs to be considered. Exploring new therapeutics aimed at delaying at the onset of menopause holds promise, particularly when targeting shared genes based on their shared genetic architecture.

Possible association between subclinical hypothyroidism and age at menopause in Colombian women.

OBJECTIVE: To evaluate the association between subclinical hypothyroidism with early menopause, premature menopause, and last menstrual bleeding before the natural age of menopause. METHODS: This was a cross-sectional study conducted in 643 postmenopausal women aged 40-69 years. Groups were formed according to last menstrual episode: ≥45 [Natural age at menopause], 40-44 and [Early menopause], <40 [Premature menopause], and <45 [last menstrual episode before the natural age of menopause]. The Zulewski scale was applied to identify manifestations related to hypothyroidism and subclinical hypothyroidism, diagnosed with a serum TSH > 4.5 µIU/mL plus T4-free between 0.7 and 1.9 ng/dL. RESULTS: It was found that 24.4% had the last menstrual episode before the natural age of menopause, 18.6% had early menopause, and 5.7% had premature menopause. Subclinical hypothyroidism was diagnosed in 4.5% of patients. Among women with subclinical hypothyroidism, there was a higher frequency of early menopause, premature menopause, and last menstrual episode before the natural age of menopause, than in women without subclinical hypothyroidism (p < 0.05). Paresthesia (50%) and dry skin (40.7%) were the most reported hypothyroidism-related manifestations. Early menopause, premature menopause, and last menstrual episode before the natural age of menopause were associated with subclinical hypothyroidism, OR: 3.37 [95% CI: 1.40-8.10], OR: 4.31 [95% CI: 1.24-14.97], and OR: 3.57 [95% CI: 1.57-8.10], respectively. CONCLUSIONS: The last menstrual episode before the natural age of menopause, early menopause, and premature menopause were significantly associated with a higher chance of subclinical hypothyroidism.

The relation between age at menopause and age at first childbirth.

Analysis of data from the representative "GGP - Contemporary Czech Family Survey" (2020-2022) on the population of women aged 40-69 years showed that the age of onset of menopause is associated with a low age at the birth of the first child. Women who had their first child before their 20th birthday, a pattern of reproductive behaviour common among generations of women before 1989, have an earlier onset of menopause than older first-time mothers. Conversely, the effect of higher age at first birth (35 years or more) on the delay of menopause has not been proved. However, this issue requires further investigation, as the sample analysed suggests certain tendencies. A larger sample size would be needed to make a conclusive finding.

Associations of reproductive factors with incidence of myocardial infarction and ischemic stroke in postmenopausal women: a cohort study.

BACKGROUND: To assess the association between the reproductive factors of age at menarche, age at menopause, and reproductive span and the incidence of myocardial infarction (MI) and ischemic stroke (IS). METHODS: We used a population-based retrospective cohort study from the National Health Insurance Service database of Korea including a total of 1,224,547 postmenopausal women. Associations between age at menarche (≤ 12, 13-14 [reference], 15, 16, and ≥ 17 years), age at menopause (< 40, 40-45, 46-50, 51-54 [reference], and ≥ 55 years), and reproductive span (< 30, 30-33, 34-36, 37-40 [reference], and ≥ 41 years) and the incidence of MI and IS were assessed by Cox proportional hazard models with adjustment for traditional cardiovascular risk factors and various reproductive factors. RESULTS: During a median follow-up of 8.4 years, 25,181 MI and 38,996 IS cases were identified. Late menarche (≥ 16 years), early menopause (≤ 50 years), and short reproductive span (≤ 36 years) were linearly associated with a 6%, 12-40%, and 12-32% higher risk of MI, respectively. Meanwhile, a U-shaped association between age at menarche and risk of IS was found, with a 16% higher risk in early menarche (≤ 12 years) and a 7-9% higher risk in late menarche (≥ 16 years). Short reproductive span was linearly associated with an increased risk of MI, whereas both shorter and longer reproductive spans were associated with an increased risk of IS. CONCLUSIONS: This study demonstrated different patterns of association between age at menarche and incidence of MI and IS: a linear association for MI versus a U-shaped association for IS. Female reproductive factors in addition to traditional cardiovascular risk factors should be considered when assessing overall cardiovascular risk in postmenopausal women.

The relationship of reproductive factors with adiposity and body shape indices changes overtime: findings from a community-based study.

BACKGROUND: Studies focusing on the relationships of adiposity and body shape indices with reproductive factors have reported conflicting results. This study aimed to investigate the influence of reproductive factors on adiposity and body shape indices changes overtime. MATERIALS AND METHODS: In this community-based prospective study, 1636 postmenopausal women were selected from Tehran Lipid and Glucose Study (TLGS). The unadjusted and adjusted Generalized Estimating Equation models (GEE) were applied to investigate secular longitudinal trends of adiposity and body shape indices. RESULTS: According to the adjusted GEE models, mean changes in body mass index (BMI) in women with early menarche was 1.18 kg/m2 higher than those with normal menarche age (P = 0.030). Moreover, the mean changes in BMI overtime were 0.11 kg/m2 higher in women with premature/early menopausal age than those with normal menopausal age (P = 0.012). Mean changes of waist circumference (WC) in women with late menopause were 2.27 cm higher than those with normal menopausal age (P = 0.036). We also observed higher mean changes in a body shape index (ABSI) in women with late menopause (P = 0.037), compared to those with normal menopausal age. We found a marginal effect of parity on BMI and WC as well. CONCLUSIONS: This study demonstrated higher BMI in females with earlier menarche age. We also showed higher values of BMI overtime in women with premature/ early menopause, whereas women with late menopausal age had higher WC and ABSI values. However, more longitudinal studies investigating body composition indices by adjusting all potential confounders are still required to confirm our study findings.

Predictable increase in female reproductive window: A simple model connecting age of reproduction, menopause, and longevity.

With the ever-increasing lifespan along with societal changes, women can marry and procreate later than in previous centuries. However, pathogenic genetic variants segregating in the population can lead to female subfertility or infertility well before the average age of normal menopause, leading to counter-selection of such deleterious alleles. In reviewing this field, we speculate that a logical consequence would be the later occurrence of menopause and the extension of women's reproductive lifespan. We illustrate this point with a simple model that applies to other variants that contribute to female infertility, including epigenetic variation. We also consider the effect of medical interventions and lifestyle.

Age at menopause and risk of heart failure and atrial fibrillation: a nationwide cohort study.

AIMS: This study aimed to examine the association of premature menopause and age at menopause with the risk of heart failure (HF) and atrial fibrillation (AF). METHODS AND RESULTS: A total of 1 401 175 postmenopausal women, who had undergone health examination provided by the Korean National Health Insurance Service, were included, and their reproductive histories were collected. Multivariable Cox proportional hazard models were performed to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HF and AF, according to the history of premature menopause and age at menopause. At a mean follow-up of 9.1 years, there were 42 699 (3.0%) and 44 834 (3.2%) new cases of HF and AF, respectively. Women with history of premature menopause had an increased risk of HF (HR: 1.33, 95% CI: 1.26-1.40) and AF (HR: 1.09, 95% CI: 1.02-1.16), compared to women without the history. Compared with women aged ≥50 years at menopause, those aged 45-49, 40-44, and <40 years at menopause showed a significantly increased trend in HRs for the incident risk of both HF and AF (P for trend <0.001). The robustness of the results of a series of sensitivity analyses further strengthens the main findings. CONCLUSION: Our findings suggest that postmenopausal women with a history of premature menopause or early menopausal age may have an increased risk of HF and AF. These reproductive factors need to be considered for preventing the future risk of HF and AF.

Exploring the association between birthweight and breast cancer using summary statistics from a perspective of genetic correlation, mediation, and causality.

BACKGROUND: Previous studies demonstrated a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations also emerged, and the nature of such relationship remains unknown. METHODS: Using summary statistics of birthweight and breast cancer, we assessed the fetal/maternal-specific genetic correlation between them via LDSC and prioritized fetal/maternal-specific pleiotropic genes through MAIUP. Relying on summary statistics we conducted Mendelian randomization (MR) to evaluate the fetal/maternal-specific origin of causal relationship between birthweight, age of menarche, age at menopause and breast cancer. RESULTS: With summary statistics we identified a positive genetic correlation between fetal-specific birthweight and breast cancer (rg = 0.123 and P = 0.013) as well as a negative but insignificant correlation between maternal-specific birthweight and breast cancer (rg = - 0.068, P = 0.206); and detected 84 pleiotropic genes shared by fetal-specific birthweight and breast cancer, 49 shared by maternal-specific birthweight and breast cancer. We also revealed fetal-specific birthweight indirectly influenced breast cancer risk in adulthood via the path of age of menarche or age at menopause in terms of MR-based mediation analysis. CONCLUSION: This study reveals that shared genetic foundation and causal mediation commonly drive the connection between the two traits, and that fetal/maternal-specific birthweight plays substantially distinct roles in such relationship. However, our work offers little supportive evidence for the fetal origins hypothesis of breast cancer originating in utero.

Ultraviolet radiation and age at natural menopause in a nationwide, prospective US cohort.

BACKGROUND: Solar ultraviolet radiation (UV) is a critical environmental factor for dermal conversion of vitamin D, which is suggested to support reproductive health. However, current epidemiological studies have reported conflicting results on the associations between vitamin D levels and ovarian reserve. Further, few studies have considered UV exposure and reproductive aging, which is closely related to declined ovarian reserve. OBJECTIVES: We sought to examine the associations of long-term UV exposure and age at natural menopause in a large, nationwide, prospective cohort. METHODS: Participants in the Nurses' Health Study II (NHS II) who were premenopausal at age 40 were included and followed through 2015. Erythemal UV radiation from a high-resolution geospatial model was linked to the participants' residential histories. Early-life UV was estimated using the reported state of residence at birth, age 15, and age 30. We used time-varying Cox proportional hazards models to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) for natural menopause, adjusting for potential confounders and predictors of menopause. RESULTS: A total of 63,801 women reported natural menopause across the 1,051,185 person-years of follow-up among 105,631 eligible participants. We found very modest associations with delayed menopause for long-term UV exposure (adjusted HR comparing highest to lowest quartile of cumulative average UV: 0.96, 95% CI: 0.94, 0.99). There was a suggestive inverse association between UV at age 30 with menopause (adjusted HR comparing highest to lowest quartile: 0.97, 95% CI: 0.95, 1.00) but not with UV at birth and age 15. CONCLUSIONS: Solar UV exposure in adulthood was modestly associated with later onset of menopause. Although consistent with previous findings on vitamin D intake and menopause in the same population, these weak associations found in this study may not be of clinical relevance.

Age at Menopause and Suicidal Ideation in Menopausal Women: A Study of Korea National Health and Nutrition Examination Survey Data.

BACKGROUND: Although menopause is considered a risk factor for depression, no association has been established between the risk of suicidal ideation and age at menopause. This study aimed to evaluate the association between age at menopause and suicidal ideation in middle-aged menopausal Korean women. METHODS: This cross-sectional study used data from the Korea National Health and Nutrition Examination Survey (2013-2018). Women aged 40-65 years were divided into the following three categories: primary ovarian insufficiency (POI), early menopause, and menopause, according to age at natural menopause (< 40, 40-45, and > 45 years, respectively). Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). RESULTS: Among 2,232 menopausal women, 25 (1.1%) experienced POI and 114 (5.1%) experienced early menopause. The PHQ-9 items that pertained to low self-esteem and suicidal ideation scored higher in women with POI than in those who experienced menopause after 45 years of age. The prevalence of suicidal ideation differed significantly according to age at menopause (POI, 30.0%; early menopause, 12.7%; menopause, 8.0%; P = 0.016). Logistic regression analysis revealed that POI was significantly associated with suicidal ideation after the adjustment for age, body mass index, and education, household income, and walking levels (odds ratio, 4.2; 95% confidence interval, 1.0-17.7). CONCLUSION: Korean middle-aged women with POI were more likely to have suicidal ideation than those who experienced menopause at 45 years or above, despite not being diagnosed with major depressive disorder.

Association of age at menopause with type 2 diabetes mellitus in postmenopausal women in the United States: National Health and Nutrition Examination Survey 2011-2018.

Introduction: The present study aimed to examine the impact of age at menopause on the type 2 diabetes mellitus (T2DM) risk in postmenopausal women. Material and methods: We included 4,968 postmenopausal women from the National Health and Nutrition Examination Survey 2011-2018. Age at menopause was measured by single year and categorically (< 40 years, 40-44 years, 45-54 years, 55 years and above). The outcome variable T2DM was measured with self-report and fasting blood glucose level. We performed logistic regression to estimate the odds ratio (OR) (95% confidence interval [CI]). Linear regression was used to examine the correlation between age at menopause and age at T2DM. Results: Of the 4,968 postmenopausal women, 796 (16.0%) had T2DM after menopause. The mean age at menopause was 44.2 years. The mean age at T2DM was 57.2 years. Adjusting for potential confounders, the ORs for the association between age at menopause of < 40 years, 40-44 years and ≥ 55 years and T2DM were 1.97 (95% CI: 1.47-2.63), 1.27 (95% CI: 0.90-1.79) and 0.98 (95% CI: 0.66-1.45), respectively, compared to women having menopause at age 45 to 54 years. Each increase by 1 year in age at menopause was associated with a 3% reduction in the prevalence of T2DM (95% CI: 2-5). Age at menopause was significantly correlated with age at T2DM. Each 1-year increase in age at menopause might lead to a decrease of 0.39 years in age at T2DM. Conclusions: Premature menopause was associated with increased T2DM risk in women. The earlier menopause occurs, the younger is the age at which T2DM may occur.

Prevalence and risks of mild cognitive impairment of Chinese community-dwelling women aged above 60 years: A cross-sectional study.

Evidence has shown that risks of cognitive impairment differ between genders. This cross-sectional study sought to determine the prevalence of mild cognitive impairment (MCI) in Chinese community-dwelling women aged above 60 years and identify risks of MCI by multivariate logistic regression analysis. Totally, 1760 Chinese community-dwelling women entered the study. Cognitive function was assessed with Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). MCI was diagnosed by Petersen's criteria. Sociodemographic information, past medical conditions, and age at menopause were screened. The primary study outcome was prevalence of MCI. MCI was diagnosed in 378 (21.5%) women. Older age was a significant risk of MCI (OR 1.621, 95%CI 1.386-1.894; P < 0.001). Low education was associated a 4-fold increase in the risk of MCI (OR 4.036, 95%CI 3.168-5.142). Furthermore, current depression was associated with 2.6-fold increase in the risk of MCI (OR 2.618, 95%CI 1.499-4.587, P = 0.001). Moreover, frequent physical exercise and more leisure and social time activities were associated with significantly reduced risks of MCI, while poor financial status was associated with a significantly increased risk of MCI. Slightly more than 20% of Chinese women aged above 60 years had MCI, and independent risks included older age, low education status, and current depression, highlighting the importance of screening for and removing or minimizing risks of MCI in this specific population.

Estimated Number of Lifetime Ovulatory Years and Its Determinants in Relation to Levels of Circulating Inflammatory Biomarkers.

Reproductive events, such as ovulation, trigger an inflammatory cascade. Few studies have examined their long-term influence on inflammatory profiles. We included 3,393 premenopausal and 3,915 postmenopausal women with intact ovaries/uterus from the Nurses' Health studies (Nurses' Health Study (1989-1990) and Nurses' Health Study II (1996-1999)) in an analysis of the association between lifetime ovulatory years (LOY) and levels of inflammatory biomarkers. We estimated LOY as age at menopause (age at blood collection for premenopausal women) minus age at menarche, subtracting years of oral contraceptive (OC) use and 1 year per pregnancy. After adjustment for other inflammation-related factors (e.g., body mass index, exercise, diet), every 5-year increase in LOY was associated with lower C-reactive protein (CRP) levels in both premenopausal (difference = -11.5%, 95% confidence interval: -15.0, -8.0; P < 0.0001) and postmenopausal (difference = -7.2%, 95% confidence interval: -10.0, -4.3; P < 0.0001) women. Older age at menopause (P = 0.007), earlier menarche (P = 0.007), and shorter duration of OC use (P = 0.002) were associated with lower CRP levels in postmenopausal women, whereas duration of OC use was positively associated with CRP levels in premenopausal women (P < 0.0001). LOY was modestly inversely associated with interleukin 6 in postmenopausal women (P = 0.03). Notably, the associations of CRP with LOY were similar in magnitude to associations with exercise and a healthy diet, though weaker than the association with body mass index. Although many reproductive events induce acute inflammation, increased LOY was associated with lower chronic systemic inflammation even after menopause.

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.

Reproductive and hormonal factors and risk of cognitive impairment among Singapore Chinese women.

BACKGROUND: Epidemiologic studies suggest that declining estrogen levels in menopause may play an important role in the pathogenesis of dementia and contribute to increased risk of cognitive impairment in women. Most previous studies have been conducted in Western populations to investigate the relationship of the length of reproductive periods and use of hormone-replacement therapy with risk of cognitive function and dementia, but the findings are inconclusive. Relevant evidence among Asian populations is limited. OBJECTIVES: To evaluate the association between reproductive and hormonal factors and the risk of cognitive impairment in Chinese women with natural menopause. STUDY DESIGN: The Singapore Chinese Health Study is a population-based study that recruited participants aged 45-74 years between 1993 and 1998, and the current study included 8222 women from this cohort who had natural menopause, complete data on reproductive factors and hormonal therapies at baseline (1993-1998), follow-up 1 (1999-2004) and follow-up 2 interviews (2006-2010), and cognitive function evaluated at ages 61-96 years using the Singapore Modified Mini-Mental State Examination during the follow-up 3 visits (2014-2016). Multivariable logistic regression models were used to estimate odds ratios and 95% confidence intervals for the risk of cognitive impairment. RESULTS: Compared with women with menopause at 50-54 years of age, the odds ratios (95% confidence interval) were 1.67 (1.32-2.11), 1.24 (1.08-1.44), and 1.06 (0.87- 1.29) for women who experienced menopause before 45 years, at 45-49 years of age, and after 54 years, respectively. Compared with women with 35-39 reproductive years from menarche to menopause, the odds ratios (95% confidence interval) were 1.28 (1.11-1.48) for women with <35 reproductive years. Furthermore, compared with women who had 1-2 children, the odds ratios (95% confidence interval) were 1.27 (1.04-1.55) for women who had more than 5 children, and the risk increased significantly by 5% per child birth (odds ratio, 1.05; 95% confidence interval, 1.01-1.09). Compared with those who had never used oral contraceptives, women with short-term use (≤5 years) of oral contraceptives had 26% lower odds of having cognitive impairment (odds ratio, 0.74; 95% confidence interval, 0.63-0.87), whereas the association was not statistically significant for those used for more than 5 years (odds ratio, 0.87; 95% confidence interval, 0.68-1.13). Women who used hormone-replacement therapy had a 39% lower odd of getting cognitive impairment compared with nonusers (odds ratio, 0.61; 95% confidence interval, 0.46-0.80). CONCLUSION: Our data suggest that shorter reproductive years and greater parity were associated with a greater risk of cognitive impairment in late life, whereas the use of oral contraceptives and hormone-replacement therapy was associated with decreased risk. As the population ages, understanding how these factors affect late-life cognitive function in women may help health professionals develop preventive measures targeting lifetime estrogen exposure from endogenous or exogenous sources.

Age at menopause, body mass index, and risk of type 2 diabetes mellitus in postmenopausal Chinese women: The Henan Rural Cohort study.

BACKGROUND AND AIM: The present study was conducted to explore the stratified and joint effects of age at menopause and body mass index (BMI) with the risk of type 2 diabetes mellitus (T2DM) in Chinese rural adults. METHODS AND RESULTS: A total of 15,406 postmenopausal Chinese women were included in this study. Multivariable logistic regression analysis was used to quantify the stratified and joint effects of age at menopause and BMI on T2DM. Overall, the mean age at menopause and BMI was 48.8 ± 4.7 years and 25.1 ± 3.6 kg/m2, respectively. In general, data suggest that: 1) women with BMI ≥ 24 had a higher risk of T2DM, irrespective of age at menopause; 2) in women with BMI < 24, later menopause had a higher risk of T2DM (OR, 1.52; 95% CI, 1.16-2.01); 3) the risk of T2DM was higher only in patients with early or normal age at menopause and BMI ≥ 24, with 0R (95% CI) of (1.58, 1.28-1.94) and (1.48, 1.31-1.67), respectively. CONCLUSION: Our findings suggest that: 1) women with BMI ≥ 24 had a higher risk of T2DM, irrespective of age at menopause; 2) in women with BMI < 24, a higher risk of T2DM was found only in those with later menopause; 3) women with later menopause had a higher risk of T2DM, irrespective of BMI; 4) in patients with early or normal age at menopause, a higher risk of T2DM was found only in patients with BMI ≥ 24. THE CHINESE CLINICAL TRIAL REGISTRATION: ChiCTR-OOC-1500669(URL:http://www.chictr.org.cn/showproj.aspx?proj=11375).

Lack of association between early menopause and non-alcoholic fatty liver disease in postmenopausal women.

Background: The possibility of an association between early menopause and the risk of non-alcoholic fatty liver disease (NAFLD) is as yet unclear.Methods: The subjects consisted of 4354 postmenopausal women who participated in the 2010-2012 Korea National Health and Nutrition Examination Survey. Early, normal, and late menopause were defined as age at menopause <45 years, 45-54 years, and ≥55 years, respectively. NAFLD was defined by a hepatic steatosis index of >36.Results: When compared with normal menopausal women, early or late menopausal women had no significant differences in the odds ratios (ORs) of NAFLD: OR = 1.05, 95% confidence interval (CI), 0.83-1.32 and OR = 1.02, 95% CI, 0.75-1.39, respectively. These results remained similar after adjustment for known risk factors for NAFLD, reproductive factors, and comorbidities. The OR for NAFLD per 1-year increase in age at menopause was 1.01 (95% CI, 0.99-1.03; p = 0.329). The prevalence of advanced fibrosis was 2.1% (95% CI, 0.7-6.4%), 2.2% (95% CI, 1.3-3.8%), and 3.9% (95% CI, 1.2-12.2%) in early, normal, and late menopausal women, respectively.Conclusions: This study provides no evidence for an association of early menopause with NAFLD risk. However, NAFLD-related advanced fibrosis is highly prevalent in postmenopausal women.

Variations in reproductive events across life: a pooled analysis of data from 505 147 women across 10 countries.

STUDY QUESTION: How has the timing of women's reproductive events (including ages at menarche, first birth, and natural menopause, and the number of children) changed across birth years, racial/ethnic groups and educational levels? SUMMARY ANSWER: Women who were born in recent generations (1970-84 vs before 1930) or those who with higher education levels had menarche a year earlier, experienced a higher prevalence of nulliparity and had their first child at a later age. WHAT IS KNOWN ALREADY: The timing of key reproductive events, such as menarche and menopause, is not only indicative of current health status but is linked to the risk of adverse hormone-related health outcomes in later life. Variations of reproductive indices across different birth years, race/ethnicity and socioeconomic positions have not been described comprehensively. STUDY DESIGN, SIZE, DURATION: Individual-level data from 23 observational studies that contributed to the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) consortium were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Altogether 505 147 women were included. Overall estimates for reproductive indices were obtained using a two-stage process: individual-level data from each study were analysed separately using generalised linear models. These estimates were then combined using random-effects meta-analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Mean ages were 12.9 years at menarche, 25.7 years at first birth, and 50.5 years at natural menopause, with significant between-study heterogeneity (I2 > 99%). A linear trend was observed across birth year for mean age at menarche, with women born from 1970 to 1984 having menarche one year earlier (12.6 years) than women born before 1930 (13.5 years) (P for trend = 0.0014). The prevalence of nulliparity rose progressively from 14% of women born from 1940-49 to 22% of women born 1970-84 (P = 0.003); similarly, the mean age at first birth rose from 24.8 to 27.3 years (P = 0.0016). Women with higher education levels had fewer children, later first birth, and later menopause than women with lower education levels. After adjusting for birth year and education level, substantial variation was present for all reproductive events across racial/ethnic/regional groups (all P values < 0.005). LIMITATIONS, REASONS FOR CAUTION: Variations of study design, data collection methods, and sample selection across studies, as well as retrospectively reported age at menarche, age at first birth may cause some bias. WIDER IMPLICATIONS OF THE FINDINGS: This global consortium study found robust evidence on variations in reproductive indices for women born in the 20th century that appear to have both biological and social origins. 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 the Australian National Health and Medical Research Council Principal Research Fellowship (APP1121844).

Premenopausal cardiovascular disease and age at natural menopause: a pooled analysis of over 170,000 women.

Early menopause is associated with an increased risk of subsequent cardiovascular disease (CVD). Few studies have investigated the converse. We examined whether premenopausal CVD events are associated with early age at menopause. We pooled the individual data of 177,131 women from nine studies. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRR) and 95% confidence intervals (CI) for the associations between age at onset of premenopausal CVD events-including coronary heart disease (CHD) and stroke-and age at natural menopause. Altogether 1561 (0.9%) premenopausal participants reported CVD events (including 1130 CHD and 469 stroke) at a mean age of 41.3 years. Compared with women without any premenopausal CVD events, women who experienced a first CVD event before age 35 years had a twofold risk of menopause before age 45 years (early menopause); adjusted RRR (95% CI) of 1.92 (1.17, 3.14) for any CVD, 1.86 (1.01, 3.43) for CHD and 2.17 (1.43, 3.30) for stroke. Women who experienced a first premenopausal CVD event after age 40 years underwent a natural menopause at the expected age (around 51 years). These associations were robust to adjustment for smoking status, BMI, educational level, race/ethnicity, age at menarche, parity, hypertension and family history of CVD. For premenopausal women, a first CVD event before age 35 years is associated with a doubling of the risk of an early menopause, while a first CVD event occurred after 35 years indicates a normal menopause at around 51 years. Shared genetic and environmental factors (such as smoking), as well as compromised vasculature following CVD events, may contribute to this outcome.

Factors related to muscle strength in postmenopausal women aged younger than 65 years with normal vitamin D status.

Objective: The study aimed to determine the impact of age, age at menopause, body mass index (BMI), and lumbar and hip bone mineral density (BMD) on muscle strength in young postmenopausal women with normal vitamin D levels. Methods: This was a cross-sectional study performed in 392 postmenopausal women aged <65 years with normal serum 25-hydroxyvitamin D levels (≥30 ng/ml) and no physical disabilities. The following variables were recorded: age, age at menopause, BMI, BMD (measured by dual-energy X-ray absorptiometry [DXA] scanning and expressed as lumbar and hip T-scores), and dominant hand grip strength (measured with a digital dynamometer). Results are reported as mean ± standard deviation or odds ratio (OR) and 95% confidence interval (CI) as appropriate. Results: The mean age of the whole sample was 57.30 ± 3.69 years with a mean age at menopause of 50.46 ± 2.16 years and a mean BMI of 24.93 ± 3.78. Mean DXA results were lumbar T-score of -1.16 ± 1.18 and hip T-score of -0.98 ± 0.93. The mean dominant hand grip force was 24.10 kg. A total of 12.2% (48/392) of women were diagnosed with dynapenia using a cut-off value of <20 kg. A weak but significant inverse correlation was found between grip strength in the dominant hand and age (r = -0.131, p = 0.009). Multivariable logistic regression analysis determined that earlier age at menopause (50 years or younger) was significantly associated with a higher risk of dynapenia (OR 2.741, 95% CI 1.23-6.11, p = 0.014). No other significant association was found with the other variables. Conclusions: A total of 12.2% of the studied young postmenopausal women with normal vitamin D status had dynapenia. There was a weak inverse correlation between grip strength and age, and earlier age at menopause was associated with an increased dynapenia risk.