Optimising health after early menopause.

The typical age at menopause is 50-51 years in high-income countries. However, early menopause is common, with around 8% of women in high-income countries and 12% of women globally experiencing menopause between the ages of 40 years and 44 years. Menopause before age 40 years (premature ovarian insufficiency) affects an additional 2-4% of women. Both early menopause and premature ovarian insufficiency can herald an increased risk of chronic disease, including osteoporosis and cardiovascular disease. People who enter menopause at younger ages might also experience distress and feel less supported than those who reach menopause at the average age. Clinical practice guidelines are available for the diagnosis and management of premature ovarian insufficiency, but there is a gap in clinical guidance for early menopause. We argue that instead of distinct age thresholds being applied, early menopause should be seen on a spectrum between premature ovarian insufficiency and menopause at the average age. This Series paper presents evidence for the short-term and long-term consequences of early menopause. We offer a practical framework for clinicians to guide diagnosis and management of early menopause, which considers the nature and severity of symptoms, age and medical history, and the individual's wishes and priorities to optimise their quality of life and short-term and long-term health. We conclude with recommendations for future research to address key gaps in the current evidence.

Female reproductive histories and the risk of chronic obstructive pulmonary disease.

BACKGROUND: Female reproductive factors may influence the development of chronic obstructive pulmonary disease (COPD) through the female hormonal environment, but studies on this topic are limited. This study aimed to assess whether age at menarche, number of children, infertility, miscarriage, stillbirth and age at natural menopause were associated with the risk of COPD. METHODS: Women from three cohorts with data on reproductive factors, COPD and covariates were included. Cause specific Cox regression models were adjusted for birth year, race, educational level, body mass index and pack years of smoking, stratified by asthma, and incorporating interaction between birth year and time. Between cohort differences and within cohort correlations were taken into account. RESULTS: Overall, 2 83 070 women were included and 10 737 (3.8%) developed COPD after a median follow-up of 11 (IQR 10-12) years. Analyses revealed a U shaped association between age at menarche and COPD (≤11 vs 13: HR 1.17, 95% CI 1.11 to 1.23; ≥16 vs 13: HR 1.24, 95% CI 1.21 to 1.27). Women with three or more children (3 vs 2: HR 1.14, 95% CI 1.12 to 1.17; ≥4 vs 2: HR 1.34, 95% CI 1.28 to 1.40), multiple miscarriages (2 vs 0: HR 1.28, 95% CI 1.24 to 1.32; ≥3 vs 0: HR 1.36, 95% CI 1.30 to 1.43) or stillbirth (1 vs 0: HR 1.38, 95% CI 1.25 to 1.53; ≥2 vs 0: HR 1.67, 95% CI 1.32 to 2.10) were at a higher risk of COPD. Among postmenopausal women, earlier age at natural menopause was associated with an increased risk of COPD (<40 vs 50-51: HR 1.69, 95% CI 1.63 to 1.75; 40-44 vs 50-51: HR 1.42, 95% CI 1.38 to 1.47). CONCLUSIONS: Multiple female reproductive factors, including age at menarche, number of children, miscarriage, stillbirth, and age at natural menopause were associated with the risk of COPD.

Ethnic Differences in the Association Between Age at Natural Menopause and Risk of Type 2 Diabetes Among Postmenopausal Women: A Pooled Analysis of Individual Data From 13 Cohort Studies.

OBJECTIVE: To investigate associations between age at natural menopause, particularly premature ovarian insufficiency (POI) (natural menopause before age 40 years), and incident type 2 diabetes (T2D) and identify any variations by ethnicity. RESEARCH DESIGN AND METHODS: We pooled individual-level data of 338,059 women from 13 cohort studies without T2D before menopause from six ethnic groups: White (n = 177,674), Chinese (n = 146,008), Japanese (n = 9,061), South/Southeast Asian (n = 2,228), Black (n = 1,838), and mixed/other (n = 1,250). Hazard ratios (HRs) of T2D associated with age at menopause were estimated in the overall sample and by ethnicity, with study as a random effect. For each ethnic group, we further stratified the association by birth year, education level, and BMI. RESULTS: Over 9 years of follow-up, 20,064 (5.9%) women developed T2D. Overall, POI (vs. menopause at age 50-51 years) was associated with an increased risk of T2D (HR 1.31; 95% CI 1.20-1.44), and there was an interaction between age at menopause and ethnicity (P < 0.0001). T2D risk associated with POI was higher in White (1.53; 1.36-1.73), Japanese (4.04; 1.97-8.27), and Chinese women born in 1950 or later (2.79; 2.11-3.70); although less precise, the risk estimates were consistent in women of South/Southeast Asian (1.46; 0.89-2.40), Black (1.72; 0.95-3.12), and mixed/other (2.16; 0.83-5.57) ethnic groups. A similar pattern, but with a smaller increased risk of T2D, was observed with early menopause overall (1.16; 1.10-1.23) and for White, Japanese, and Chinese women born in 1950 or later. CONCLUSIONS: POI and early menopause are risk factors for T2D in postmenopausal women, with considerable variation across ethnic groups, and may need to be considered in risk assessments of T2D among women.

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.

Cohort profile: a prospective Australian cohort study of women's reproductive characteristics and risk of chronic disease from menarche to premenopause (M-PreM).

PURPOSE: Previous studies have identified associations between individual reproductive factors and chronic disease risk among postmenopausal women. However, few have investigated the association of different markers of reproductive function, their interactions and risk factors of chronic disease among women approaching menopause. The Menarche-to-PreMenopause (M-PreM) Study aims to examine the relationship between reproductive factors across the reproductive lifespan and risk indicators for chronic disease among women in their early-to-mid-40s. The purpose of this cohort profile paper is to describe the rationale, study design and participant characteristics of the M-PreM Study. PARTICIPANTS: Women born in 1973-1978 who participated in the Australian Longitudinal Study on Women's Health (ALSWH) were invited to undertake a clinical or self-administered assessment. A total of 1278 women were recruited from June 2019 to June 2021. FINDINGS TO DATE: The study measures included functional, cognitive and cardiometabolic tests, anthropometry, spirometry, respiratory health questionnaires, physical activity, sleep patterns, sex hormones, and cardiovascular and metabolic markers; whereas blood and saliva samples were used for the analysis of genetic variants of genes associated with reproductive characteristics and chronic disease. The mean age of the clinic and self-assessed participants was 44.6 and 45.3 years, respectively. The menopausal status of participants was similar between the two arms of the study: 38%-41% premenopausal, 20% perimenopausal, and 36% took oral contraception or hormone replacement therapy. Approximately 80% of women had at least one child and participants reported experiencing pregnancy complications: preterm birth (8%-13% of pregnancies), gestational diabetes (10%) and gestational hypertension (10%-15%). FUTURE PLANS: The biomedical data collected in the M-PreM Study will be linked to existing ALSWH survey data on sociodemographic factors, health behaviour, reproductive function, and early life factors collected over the past 20 years and health administrative data. The association between reproductive factors and risk indicators of chronic disease will be analysed.

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.

Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women.

OBJECTIVE: To examine the associations of infertility, recurrent miscarriage, and stillbirth with the risk of first non-fatal and fatal stroke, further stratified by stroke subtypes. DESIGN: Individual participant pooled analysis of eight prospective cohort studies. SETTING: Cohort studies across seven countries (Australia, China, Japan, Netherlands, Sweden, the United Kingdom, and the United States) participating in the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium, which was established in June 2012. PARTICIPANTS: 618 851 women aged 32.0-73.0 years at baseline with data on infertility, miscarriage, or stillbirth, at least one outcome event (non-fatal or fatal stroke), and information on covariates were included; 93 119 women were excluded. Of the participants, 275 863 had data on non-fatal and fatal stroke, 54 716 only had data on non-fatal stroke, and 288 272 only had data on fatal stroke. MAIN OUTCOME AND MEASURES: Non-fatal strokes were identified through self-reported questionnaires, linked hospital data, or national patient registers. Fatal strokes were identified through death registry data. RESULTS: The median follow-up for non-fatal stroke and fatal stroke was 13.0 years (interquartile range 12.0-14.0) and 9.4 years (7.6-13.0), respectively. A first non-fatal stroke was experienced by 9265 (2.8%) women and 4003 (0.7%) experienced a fatal stroke. Hazard ratios for non-fatal or fatal stroke were stratified by hypertension and adjusted for race or ethnicity, body mass index, smoking status, education level, and study. Infertility was associated with an increased risk of non-fatal stroke (hazard ratio 1.14, 95% confidence interval 1.08 to 1.20). Recurrent miscarriage (at least three) was associated with higher risk of non-fatal and fatal stroke (1.35, 1.27 to 1.44, and 1.82, 1.58 to 2.10, respectively). Women with stillbirth were at 31% higher risk of non-fatal stroke (1.31, 1.10 to 1.57) and women with recurrent stillbirth were at 26% higher risk of fatal stroke (1.26, 1.15 to 1.39). The increased risk of stroke (non-fatal or fatal) associated with infertility or recurrent stillbirths was mainly driven by a single stroke subtype (non-fatal ischaemic stroke and fatal haemorrhagic stroke), while the increased risk of stroke (non-fatal or fatal) associated with recurrent miscarriages was driven by both subtypes. CONCLUSION: A history of recurrent miscarriages and death or loss of a baby before or during birth could be considered a female specific risk factor for stroke, with differences in risk according to stroke subtypes. These findings could contribute to improved monitoring and stroke prevention for women with such a history.

Association between reproductive lifespan and risk of incident type 2 diabetes and hypertension in postmenopausal women: Findings from a 20-year prospective study.

BACKGROUND: This study examined the association between reproductive lifespan and incident type 2 diabetes mellitus (T2DM) and hypertension in mid-age women. Also, the combined effect of reproductive lifespan and body mass index (BMI) on the risks of T2DM and hypertension were explored. METHODS: Reproductive lifespan was defined as the difference between age at menopause and age at menarche, and categorized as <35, 35-37, 38-40, and ≥41 years based on the quartile distribution. A multivariable Cox proportional hazard regression was used, adjusting for socio-demographic, lifestyle, and reproductive factors. RESULTS: Of 6357 postmenopausal women included (mean [SD] age at last follow-up, 66.3[3.3] years), a total of 655 developed incident T2DM (10.3%) and 1741 developed hypertension (30.0%) during 20 years of follow-up. The total sample had a mean (SD) reproductive lifespan of 37.9 (4.5). Compared with the women who had a reproductive lifespan of 38-40 years, those with a short reproductive lifespan (<35 years) had a 30% increased risk of T2DM and twice the risk of hypertension. Under the combined model, women who had a short reproductive lifespan (<35 years) and who had a BMI ≥30 kg/m2 at baseline showed a higher risk of T2DM (HR: 6.30, 95% CI: 4.41-8.99) and hypertension (HR: 6.06, 4.86-7.55) compared with women who had a reproductive lifespan of 38-40 years and a BMI < 25 kg/m2. CONCLUSIONS: A higher risk of both incident T2DM and hypertension at midlife was found among women experiencing a shorter reproductive lifespan, with pronounced risk for women experiencing both a short reproductive lifespan (<35 years) and a higher baseline BMI (≥30 kg/m2). Women with a short reproductive lifespan may benefit from maintaining healthy body weight in midlife.

Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Stroke is one of the leading causes of mortality, and women are impacted more from stroke than men in terms of their absolute number and in having worse outcomes. A growing number of studies have explored the association between pregnancy complications, pregnancy outcomes, and stroke. Limited studies, however, have investigated links involving infertility, miscarriage, and stillbirth, which could plausibly be associated via a background of endocrine conditions, endothelial dysfunction, and chronic systematic inflammation. This review aims to summarize current evidence and provide up-to-date information on the associations of infertility, miscarriage, and stillbirth, with stroke incidence. METHODS: A comprehensive literature search was conducted for cohort and case-control studies on associations between infertility, miscarriage, stillbirth, and stroke up to September 26, 2020. Seven databases were searched: PubMed, Embase, Cochrane, CINIHL, PsyclNFO, Wanfang, and CNKI. Random-effects models were used to estimate the pooled hazard ratios (HRs) and 95% CIs. RESULTS: Sixteen cohort studies and 2 case-control studies enrolling 7 808 521 women were included in this meta-analysis. Women who had experienced miscarriage or stillbirth were at higher risk of stroke (miscarriage: HR, 1.07 [95% CI, 1.00-1.14]; stillbirth: HR, 1.38 [95% CI, 1.11-1.71]) than other women. The HRs of stroke for each additional miscarriage and stillbirth were 1.13 (95% CI, 0.96-1.33) and 1.25 (95% CI, 1.06-1.49), respectively. In subgroup analysis, increased risk of stroke was associated with repeated miscarriages and stillbirths (miscarriage ≥3: HR, 1.42 [95% CI, 1.05-1.90]; stillbirth ≥2: HR, 1.14 [95% CI, 1.04-1.26]). Associations between infertility and stroke were inconsistent and inconclusive (HR, 1.07 [95% CI, 0.87-1.32]). CONCLUSIONS: Miscarriage and stillbirth are associated with increased risk of stroke among women, which could be used as a contributing risk factor to help identify women at higher risk of stroke.

Epidemiological studies of the association between reproductive lifespan characteristics and risk of Type 2 diabetes and hypertension: A systematic review.

Some reproductive factors are found to be associated with metabolic outcomes in women; however, little is known about reproductive lifespan characteristics and the mutual effect of age at menarche and age at menopause on cardiovascular risk. This systematic review evaluated reproductive lifespan characteristics and describes the mutual effect of age at menarche and age at menopause on the risk of type 2 diabetes (T2DM) and hypertension at midlife. PubMed, EMBASE, and Web of Science were screened for studies published up to September 1, 2020. The individual effect estimates were reviewed and synthesized without meta-analysis due to methodological and clinical or conceptual diversity in reported studies. Of the 3033 identified studies, 20 were included in the final synthesis: 6 reported reproductive life span; 12 reported age at menarche, and 7 reported age at menopause. Synthesis of two cohorts, with a median follow-up of 9-11 years, showed that a shorter reproductive lifespan was positively associated with T2DM, yielding 6-15% higher risk of T2DM for a one-year decrease in reproductive lifespan. A few studies also demonstrated that women who experienced early menarche (four of six studies) and early menopause (two of five studies) were positively associated with risk of T2DM. The association between reproductive lifespan and hypertension was unclear due to the limited availability of studies. Our findings suggest that a shorter reproductive lifespan is associated with T2DM risk in postmenopausal women, especially those with early menarche and early menopause. Large cohort studies are needed to assess the association between reproductive lifespan and incident hypertension in midlife.

Age at menopause and risk of lung cancer: A systematic review and meta-analysis.

Previous reviews have found that menstrual and reproductive factors are associated with lung cancer risk, but evidence on a possible association with age at menopause is inconsistent. This review aimed to determine the association of early and late menopause with lung cancer risk. Publications were reviewed and obtained through PubMed, EMBASE and Scopus database search up to March 2021. The pooled relative risks (RRs) or odds ratios (ORs) and corresponding 95% CIs were estimated using a random-effects meta-analysis. Twenty-eight studies were included in at least one meta-analysis, of age at menopause (lowest vs highest; n=26), early menopause (≤45 vs ≥50/51 years or middle; n=11), late menopause (≥55 vs <50 years or middle; n=6), or continuous (per additional year; n=6). We found that early menopause was associated with lung cancer in both cohort studies (RR 1.26, 1.10-1.41; n=6) and case-control studies (OR 1.38, 1.11-1.66; n=5). Three large cohort studies showed that the increased risk was primarily evident among smokers (RR 1.38, 1.10-1.66) but not among non-smokers (RR 1.02, 0.63-1.40). Four case-control studies found that late menopause was also associated with lung cancer (OR 1.29, 1.08-1.51); conversely, the association was mainly observed among non-smokers (OR 1.35, 1.11-1.59) but not among smokers (OR 1.05, 0.75-1.36). In conclusion, evidence from this review indicates an increased risk of lung cancer in women who experience early menopause (≤45 years), although this risk is primarily among smokers. Large prospective cohort studies are needed to confirm the association between late menopause (≥55 years) and lung cancer risk among non-smokers. PROSPERO registration: CRD42020205429.

Meta-analysis for individual participant data with a continuous exposure: A case study.

OBJECTIVE: Methods for meta-analysis of studies with individual participant data and continuous exposure variables are well described in the statistical literature but are not widely used in clinical and epidemiological research. The purpose of this case study is to make the methods more accessible. STUDY DESIGN AND SETTING: A two-stage process is demonstrated. Response curves are estimated separately for each study using fractional polynomials. The study-specific curves are then averaged pointwise over all studies at each value of the exposure. The averaging can be implemented using fixed effects or random effects methods. RESULTS: The methodology is illustrated using samples of real data with continuous outcome and exposure data and several covariates. The sample data set, segments of Stata and R code, and outputs are provided to enable replication of the results. CONCLUSION: These methods and tools can be adapted to other situations, including for time-to-event or categorical outcomes, different ways of modelling exposure-outcome curves, and different strategies for covariate adjustment.

The association between menstrual symptoms and hypertension among young women: A prospective longitudinal study.

OBJECTIVES: To investigate whether menstrual symptoms are associated with increased risk of hypertension among young women, and whether the relationship is bi-directional. STUDY DESIGN: We included 7729 women participating in the Australian Longitudinal Study on Women's Health, aged 22-27 years in 2000 and who were followed up every 3 years until 2015. Premenstrual syndrome, painful (dysmenorrhoea), heavy (menorrhagia), and irregular menstrual periods over the previous 12 months were self-reported and recorded as 'never', 'rarely', 'sometimes', or 'often'. Questions regarding physician-diagnosed hypertension were asked, specifically for other than during pregnancy (defined as chronic hypertension) and during pregnancy (hypertensive disorder in pregnancy, HDP). Longitudinal data were analysed with generalised estimating equation time-lagged models to estimate relative risks (RRs) and 95 % confidence intervals (CI), adjusted for time-varying covariates. MIAN OUTCOME MEASURES: Chronic hypertension, HDP, and menstrual disorders. RESULTS: Over 15 years of follow-up, 757 women (9.8 %) reported having been diagnosed with chronic hypertension. Among 4473 parous women, 483 (10.8 %) reported a diagnosis of HDP. Women who often experienced heavy periods had an increased risk of incident chronic hypertension (RR 1.53, 1.13-2.09), compared with those who had not experienced heavy periods. We also found that women with chronic hypertension had an increased risk of incident heavy (RR 1.23, 1.02-1.50) and irregular periods (RR 1.42, 1.17-1.72). However, there was no apparent association between any menstrual symptoms and subsequent risk of HDP. CONCLUSIONS: The association between heavy periods (menorrhagia) and chronic hypertension may be bi-directional in young women. Chronic hypertension may also be associated with subsequent risk of irregular periods.

Association of the length of oestrogen exposure with risk of incident stroke in postmenopausal women: Insights from a 20-year prospective study.

BACKGROUND: To examine the relationship between the length of oestrogen exposure and risk of incident stroke. Also, the additive value of each model was compared for assessing oestrogen exposure and stroke risk in postmenopausal women. STUDY DESIGN AND SETTING: Prospective study of 5632 post-menopausal women without a prior history of stroke from 1996 through 2016 in Australian Longitudinal Study on Women's Health. Data on surrogate measures of oestrogen exposure were used to derive five indices of oestrogen exposure including reproductive lifespan (RLS) (age at menopause-age at menarche), endogenous oestrogen and total oestrogen exposure (which included menopausal hormone therapy (MHT use)). The relationships between the length of oestrogen exposure (quartiles) and incident stroke events were examined using multivariable adjusted Cox proportional hazard regression and their predictive accuracy were compared using area under the Receiver Operating Characteristic Curve. RESULTS: The mean (SD) for RLS was 37.9(4.3) years. A shorter RLS (≤34 years) was associated with a higher risk of incident stroke after adjustment (HR: 1.85, 95%CI: 1.08, 3.15), compared with 38-40 years. There was 7% decrease in risk of stroke per 1-year increase in RLS (HR: 0.93, 95%CI: 0.89, 0.97). Even though the combination of endogenous oestrogen and exogenous hormones aimed to provide more accurate length of oestrogen exposure, the results showed that each model had similar goodness of fit and did not improve the model of just using RLS as a predictor of incident stroke. CONCLUSIONS: A shorter RLS (≤34 years) was associated with higher risk of incident stroke compared to medium RLS. Endogenous oestrogen and of total oestrogen exposure (which included MHT use) did not improve the model of just using RLS as a predictor of incident stroke.

Association Between Reproductive Life Span and Incident Nonfatal Cardiovascular Disease: A Pooled Analysis of Individual Patient Data From 12 Studies.

Importance: Early menarche and early menopause are associated with increased risk of cardiovascular disease (CVD) in midlife, but little is known about the association between reproductive life span and the risk of CVD. Objective: To investigate the association between the length of reproductive life span and risk of incident CVD events, while also considering the timing of menarche and menopause. Design, Setting, and Participants: Individual-level data were pooled from 12 studies participating in the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events consortium. Women provided complete information on the timing of menarche and menopause, nonfatal CVD events, and covariates. Cox proportional hazards models were used to estimate hazard ratios and 95% CIs, adjusted for covariates. The association between reproductive life span and CVD was adjusted for age at menarche and age at menopause separately. Analysis began March 2018 and ended December 2019. Exposures: Reproductive life span was calculated by subtracting age at menarche from age at menopause and categorized as younger than 30, 30 to 32, 33 to 35, 36 to 38 (reference group), 39 to 41, 42 to 44, and 45 years or older. Main Outcomes and Measures: First nonfatal CVD event, including coronary heart disease and stroke events. Results: A total of 307 855 women were included. Overall, the mean (SD) ages at menarche, menopause, and reproductive life span were 13.0 (1.5) years, 50.2 (4.4) years, and 37.2 (4.6) years, respectively. Pooled analyses showed that women with a very short reproductive life span (<30 years) were at 1.71 (95% CI, 1.58-1.84) times higher risk of incident CVD events than women with a reproductive life span of 36 to 38 years after adjustment for covariates. This association remained unchanged when adjusted for age at menarche but was attenuated to 1.26 (95% CI, 1.09-1.46) when adjusted for age at menopause. There was a significant interaction between reproductive life span and age at menarche associated with CVD risk (P < .001). Women who had both short reproductive life span (<33 years) and early menarche (age ≤11 years) had the highest risk of CVD (hazard ratio, 2.06; 95% CI, 1.76-2.41) compared with those with a reproductive life span of 36 to 38 years and menarche at age 13 years. Conclusions and Relevance: Short reproductive life span was associated with an increased risk of nonfatal CVD events in midlife, and the risk was significantly higher for women with early age at menarche.

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.

Vasomotor menopausal symptoms and risk of cardiovascular disease: a pooled analysis of six prospective studies.

BACKGROUND: Menopausal vasomotor symptoms (ie, hot flashes and night sweats) have been associated with unfavorable risk factors and surrogate markers of cardiovascular disease, but their association with clinical cardiovascular disease events is unclear. OBJECTIVE: To examine the associations between different components of vasomotor symptoms, timing of vasomotor symptoms, and risk of cardiovascular disease. STUDY DESIGN: We harmonized and pooled individual-level data from 23,365 women in 6 prospective studies that contributed to the International Collaboration for a Life Course Approach to Women's Reproductive Health and Chronic Disease Events consortium. Women who experienced cardiovascular disease events before baseline were excluded. The associations between frequency (never, rarely, sometimes, and often), severity (never, mild, moderate, and severe), and timing (before or after age of menopause; ie, early or late onset) of vasomotor symptoms and incident cardiovascular disease were analyzed. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. RESULTS: In the adjusted model, no evidence of association was found between the frequency of hot flashes and incident cardiovascular disease, whereas women who reported night sweats "sometimes" (hazard ratio, 1.22; 95% confidence interval, 1.02-1.45) or "often" (hazard ratio, 1.29; 95% confidence interval, 1.05-1.58) had higher risk for cardiovascular disease. Increased severity of either hot flashes or night sweats was associated with higher risk of cardiovascular disease. The hazards ratios of cardiovascular disease in women with severe hot flashes, night sweats, and any vasomotor symptoms were 1.83 (95% confidence interval, 1.22-2.73), 1.59 (95% confidence interval, 1.07-2.37), and 2.11 (95% confidence interval, 1.62-2.76), respectively. Women who reported severity of both hot flashes and night sweats had a higher risk for cardiovascular disease (hazard ratio, 1.55; 95% confidence interval, 1.24-1.94) than those with hot flashes alone (hazard ratio, 1.33; 95% confidence interval, 0.94-1.88) and night sweats alone (hazard ratio, 1.32; 95% confidence interval, 0.84-2.07). Women with either early-onset (hazard ratio, 1.38; 95% confidence interval, 1.10-1.75) or late-onset (hazard ratio, 1.69; 95% confidence interval, 1.32-2.16) vasomotor symptoms had an increased risk for incident cardiovascular disease compared with women who did not experience vasomotor symptoms. CONCLUSION: Severity rather than frequency of vasomotor symptoms (hot flashes and night sweats) was associated with increased risk of cardiovascular disease. Vasomotor symptoms with onset before or after menopause were also associated with increased risk of cardiovascular disease.

Obesity, smoking, and risk of vasomotor menopausal symptoms: a pooled analysis of eight cohort studies.

BACKGROUND: Frequent and severe vasomotor symptoms during menopause are linked with adverse health outcomes. Understanding modifiable lifestyle factors for the risk of vasomotor menopausal symptoms is important to guide preventive strategies. OBJECTIVE: We investigated the associations between body mass index and smoking, their joint effects with the risk of vasomotor symptoms, and whether the associations differed by menopausal stage. STUDY DESIGN: The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events pooled data on 21,460 midlife women from 8 studies (median age, 50 years; interquartile range, 49-51 years) for the cross-sectional analysis. Four studies provided data for the prospective analysis (n=11,986). Multinomial logistic regression models with 4 categories of frequency/severity for the outcome of vasomotor symptoms were used to estimate relative risk ratios and 95% confidence intervals that were adjusted for within-study correlation and covariates. RESULTS: At baseline, nearly 60% of the women experienced vasomotor symptoms. One-half of them were overweight (30%) or obese (21%), and 17% were current smokers. Cross-sectional analyses showed that a higher body mass index and smoking more cigarettes with longer duration and earlier initiation were all associated with more frequent or severe vasomotor symptoms. Never smokers who were obese had a 1.5-fold (relative risk ratio, 1.52; 95% confidence interval, 1.35-1.73) higher risk of often/severe vasomotor symptoms, compared with never smokers who were of normal-weight. Smoking strengthened the association because the risk of often/severe vasomotor symptoms was much greater among smokers who were obese (relative risk ratio, 3.02; 95% confidence interval, 2.41-3.78). However, smokers who quit at <40 years of age were at similar levels of risk as never smokers. Prospective analyses showed a similar pattern, but the association attenuated markedly after adjustment for baseline vasomotor symptoms. Furthermore, we found that the association between body mass index and vasomotor symptoms differed by menopausal status. Higher body mass index was associated with increased risk of vasomotor symptoms in pre- and perimenopause but with reduced risk in postmenopause. CONCLUSION: High body mass index (≥25 kg/m2) and cigarette smoking substantially increased women's risk for experiencing frequent or severe vasomotor symptoms in a dose-response manner, and smoking intensified the effect of obesity. However, the effect of body mass index on the risk of vasomotor symptoms was opposite among postmenopausal women. Maintaining a normal weight before the menopausal transition and quitting smoking at <40 years of age may mitigate the excess risk of vasomotor symptoms in midlife.

Blood biomarkers of various dietary patterns correlated with metabolic indicators in Taiwanese type 2 diabetes.

BACKGROUND: Metabolic alterations correlate with adverse outcomes in type 2 diabetes. Dietary modification serves as an integral part in its treatment. OBJECTIVE: We examined the relationships among dietary patterns, dietary biomarkers, and metabolic indicators in type 2 diabetes (n = 871). DESIGN: Diabetic patients (n = 871) who provided complete clinical and dietary data in both 2008 and 2009 were selected from a cohort participating in a diabetic control study in Taiwan. Dietary data were obtained using a short, semiquantitative food frequency questionnaires, and dietary pattern identified by factor analysis. Multiple linear regressions were used to analyze the association between dietary biomarkers (ferritin, folate, and erythrocyte n-3 polyunsaturated fatty acids [n-3 PUFAs]) and metabolic control upon adjusting for confounders. RESULTS: Three dietary patterns (high-fat meat, traditional Chinese food-snack, and fish-vegetable) were identified. Ferritin correlated positively with high-fat meat factor scores (P for trend <0.001). Erythrocyte n-3 PUFAs (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], n-3/n-6 PUFA ratio) correlated positively with fish-vegetable factor scores (all P for trends <0.001). Multiple linear regressions revealed a positive relationship between ferritin concentrations and fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), and triglycerides, but a negative relationship with high-density lipoprotein cholesterol (HDL-C). Erythrocyte n-3 PUFA, EPA+DHA, and n-3/n-6 PUFA ratio were negatively linked to FPG, HbA1c, and triglycerides (all P < 0.05) and positively with HDL-C (though n-3/n-6 ratio marginally correlated). CONCLUSIONS: Ferritin and n-3 PUFA can serve as valid biomarkers for high-fat meat and fish-vegetable dietary patterns. Unlike ferritin, erythrocyte n-3 PUFA status was related to better glycemic and blood lipid profiles. Our results suggest that habitual consumption of diet pattern rich in fish and vegetables may contribute in part to a healthier metabolic profile in type 2 diabetes.