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Background: The prevalence of obstructive sleep apnea is higher in women after menopause. This is suggested to be a result of an altered sex hormone balance but has so far not been confirmed in a population-based study., Objective: To investigate whether serum concentration of estrogens and progesterone are associated with the prevalence of sleep apnea symptoms in middle-aged women of the general population., Methods: We analyzed data from 774 women (40-67 years) from 15 study centers in seven countries participating in the second follow-up of the European Community Respiratory Health Survey (2010-2012). Multiple logistic regression models were fitted with self-reported symptoms of sleep apnea as outcomes and serum concentrations of various estrogens and progesterone as predictors. All analyses were adjusted for relevant covariates including age, BMI, education, study center, smoking habits, and reproductive age., Results: Among all included women, a doubling of serum concentrations of estrone and progesterone was associated with 19% respectively 9% decreased odds of snoring. Among snorers, a doubling of the concentrations of 17β-estradiol, estrone and estrone 3-sulfate was associated with 18%, 23% and 17% decreased odds of breathing irregularly, and a doubling of the progesterone concentration was further associated with 12% decreased odds of waking up suddenly with a chocking sensation. Other evaluated associations were not statistically significant., Conclusions: Middle-aged women with low serum estrogen and progesterone levels are more likely to snore and report symptoms of obstructive sleep apnea., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate markers of premature menopause (<40 years) and specifically the prevalence of autoimmune primary ovarian insufficiency (POI) in European women., Design: Postmenopausal women were categorized according to age at menopause and self-reported reason for menopause in a cross-sectional analysis of 6870 women., Methods: Variables associated with the timing of menopause and hormone measurements of 17β-estradiol and follicle-stimulating hormone were explored using multivariable logistic regression analysis. Specific immunoprecipitating assays of steroidogenic autoantibodies against 21-hydroxylase (21-OH), side-chain cleavage enzyme (anti-SCC) and 17alpha-hydroxylase (17 OH), as well as NACHT leucine-rich-repeat protein 5 were used to identify women with likely autoimmune POI., Results: Premature menopause was identified in 2.8% of women, and these women had higher frequencies of nulliparity (37.4% vs 19.7%), obesity (28.7% vs 21.4%), osteoporosis (17.1% vs 11.6%), hormone replacement therapy (59.1% vs 36.9%) and never smokers (60.1% vs 50.9%) (P < 0.05), compared to women with menopause ≥40 years. Iatrogenic causes were found in 91 (47%) and non-ovarian causes in 27 (14%) women, while 77 (39%) women were classified as POI of unknown cause, resulting in a 1.1% prevalence of idiopathic POI. After adjustments nulliparity was the only variable significantly associated with POI (odds ratio 2.46; 95% CI 1.63-3.42). Based on the presence of autoantibodies against 21 OH and SCC, 4.5% of POI cases were of likely autoimmune origin., Conclusion: Idiopathic POI affects 1.1% of all women and almost half of the women with premature menopause. Autoimmunity explains 4.5% of these cases judged by positive steroidogenic autoantibodies.

Background: The premenstrual syndrome (PMS) causes clinically relevant psychological and physical symptoms in up to 20% of women of reproductive age. To date, no studies have investigated the relationship between PMS and residential surrounding greenspace, although a green living environment has been reported to have beneficial associations with overall and reproductive health., Objective: To investigate whether lifelong exposure to residential surrounding greenspace is associated with PMS and whether such an association is mediated by BMI, air pollution or physical activity., Methods: This study used data collected in 2013-2015 from 1069 Scandinavian women aged 18-49 years, participating in RHINESSA, a European multi-centre and population-based cohort. Satellite-derived Normalised Difference Vegetation Index was used as a proxy of greenspace. Presence of eight common PMS symptoms and their sum (PMS symptom count) were used as outcomes. The associations were assessed by adjusted multilevel logistic and negative binomial regressions. Subsequently we carried out mediation analyses for physical activity, BMI and air pollution exposure., Results: Higher exposure to residential surrounding greenspace was associated with "Anxiety or tension" (Odds Ratio 0.82, 95% Confidence Interval (CI): 0.70 - 0.95), "Depression or hopelessness" (0.84, 0.73 - 0.98), "Difficulty with sleeping" (0.82, 0.68 - 1.00) and "Breast tenderness and abdominal bloating" (0.84, 0.71 - 0.99) before or around the start of the menstrual period. There was also an association with a lower PMS symptom count (Risk Ratio: 0.94, 95% CI: 0.91 - 0.99). These associations were robust to sensitivity analyses and were not mediated by BMI, physical activity or air pollution., Conclusions: Living in greener areas may be beneficial against PMS symptoms. Further studies are needed to confirm these novel findings and to explore the underlying biological mechanisms., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Air pollution is hypothesized to affect pubertal development. However, the few studies on this topic yielded overall mixed results. These studies did not consider important pollutants like ozone, and none of them involved pubertal development assessed by estradiol and testosterone measurements. We aimed to analyze associations between long-term exposure to four pollutants and pubertal development based on sex hormone concentrations among 10-year-old children., Methods: These cross-sectional analyses were based on the 10-year follow-up medical examinations of 1945 children from the Munich and Wesel centers of the GINIplus and LISA German birth cohorts. Female and male pubertal development was assessed by dichotomizing the concentration of hormones in serum at 18.4 pmol/L and 0.087 nmol/L using the lower limits of quantification for estradiol and testosterone, respectively. Land-use regression models derived annual average concentrations of particulate matter with an aerodynamic diameter < 2.5 and 10 µm (PM 2.5 and PM 10 ), as well as spatial models assessed yearly average concentrations of nitrogen dioxide (NO 2 ) and ozone, were calculated at the 10-year residential addresses. To evaluate associations, we utilized logistic regressions adjusted for potential covariates. The analyses were stratified by area and sex., Results: Around 73% of the 943 females and 25% of the 1002 males had a high level of hormones and had already started puberty at the age of 10. Overall, we found no statistically significant associations between exposure to particles (PM 2.5 or PM 10 ) and pubertal development. Results on NO 2 and ozone were not significant as well; for instance, per 10 µg/m 3 increase in ozone concentration, odds ratios and 95% confidence intervals were 0.900 (0.605, 1.339) and 0.830 (0.573, 1.203) for females and males, respectively. Stratified by area, the aforementioned results did not reveal any associations either., Conclusions: Our study did not observe the associations between ambient air pollutants and pubertal development determined by estradiol and testosterone levels in children. However, due to the current limited number of studies on this topic, our results should be cautiously interpreted. Future longitudinal studies are needed to assess the association., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: Most women live to experience menopause and will spend 4-8 years transitioning from fertile age to full menstrual stop. Biologically, reproductive ageing is a continuous process, but by convention, it is defined categorically as pre-, peri- and postmenopause; categories that are sometimes supported by measurements of sex hormones in blood samples. We aimed to develop and validate a new tool, a reproductive ageing score (RAS), that could give a simple and yet precise description of the status of reproductive ageing, without hormone measurements, to be used by health professionals and researchers., Methods: Questionnaire data on age, menstrual regularity and menstrual frequency was provided by the large multicentre population-based RHINE cohort. A continuous reproductive ageing score was developed from these variables, using techniques of fuzzy mathematics, to generate a decimal number ranging from 0.00 (nonmenopausal) to 1.00 (postmenopausal). The RAS was then validated with sex hormone measurements (follicle stimulating hormone and 17β-estradiol) and interview-data provided by the large population-based ECRHS cohort, using receiver-operating characteristics (ROC)., Results: The RAS, developed from questionnaire data of the RHINE cohort, defined with high precision and accuracy the menopausal status as confirmed by interview and hormone data in the ECRHS cohort. The area under the ROC curve was 0.91 (95% Confidence interval (CI): 0.90-0.93) to distinguish nonmenopausal women from peri- and postmenopausal women, and 0.85 (95% CI: 0.83-0.88) to distinguish postmenopausal women from nonmenopausal and perimenopausal women., Conclusions: The RAS provides a useful and valid tool for describing the status of reproductive ageing accurately, on a continuous scale from 0.00 to 1.00, based on simple questions and without requiring blood sampling. The score allows for a more precise differentiation than the conventional categorisation in pre-, peri- and postmenopause. This is useful for epidemiological research and clinical trials., Competing Interests: The authors have declared that no competing interests exist.

Background: Emerging evidence suggests that androgens and estrogens have a role in respiratory health, but it is largely unknown whether levels of these hormones can affect lung function in adults from the general population. This study investigated whether serum dehydroepiandrosterone sulfate (DHEA-S), a key precursor of both androgens and estrogens in peripheral tissues, was related to lung function in adult women participating in the European Community Respiratory Health Survey (ECRHS)., Methods: Lung function and serum DHEA-S concentrations were measured in n  = 2,045 and n  = 1,725 women in 1999-2002 and in 2010-2013, respectively. Cross-sectional associations of DHEA-S levels (expressed as age-adjusted z-score) with spirometric outcomes were investigated, adjusting for smoking habits, body mass index, menopausal status, and use of corticosteroids. Longitudinal associations of DHEA-S levels in 1999-2002 with incidence of restrictive pattern and airflow limitation in 2010-2013 were also assessed., Findings: Women with low DHEA-S (z-score<-1) had lower FEV1 (% of predicted, adjusted difference: -2.2; 95%CI: -3.5 to -0.9) and FVC (-1.7; 95%CI: -2.9 to -0.5) and were at a greater risk of having airflow limitation and restrictive pattern on spirometry than women with higher DHEA-S levels. In longitudinal analyses, low DHEA-S at baseline was associated with a greater incidence of airflow limitation after an 11-years follow-up (incidence rate ratio, 3.43; 95%CI: 1.91 to 6.14)., Interpretation: Low DHEA-S levels in women were associated with impaired lung function and a greater risk of developing airflow limitation later in adult life. Our findings provide new evidence supporting a role of DHEA-S in respiratory health., Funding: EU H2020, grant agreement no.633212., Competing Interests: Dr Demoly reports presentation honoraria from Stallergène Greer, ALK, Mylan, Astra Zeneca, Bausch&Lomb and personal fees as board advisor from Chiesi, Sanofi, Thermo Fisher Scientific, outside the submitted work. Dr Jogi reports personal grants from the Estonian Research Council [personal research grant no.562], and reports travel grants and presentation honoraria from GSK, Novartis, Boehringer, outside the submitted work. Dr Pin reports travel grants and presentation honoraria from GSK, Novartis, Astra Zeneca, Zambon Pharma, outside the submitted work. All the authors declare no competing interests., (© 2020 The Authors.)

Lung function, strongly associated with morbidity and mortality, decreases with age. This study examines whether poor adult lung function is associated with age accelerations (AAs). DNA methylation (DNAm) based AAs, lifespan predictors (GrimAge and plasminogen activator inhibitor 1-PAI1) and their related age-adjusted measures were estimated from peripheral blood at two time points (8-to-11 years apart) in adults from two cohorts: SAPALDIA (n=987) and ECRHS (n=509). Within each cohort and stratified by gender (except for estimators from GrimAge and PAI1), AAs were used as predictors in multivariate linear regression with cross-sectional lung function parameters, and in covariate-adjusted mixed linear regression with longitudinal change in lung function and meta-analysed.AAs were found cross-sectionally associated with lower mean FEV1 (Forced Expiratory Volume in one second) (AA-residuals:P-value=4x10 -4 ; Intrinsic Epigenetic AA:P-value=2x10 -4 ) in females at the follow-up time point only, and the same trend was observed for FVC (Forced Vital Capacity). Both lifespan and plasma level predictors were observed strongly associated with lung function decline and the decline was stronger in the follow-up time points (strongest association between FEV1 and DNAmAge GrimAge:P-value=1.25x10 -17 ).This study suggests that DNAm based lifespan and plasma level predictors can be utilised as important factors to assess lung health in adults.

Background: Menopause is associated with a number of adverse health effects and its timing has been reported to be influenced by several lifestyle factors. Whether greenspace exposure is associated with age at menopause has not yet been investigated., Objective: To investigate whether residential surrounding greenspace is associated with age at menopause and thus reproductive aging., Methods: This longitudinal study was based on the 20-year follow-up of 1955 aging women from a large, population-based European cohort (ECRHS). Residential surrounding greenspace was abstracted as the average of satellite-based Normalized Difference Vegetation Index (NDVI) across a circular buffer of 300 m around the residential addresses of each participant during the course of the study. We applied mixed effects Cox models with centre as random effect, menopause as the survival object, age as time indicator and residential surrounding greenspace as time-varying predictor. All models were adjusted for smoking habit, body mass index, parity, age at menarche, ever-use of contraception and age at completed full-time education as socio-economic proxy., Results: An increase of one interquartile range of residential surrounding greenspace was associated with a 13% lower risk of being menopausal (Hazard Ratio: 0.87, 95% Confidence Interval: 0.79-0.95). Correspondingly the predicted median age at menopause was 1.4 years older in the highest compared to the lowest NDVI quartile. Results remained stable after additional adjustment for air pollution and traffic related noise amongst others., Conclusions: Living in greener neighbourhoods is associated with older age at menopause and might slow reproductive aging. These are novel findings with broad implications. Further studies are needed to see whether our findings can be replicated in different populations and to explore the potential mechanisms underlying this association., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: Menopause is associated with changes in sex hormones, which affect immunity, inflammation, and osteoporosis and may impair lung function. Lung function decline has not previously been investigated in relation to menopause., Objectives: To study whether lung function decline, assessed by FVC and FEV 1 , is accelerated in women who undergo menopause., Methods: The population-based longitudinal European Community Respiratory Health Survey provided serum samples, spirometry, and questionnaire data about respiratory and reproductive health from three study waves (n = 1,438). We measured follicle-stimulating hormone and luteinizing hormone and added information on menstrual patterns to determine menopausal status using latent class analysis. Associations with lung function decline were investigated using linear mixed effects models, adjusting for age, height, weight, pack-years, current smoking, age at completed full-time education, spirometer, and including study center as random effect., Measurements and Main Results: Menopausal status was associated with accelerated lung function decline. The adjusted mean FVC decline was increased by -10.2 ml/yr (95% confidence interval [CI], -13.1 to -7.2) in transitional women and -12.5 ml/yr (95% CI, -16.2 to -8.9) in post-menopausal women, compared with women menstruating regularly. The adjusted mean FEV 1 decline increased by -3.8 ml/yr (95% CI, -6.3 to -2.9) in transitional women and -5.2 ml/yr (95% CI, -8.3 to -2.0) in post-menopausal women., Conclusions: Lung function declined more rapidly among transitional and post-menopausal women, in particular for FVC, beyond the expected age change. Clinicians should be aware that respiratory health often deteriorates during reproductive aging.