Menopause and respiratory health: The role of sex hormones, life-style factors and hormone therapy

Our knowledge of lung health in menopausal women has been very limited. This is due to lack of knowledge about gender differences in lung health, lacking interest in women's lung health in relation to hormonal and reproductive factors, and lack of appropriate databases. We have previously found indications that sex hormones affect lung health and that lifestyle factors (body mass, physical activity and smoking) can say something about this effect. However, previous analyses have been based on cross-sectional studies. NFR funded project "Menopause and respiratory health" has given us the opportunity to perform longitudinal analyses and use measured hormone values, thus giving new results with much greater precision. The project is mainly based on three population-based studies: the major North-European multi-center study Respiratory Health in Northern Europe (RHINE), the North, Western Europe and Australia based European Community Respiratory Health (ECRHS) and the Australian Tasmanian Health Survey (TAHS), which have data from interview, lung function and hormone measurements for several thousand women. This project also contributes in the Ageing Lungs in the European Cohorts (ALEC) study. We have found that the risk of new asthma and airway symptoms increases in connection with menopause and that the risk is higher among women with larger body mass (BMI). The study is based on a longitudinal analysis of RHINE. These results were published in the high-cited Journal of Allergy and Clinical Immunology (impact factor 12.5) ("Menopause as a predictor of new-onset asthma: A longitudinal Northern European population study", Triebner K ... Real FG; JACI 2016 Jan). Furthermore, we found that menopausal women have a faster pulmonary function fall than expected by their age, especially in smokers and those with higher weight (BMI). These results are based on longitudinal analyzes in ECRHS, and were published in the high-cited journal American Journal of Respiratory and Critical Care Medicine (impact factor 13) ("Menopause is associated with accelerated lung function decline", Triebner K ... Real FG; Am J Resp With Crit Care, 2016 Sept). We confirmed the findings in cross-sectional analyses of the UK Biobank cohort, with over 140,000 women, and found lower lung function in women in menopause. In addition, we found in the same study that women with early menopause or those who came in menopause after removal of the uterus and / or ovaries had lower lung function than other women of the same age. The results were published in the high-cited European Respiratory Journal (impact factor 8) ("Lower lung function associates with cessation of menstruation: UK Biobank data", Amaral AF ... Real FG ...; ERJ, 2016 Sept) We have also found that the use of hormones in menopause seems to counteract to a certain extent the menopause related decline of lung function. The results have been presented in the annual European Respiratory Society (ERS) meeting in Milan ("HRT is associated with reduced lung function decline", Triebner K et al., ERS 2017 Sept). There is a manuscript that is expected to be published in a highly quoted journal. During the project period, we have also conducted further research on lung health in women, which supports the understanding of menopause in women. We have found that other reproductive and hormonal factors in women also affect their pulmonary health, namely the use of birth control pills, polycystic ovarian syndrome (PCOS) and early age at first menstruation. We have studied risk factors for menstrual related asthma. We have also found that sleep-disturbed breathing patterns are diagnosed less frequently in women than men. Furthermore, we studied the risk of asthma in relation to physical activity. During this project, we have also developed a method for studying body mass over time using self-reported drawings. A sensitive method for measuring sex hormones in serum has been developed. We have also developed a mathematical model to calculate how far a woman has reached into the menopausal transition or menopause. We have also used new mathematical methods to extract the most objective information from data sets. This project has resulted in 11 published articles during the project period, with over 50 «impact factor» points. There are also several ongoing manuscripts. A comprehensive collaboration has been developed with researchers in Europe and Australia participating in RHINE, ECRHS, TAHS, ALEC, RHINESSA, NFBC and ALSWH. We have had research stays in Australia and Spain and presented in several congresses and meetings. There has been extensive media awareness about the results, This project has also contributed significantly to a completed doctorate, a postdoctoral research position, and a professorship. The project has given the foundation for studying lung health of women after menopause. We have applied for funding for the continuation of the study at NFR.

Rationale: There is growing understanding of the importance of reproductive factors for respiratory health. Preventable factors such as smoking, obesity, physical activity and hormone therapy are known to affect both menopause and the airways. However, t here is scarcely any knowledge on respiratory health changes during menopause, how sex hormones mediates such changes, or the potential for intervention. The issue is complex, and few study cohorts have sufficient information and numbers in the right age range. Understanding respiratory health changes during menopause is important, as women expect to live longer and with better life-quality, obesity is increasing globally with unknown consequences for reproductive and respiratory health, and obstructive l ung diseases remain high in spite of decreasing smoking prevalence. The well characterised study cohorts RHINE, ECRHS and TASH are now entering the age of menopausal. This provides a natural experiment and a unique brief window of opportunity to study ho w hormonal changes influence respiratory health. These cohorts include extensive longitudinal data about respiratory and reproductive health, and blood samples from two time points 5-10 years apart available for hormone analyses. Aims: We will study how menopause and the menopausal transition influences respiratory health (asthma, COPD, allergy and lung function), how potential changes are mediated by sex hormones, identify effects of hormone therapy and of life-style factors (smoking, obesity, physical activity), and design intervention strategies. Relevance: The prosed research will provide unique insight in respiratory health during menopause, with implications for women's health during menopause, gender and social inequalities, life-style preventio n and treatment. The project will strengthen interdisciplinary research and local competence,and includes plans for researcher recruitment and international cooperation with researcher exchange.