Exploring lifestyle, inflammation and body composition across the stages of menopause

Laura E Pernoud

doi:10.25907/01079

Midlife represents a critical period for women’s health, characterised by the menopausal transition and its accompanying physiological changes (1, 2). Menopause coincides with an increased risk of chronic diseases including cardiovascular disease, type 2 diabetes, osteoporosis and cognitive decline (1, 3). Menopause is defined retrospectively following 12 months of amenorrhoea, however the years preceding menopause encompass substantial endocrine change and systemic adaptation that may influence long-term health trajectories (1, 4). Lifestyle behaviours such as physical activity, sitting time and sleep are established determinants of chronic disease risk and may shape health outcomes during this period (5-7). Concurrently, the menopausal transition is accompanied by symptomatic changes and potential alterations in inflammatory regulation that may reflect broader endocrine and metabolic adaptation (8). Indeed, ovarian hormone withdrawal, changes in adipose tissue distribution toward more metabolically active visceral deposits, and lifestyle factors may collectively influence chronic inflammation across reproductive ageing (8, 9). However, variability in inflammatory markers assessed, limited consideration of adiposity and lifestyle, and inconsistent classification of menopausal stage reduces comparability of findings and limits the conclusions that can be drawn across studies (10). Accordingly, this thesis aimed to improve methodological consistency in menopausal stage classification and explore lifestyle behaviours and systemic inflammation across clearly defined stages of reproductive ageing to better understand chronic disease risk in this population. Study 1, presented in Chapter 3, developed and validated the Reproductive Ageing in Women (RAW) questionnaire and accompanying framework to classify reproductive ageing stages in research settings, including individuals with non-observable menstrual cycles. Validation was conducted across multiple cohorts, including content (n = 3), face (n = 14), construct (n = 30), and biological validity (n = 156), and test-retest reliability (n = 128). The RAW questionnaire demonstrated high test-retest reliability (τb = 0.940, p < 0.001) and strong agreement (96%) between classification and expected hormone thresholds for pre and postmenopausal groups. Study 2, presented in Chapter 4, identified lifestyle behaviour profiles (moderate-to-vigorous physical activity (MVPA), sitting time and sleep quality) across the stages of menopause, and investigated whether menopausal symptom severity was associated with less favourable lifestyle profiles, independent of age and menopausal stage. Application of the RAW questionnaire and accompanying framework was undertaken in an Australian-wide cohort (n= 395) and lifestyle behaviours were self-reported and included validated assessments of sleep quality, sitting time, and physical activity (n = 338). Latent profile analysis identified two subgroups, characterised primarily by differences in sleep and physical activity. Approximately 29% of participants were classified in a less active, poorer sleep profile. Higher vasomotor, psychosocial, and physical symptoms were associated with belonging to the less active, poorer sleep profile (all p < 0.001). Study 3 (Chapter 5) used a systematic review and meta-analysis to identify differences in inflammatory markers and adiposity before and after menopause. Meta-analyses demonstrated that adiponectin and leptin were significantly higher in postmenopausal participants, alongside greater measures of adiposity. In contrast, interleukin-6 (IL-6) and c-reactive protein (CRP) did not differ by menopausal stage. Notably, evidence for chemokines was limited, and monocyte chemoattractant protein-1 (MCP-1) was reported in only five studies, three of which reported higher levels in postmenopausal participants. Substantial heterogeneity in menopausal classification methods, and inclusion of lifestyle characteristics was identified across studies. To address these limitations, Study 4, presented in Chapter 6, investigated the cross-sectional relationships between lifestyle, inflammation and body adiposity across the stages of menopause within a cohort study. Body composition was assessed using the four-compartment model (% body fat), dual x-ray absorptiometry (DXA)-derived visceral adipose mass and android/gynoid ratio. Inflammatory markers that showed significant between-group differences were further investigated using generalised linear models with adjustment for adiposity, and age. Interleukin-8 (IL-8) and MCP-1 differed by menopausal stage (both p < 0.001), whereas interleukin-1β, IL-6, interleukin-10 and tumour necrosis factor-α (TNF-α) did not. No differences were observed for MVPA, daily energy intake or smoking status (all p > 0.05), however, alcohol intake differed across groups (p = 0.023). Associations between IL-8 and MCP-1 with menopausal stage remained significant after adjustment for adiposity and lifestyle factors (all p < 0.001). After adjustment for age the peri vs postmenopausal MCP-1 comparison and the pre vs postmenopausal IL-8 comparison were attenuated. The pre vs postmenopausal MCP-1 comparison (β = -0.167, p = 0.018), and peri vs postmenopausal IL-8 comparison (β = -0.150, p = 0.006) remained significant. In summary, the research presented in this thesis contributes to improving the consistency and inclusivity of menopausal stage classification, enhancing comparability across research settings. It demonstrates that greater symptom burden is associated with less favourable lifestyle patterns during midlife, which highlights a window of opportunity for targeted lifestyle strategies and improved symptom management at a time when chronic disease risk begins to increase. In parallel, specific inflammatory markers differed across menopausal stage independent of adiposity. As systemic inflammation is a recognised contributor to chronic disease development, identifying menopausal stage-related inflammatory differences provides a basis for further investigation of midlife disease risk. Collectively, this body of work positions the menopausal transition, including early postmenopause, as a critical period for proactive management of lifestyle and inflammatory factors to support healthy ageing.

Exploring lifestyle, inflammation and body composition across the stages of menopause

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