Silveyra, Patricia

This review identifies the menopausal transition as a critical yet underrecognized determinant of asthma heterogeneity in midlife women. It synthesizes evidence that fluctuating sex hormones may shape distinct asthma phenotypes and endotypes, influencing clinical manifestations, disease modifiers, and therapeutic responses. By framing menopause-associated asthma as a biologically distinct, hormone-driven condition, the article highlights key research priorities for precision medicine approaches tailored to women’s respiratory health.

Abstract RATIONALE. Significant sex-differences exist in asthma across the lifespan. Asthma prevalence and severity are greater in pre-pubescent boys compared to girls but greater in women after puberty. In women, asthma may improve after menopause when sex hormones wane. To address potential mechanisms underlying these changes, we compared the airway transcriptomics signatures of post-menopausal vs. premenopausal women. METHODS. We used bulk RNA seq data from bronchial epithelial cells from three different cohorts (SARP III, GEO-GSE85567, GEO-GSE201955) to perform a comprehensive analysis of differential gene expression and regulation. Data were combined into a meta-analysis, to compare pre-menopausal (n=114 cases with asthma, 48 controls) to post-menopausal women (n=52 cases with asthma, 13 controls). Differential gene expression between pre- and postmenopausal women was analyzed separately for asthma (Figure 1A) and control groups (not shown). Significant differentially expressed genes (DEGs) were identified by contrasting effect sizes (log fold-changes) between asthma and control groups using a Z-score interaction test. Accordingly, a scatter plot (Figure 1B) was created to represent whether differential gene expression between pre- and post-menopausal conditions is modified by disease status (asthma vs. control). The scatter plot also highlights that these findings are related to asthma per. se. and not to normal aging and menopausal transition. Pathway enrichment analysis was conducted using the differential expression data, followed by differential regulation analysis of the identified pathways. Statistical significance was assessed using a false discovery rate (FDR) threshold of 5%. RESULTS. Out of 15,468 genes that passed quality control, 19 genes were differentially expressed in bronchial epithelial cells from pre- and post-menopausal women with asthma (as compared to controls) (Figure 1A). Of these, 5 genes were down-regulated (ITLN1, POSTN, FCRL3, CCL22, PCSK6), and 14 genes were up-regulated (SPP1, S100A9, A2ML1, TNFRSF10C, CSF3R, OLFM1, C1QL2, NLRP3, HAL, PI3, RNASE1, TMEM178B, TNNI3, RNF175) when comparing pre- and post-menopausal women with asthma (Figure 1A). Of these 19 DEGs, 14 were differentially expressed in pre- as compared to post-menopausal women with asthma, but not in controls (Figure 1B). Comparing pre- to post-menopausal women with asthma, biologic pathways related to the innate and adaptive immune system activation and mitochondrial function (Electron transport Chain oxidative phosphorylation and ATP production) were both differentially regulated and expressed. CONCLUSIONS. This analysis highlights several DEGs and pathways that characterize asthma pathogenesis when comparing pre- and post-menopausal women, and emphasize the role of female sex hormones on the immune system response and mitochondrial function in asthma pathogenesis.

Abstract RATIONALE: Significant sex differences exist in the prevalence and severity of asthma across the lifespan. Asthma is more prevalent and severe in pubescent boys compared to girls but worse in girls and women after puberty. The transition to menopause brings significant reductions in estrogen and progesterone levels. In this study, we test the hypothesis that the effect of menopause on asthma prevalence and outcomes is modified by the use of female sex hormones. METHODS: We used data from nine two-year cycles (1999-2000 to 2015-2016) from NHANES to determine the association between menopause and asthma outcomes. We defined severe asthma based on GINA treatment classes 4&5. We used analytic sample weights to compute national estimates according to NHANES guidelines. Adult (age >18 years) women were considered to be menopaused if (1) they reported to be menopaused during the NHANES survey, (2) they had bilateral oophorectomy, or (3) they were ≥52 years. Weighted logistic regression analyses were used to adjust for age, race, body mass index (BMI), smoking, blood eosinophil count, female hormone therapy, and oral contraceptives. Analyses were performed using the SURVEY package in R. RESULTS: The cohorts’ clinical characteristics are listed in table 1. Compared to pre-menopause (weighted n=60,394,897), menopause (weighted n=52,364,594) was associated with higher rates of active asthma (9.2 vs. 8.9%, p=0.004) and severe asthma (5% vs. 1.8%, p<0.001), but not lifetime asthma (15.1 vs. 16.3%, p=0.063). Notably, postmenopausal women had higher BMIs (weighted median [IQR]: 28.1 [24.2-33.1] vs. 26.1 [22.6-32.1], p<0.001), longer asthma durations (weighted median [IQR]: 20.0 [7.0-41.0] vs. 15.0 [8.0-24.0], p<0.001), and lower lung functions (p<0.001) (table 1). Adjusted analysis did not show significant associations between menopause and lifetime asthma (adjusted OR, 1.074; 95% CI, 0.901-1.280), active asthma (adjusted OR, 1.072; 95% CI, 0.865-1.328), or severe asthma (adjusted OR, 1.369; 95% CI, 0.958-1.954). Interestingly, a history of female hormone therapy and oral contraceptives use was associated with a higher risk of lifetime asthma (adjusted OR, 1.191; 95% CI, 1.031-1.375 and adjusted OR, 1.287; 95% CI, 1.169-1.417 respectively). Among women with active asthma, menopause was not associated with non-severe exacerbations (adjusted OR, 1.335; 95% CI, 0.883-2.021) or with severe exacerbations requiring ER visits (adjusted OR, 1.416; 95% CI, 0.818-2.451). Conclusion: The increased prevalence of active asthma and severe asthma among menopausal women can largely be attributed to age-related changes, comorbidities, and hormone therapy use rather than menopause alone.

Abstract RATIONALE: Women are more likely to develop asthma after puberty, and their symptoms can fluctuate during the menstrual cycle, pregnancy, and menopause. Menopausal women with asthma face unique challenges, as hormonal fluctuations during this stage can impact respiratory health. About one-third of women undergo hysterectomy before age 60, with most procedures occurring before natural menopause. While half of these surgeries preserve the ovaries, the other half include oophorectomy, creating distinct hormonal environments. Despite the traditional view of the uterus as hormonally inactive, there remains a critical gap in our understanding of the potential impact of hysterectomy on respiratory health.METHODS: We used data from nine two-year cycles (1999-2000 to 2015-2016) from NHANES to determine the association between hysterectomy and asthma phenotypes. Severe asthma was defined based on GINA treatment classes 4&5. Analytic sample weights were used according to published NHANES guidelines to create national estimates. Asthma status (lifetime, active, severe) was obtained for women without (weighted n=90,348,593) or with a history of hysterectomy (weighted n=22,310,898). Weighted logistic regression analyses were used to determine the impact of hysterectomy on asthma prevalence, severity, exacerbations, and asthma-related emergency room (ER) visits adjusting for age, race, body mass index (BMI), smoking history, blood eosinophil count, a history of unilateral or bilateral oophorectomy, female hormone therapy, and oral contraceptive use. Analyses were performed using the SURVEY package in R.RESULTS: Clinical characteristics of women with and without a history of hysterectomy are listed in Table 1. Overall, hysterectomy was associated with higher asthma prevalence (18.1 vs. 15.1%) and severity (5.1 vs. 2.9%). For all women, hysterectomy was associated with a higher risk for lifetime asthma (adjusted OR, 1.262; 95% CI, 1.1079-1.477) but not for active asthma (adjusted OR, 1.146; 95% CI, 0.93-1.412) or severe asthma (adjusted OR, 0.996; 95% CI, 0.748-1.325). Interestingly, oophorectomy was associated with a higher risk for lifetime asthma (adjusted OR, 1.228; 95% CI, 1.102-1.368 for unilateral; adjusted OR, 1.232; 95% CI, 1.232-1.513 for bilateral) and active asthma (adjusted OR, 1.417; 95% CI, 1.232-1.629 for unilateral; adjusted OR, 1.507; 95% CI, 1.143-1.986 for bilateral). Among women with active asthma, hysterectomy was associated with severe exacerbations requiring ER visits (adjusted OR, 1.845; 95% CI, 1.157-2.941) but not with non-severe exacerbations (adjusted OR, 1.176; 95% CI, 0.811-1.705).CONCLUSIONS: This study highlights the influence of hysterectomy on asthma risk and severity and emphasizes the role of female hormones in asthma pathogenesis.