The impact of estrogen replacement during perimenopause on lung function and airway inflammation in the VCD mouse model

Menopause associated asthma impacts a subset of women and is less responsive to current treatments. Mechanisms driving this late-onset asthma are unknown. We recently developed a mouse model of menopause associated asthma using a combination of 4-vinylcyclohexene diepoxide (VCD) and house dust mite (HDM) exposures. The goal of this study was to determine how hormone replacement therapy during perimenopause impacts lung function and inflammation. The experimental groups included menopausal mice (VCD) with and without exposure to HDM (to model allergic airways disease) and menopausal mice with and without hormone replacement therapy (HRT; via estrogen pellet implantation). Lung function during methacholine challenge was assessed by flexiVent. Serum, bronchoalveolar lavage fluid (BALF), and histological samples were collected for assessment. Mice that received HRT during perimenopause had enhanced airway hyperresponsiveness (AHR) detected by total airway resistance (<i>R</i>_rs), tissue damping (<i>G</i>), and downward shifts in pressure-volume (PV) curves compared with controls, independent of HDM challenge. Although HRT in perimenopause resulted in decreased eosinophils in the HDM model, neutrophil levels and mucus production were unchanged. Mice receiving HRT in perimenopause also had significantly increased collagen production and inflammation associated with large and small airways, independent of HDM challenge. HRT given during perimenopause may be detrimental to lung responses, including increased AHR and decreased lung function, as well as increased tissue inflammation and airway remodeling.<b>NEW & NOTEWORTHY</b> Menopause-associated asthma is a subtype of asthma that is still largely unexplored and difficult to manage. Women experiencing menopause-associated asthma often have more severe exacerbations, higher rates of exacerbation, and most importantly, poor response to standard treatments. This study examined the impact of estrogen replacement given during the perimenopause phase on lung inflammation and function after menopause. While decreasing eosinophil recruitment, estrogen replacement actually led to worse lung function and more airway remodeling.