Oestrogen amplifies pre‐existing atopy‐associated Th2 bias in an experimental asthma model

Abstract

Background The prevalence and severity of asthma, particularly the most common (atopic) form of the disease, increase amongst females but not males after puberty, and asthma activity also changes throughout the menstrual cycle and during pregnancy. The contribution of female sex hormones to asthma pathogenesis is incompletely understood. Objective To obtain insight into the role of oestrogen (E2) in experimental atopic asthma, and guide future research on sex‐related variations in atopic asthma susceptibility/intensity in humans. Methods We utilized an experimental model comprising rat strains expressing dichotomous Th2‐high vs Th2‐low immunophenotypes exemplified by eosinophilia, mirroring differences between human atopics/non‐atopics. We compared the efficiency of Th2‐associated immunoinflammatory mechanisms, which differed markedly between the two strains, and between sexes in the Th2‐high strain, and determined the effects of E2 administration on these differences. Results Unique to the Th2‐high strain, eosinophil: neutrophil ratios in the airways at baseline and following sensitization/aeroallergen challenge were logfold higher in females relative to males, and this was reflected by higher baseline blood eosinophil numbers in females. Pretreatment of Th2‐high males with E2 abrogated this sex difference by selectively boosting Th2‐associated genes in the airways and eosinophilia, but was without corresponding effect in the Th2‐low strain. In contrast, parallel E2 effects on myeloid and lymphoid cell populations were relatively modest. Conclusions and Clinical Relevance E2 acts to amplify the eosinophilic component of pre‐existing Th2‐high immunophenotype, possibly acting at the level of the common eosinophil/neutrophil precursor in bone marrow to preferentially drive eosinophil differentiation. Constitutive granulocyte profiles in which the balance between eosinophils and neutrophils is skewed towards eosinophils have been identified in independent cohort studies as markers of asthma risk, and these findings suggest that more detailed studies on the role of E2 in this context, and in relation to asthma pathogenesis in post‐pubertal females in particular, appear warranted.

Prevalence, time trends and treatment practices of asthma in India: the Global Asthma Network study

“…3 The self-reported prevalence of wheeze was significantly more common in boys in both age groups (p<0.001). 25 It is unclear why this gender difference exists in the children; probable explanation could be variations in sex hormone levels, 26 bronchial lability 27 , and allergen sensitivities. 28 Interestingly, among adults this difference was not noted for current wheeze and a significantly higher prevalence of asthma ever and doctor-diagnosed asthma were seen in women, which is consistent with previous reports in adults.…”

Potential immunological effects of gender-affirming hormone therapy in transgender people – an unexplored area of research

“… 108 It is well reported that cis male children exhibit higher rates of allergic asthma compared with cis females before puberty, however, following puberty, asthma prevalence and severity increases in cis females, and conversely decreases in cis males. 109 , 110 This suggests that testosterone may be protective in allergic disease, whereas oestrogen may aggravate allergic diseases, such as asthma. 110 In non-pregnant cis females, the levels of sex hormones fluctuate significantly throughout the menstrual cycle.…”

“… 109 , 110 This suggests that testosterone may be protective in allergic disease, whereas oestrogen may aggravate allergic diseases, such as asthma. 110 In non-pregnant cis females, the levels of sex hormones fluctuate significantly throughout the menstrual cycle. 24 These are associated with variability in allergic reactions, and may influence the outcome of skin prick test results.…”

Developments in the field of allergy in 2020 through the eyes of Clinical and Experimental Allergy

“…We have finally entered the much‐anticipated era of personalized medicine for asthma, and several articles evaluated biologics and the variation in individual response to these in people with asthma 25‐27 , 28‐36 , 37 , 38 Others evaluated more traditional treatments for asthma, such as corticosteroids or mechanisms that may underlie impaired airway function in asthma 39‐59 . New interventions studied in clinical trials included air cleaners, triple inhaler therapy, an oral prostaglandin D2 antagonist 60‐62 and other more preliminary data from various interventions, from cinnamon and bacterial peptides to allergen immunotherapy 63‐67 .…”