Exogenous sex steroid hormones and asthma phenotypes: a population-based prospective cohort study using UK-wide Primary Care Databases

Background
After puberty, asthma is more common and severe in females than males. Both endogenous and exogenous sex hormones have previously been shown to impact asthma in females and likely explain the substantial sex-related differences. We recently undertook the largest population-based, longitudinal study and found a substantial reduction in risk of new-onset asthma and asthma exacerbations amongst reproductive age women associated with hormonal contraceptives. We also found a substantial reduction in risk of new-onset asthma but an increased risk of asthma exacerbations amongst menopausal women with hormone replacement therapy (HRT). However, the potential mechanisms that lead to sex-related differences between males and females are still poorly understood, partly due to phenotypic heterogeneity in asthma. A notable example of distinct phenotype is a subset of asthma patients who also have the metabolic syndrome-associated condition (obesity, hypertension, insulin resistance, dyslipidaemia). Previous studies have reported an association between metabolic syndrome-associated conditions and asthma. There is a clear need to account for phenotypic heterogeneity when investigating the role of sex hormones in asthma development and clinical manifestation.
Aims
(i): Investigate the association between exogenous sex hormones (hormonal contraceptives, and HRT) and late asthma onset in females and whether this association is dependent on asthma phenotypes
(ii): Investigate how exogenous sex hormones (hormonal contraceptives and HRT) affect asthma outcomes (asthma exacerbations, severity, and control) in females and whether the impact of sex hormones on asthma outcomes is affected by asthma phenotypes
(iii): Investigate whether the association between therapeutic interventions that are used to treat metabolic syndrome on asthma outcomes (asthma exacerbations, severity, and control) is different between females and males with asthma. If they are different, then further investigate if, amongst women, the association between therapeutic interventions to treat metabolic syndrome and asthma is impacted by exogenous sex hormones.

Expected Outcomes
This study will provide novel insights into the role of exogenous sex hormones in the development and clinical manifestation of asthma phenotypes. More specifically, the findings will help identify the specific asthma phenotypes that are likely to be at a reduced risk of late-onset asthma and severe asthma outcomes and those that are at elevated risk due to exogenous sex hormones. The findings from this study will also help understand the extent of the impact of sex hormones on the association between medications used to treat metabolic syndrome and asthma outcomes. Overall, the findings from this study will help identify the specific asthma phenotypes that are most likely to benefit from the use of exogenous sex hormones as a therapeutic intervention.

Potential Impacts
The outcomes from this work will support the development of complex interventions and be able to identify which group of women can benefit from any sex steroid hormone-based intervention, and which women may be at risk. The findings from this study will also provide novel contextual information that has the potential to feed into asthma guidelines and pave the way for targeted asthma management in women with exogenous sex hormones. Lastly, this study will potentially provide novel insights into the potential links between sex hormones, metabolic syndrome, and asthma phenotypes that will lay the foundation for follow-on mechanistic studies to test new hypotheses.