# Gonadal hormones as mediators of sex and gender influences in asthma

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2022 · $535,424

## Abstract

ABSTRACT
Asthma is a lung disease caused by exaggerated lung inflammation leading to airway obstruction and
compromised airflow. Despite significant advances in its diagnosis and treatment, asthma continues to be a
significant health problem affecting more than 25 million patients in the US, and over 300 million around the
world. Well-characterized sex and gender differences in asthma have been reported, with changes in morbidity
throughout life. Starting around puberty and peaking during mid-life, women have increased asthma prevalence
and higher rates of asthma exacerbations than men. Causes of these disparities remain unclear; however,
studies have shown that sex-specific inflammatory mechanisms controlled by hormones contribute to differences
in airway reactivity in response to environmental stimuli. Despite this, experimental models of asthma have not
explored the contributions of sex hormones to inflammatory mechanisms in the female and male lung, and no
studies have explored the effects of feminizing hormone therapy with estrogen in the lungs of trans women. Prior
studies from our laboratory using mouse models have reported sex differences and influences of the estrous
cycle and circulating sex hormones in the inflammatory response to environmental exposures. Based on these
findings, we hypothesized that female sex hormones, specifically estrogens, contribute to asthma phenotypes
in the lung via activation of inflammatory mechanisms mediated by estrogen receptors. In the proposed study,
we will test this hypothesis by determining the mechanisms by which estrogen mediates sex and gender
influences in asthma. In Aim 1, we will determine the contributions of sex chromosome complement (XX vs. XY)
vs. gonadal hormones in asthma phenotypes, by developing a mouse house dust mite (HDM) asthma model on
the four core genotypes (FCG) model. In Aim 2, we will study the contributions of estrogens to HDM-induced
asthma outcomes using male and female gonadectomized mice treated with estradiol, as well as bronchial
epithelial cells from male and female healthy and asthma patients to exposed to HDM in the presence/absence
of estrogen receptor agonists/antagonists. In Aim 3, we will determine the roles of nuclear (ER) and membrane-
bound (GPER-1) estrogen receptors in estrogen-mediated mechanisms of inflammation in HDM-induced
asthma, using ER and GPER1 knockout mice. Our studies will be the first to characterize estrogen-mediated
mechanisms of inflammation in asthma phenotypes in the male and female lung, contributing to the
characterization of sex- and gender-specific factors accounting for inter-individual differences, as well as the
effects of feminizing hormone therapy in lung pathobiology. We expect that our studies would serve to develop
potential sex- and gender-specific treatments and recommendations for dosage of therapeutic agents to treat
and prevent asthma in cis and transgender women.

## Key facts

- **NIH application ID:** 10448428
- **Project number:** 5R01HL159764-02
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Patricia Silveyra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $535,424
- **Award type:** 5
- **Project period:** 2021-07-10 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448428

## Citation

> US National Institutes of Health, RePORTER application 10448428, Gonadal hormones as mediators of sex and gender influences in asthma (5R01HL159764-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10448428. Licensed CC0.

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