Boys are more likely to have asthma than girls, but the situation reverses with adolescence, prompting researchers to examine role sex hormones might play

The puzzle of why asthma is about twice as common in women as men may have been solved, according to researchers who say it might partly be down to testosterone.

While boys are about 1.5 times as likely to have asthma as girls, the situation changes with adolescence – a factor that has led scientists to probe whether sex hormones could be behind the trends.

To unpick possible mechanisms behind the gender differences, a team of researchers from the US focused on a type of white blood cells, known as ILC2 cells, that originate in the bone marrow and become “seeded” in particular tissues of the body, including the lungs, early in life.

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When an allergen enters the lungs, the cells lining the airways secrete proteins which in turn trigger ILC2 to expand and produce yet more proteins, which kick off a cascade of inflammatory response.

“We were interested in determining whether or not sex hormones regulate these cells, since they are important in initiating the inflammatory response and so little is known about them,” said Dr Dawn Newcomb, co-author of the research from Vanderbilt University.

Newcomb and colleagues began by looking at the levels of ILC2 cells in the blood of a group of four healthy men and four healthy women, as well as six women and seven men with asthma.

The findings, published in the journal Cell Reports, revealed individuals with asthma had higher levels of ILC2 cells than those without. Moreover, while there was little difference in levels of the cells for healthy participants, women with asthma had about twice the levels of ILC2 cells compared with men with the condition.

The team then turned to mice, and found that adult females had more ILC2 cells in their lung tissue than males or young mice of either sex.



They then carried out a series of experiments manipulating hormone levels in mice and probing the impact on ILC2 cells. Among their studies, the team compared the situation between mice with sex hormones present in their bodies, and those who had had their testes or ovaries removed early in life. “What we found is that the mice that lacked testosterone had significantly more ILC2 expansion and function compared to the male mice that had testosterone,” said Newcomb.

Together, the results suggest that testosterone is important in dampening the expansion and protein production from the ILC2 cells in the lungs, keeping the immune response in check.

Dr Dominick Shaw, severe asthma lead at the University of Nottingham who was not involved in the study, welcomed the research.

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“It appears testosterone and oestrogen change this inflammatory pathway in different ways within mouse lungs. Now mice are a long way from patients … but it is plausible,” he said, noting that more women than men have severe asthma, and changes in asthma symptoms have been linked to the menstrual cycle. “What is interesting about these data is it starts to drill down into what the sex hormones might be doing in terms of the asthma mechanisms.”

Shaw said the study adds weight to recent efforts by pharmaceutical companies to target particular proteins involved in asthma, and that the work suggests it could be beneficial to target proteins produced by ILC2 cells.

“For many years asthma has been seen as a simple diagnosis, and you just give steroids. What we have realised over the last five or 10 years is that it is a highly complex diagnosis and different people have different types of asthma, so we are trying to personalise the treatments to individuals with asthma,” he said. “What this paper suggests is that there might be differential responses based on gender to some of those drugs [coming] in the future.”