Asthma, a disease of the lungs that causes inflammation, swelling, wheezing and shortness of breath, affects both sexes, but with one notable difference: Boys tend to grow out of asthma after puberty, and men are far less likely to develop it in adulthood than women are. Australian researchers explored the idea that testosterone may have a protective effect against asthma—and they believe it does, pinpointing some of the mechanisms by which it occurs. Their study results are published in the Journal of Experimental Medicine.
To understand testosterone’s effects, says co-lead author Gabrielle Belz, a professor of molecular immunology at the University of Melbourne, you must first understand a family of immune cells known as innate lymphoid cells, or ILC2s. These cells are found on various surfaces in the body: the lungs, gastrointestinal tract, and the skin, to name a few. “Their job is to sense what’s happening in the external environment and make adjustments based on that,” Belz tells Mental Floss. In asthma, these cells proliferate in high numbers and accumulate in the airways where they trigger chemicals, such as cytokines and leukocytes, “that promote that inflammatory response that results in the airways swelling [and] narrowing, and shortness of breath occurs,” she says.
Males have fewer of these cells than females, Belz says, “because the testosterone receptor regulates the generation of these cells.” Plus, the androgen receptors, whose job it is to sense testosterone, become activated in the presence of testosterone. This suppresses the generation of these ILC2 cells, though Belz and her team are still exploring the mechanism by which it does so. With fewer cells present, there are fewer pro-inflammatory signals—which explains why men are less likely to develop asthma.
To test these effects in mouse models, the researchers ran a number of different experiments, beginning with a baseline analysis of the tissues of healthy male and female mice. They found a significantly increased presence of ILC2s in female mice compared to males, specifically in the lungs of the female mice, where the frequencies and total numbers of ILC2s were “twofold higher” than in males.
In another experiment, the researchers tested the tissue of mice that had been genetically modified not to have the testosterone-sensing androgen receptors—essentially, these mice lacked the ability to suppress the ILC2 cells, making them more likely to have asthma symptoms. These mice showed ILC2 numbers comparable to female mice, as did castrated male mice. The castrated male mice “responded as intact females, indicating that endogenous male sex hormones act as critical regulators [of ILC2s],” the authors write in their paper.
They also took tissue from male and female mice that had been given ovalbumin-induced asthma, and found that there were higher numbers of inflammatory leukocytes in the female mice than in the males.
The mouse models suggest that testosterone is protective against asthma, so the next steps are to study human immune cells from blood samples in a dish. Scientists could expose the human cells to different mediators to stimulate the testosterone pathway. They can also implant the human cells into mouse models to get a more accurate understanding of how the human cells might function. “Our preclinical animal modes are surrogates for the situations that might occur in humans,” Belz says.
This is all well and good if you’re male, but if you’re female, or a prepubescent child, further research is needed to come up with a treatment for asthma. Hormones are crucial for the development and growth of the body, so they can’t simply give testosterone to women and children with asthma “because that could disrupt a whole heap of things in the body,” Belz says. What they hope to do next is to discover receptors in women and children that they can target, and to create synthetic molecules that function in the same way as testosterone—without the impact of a hormone.
If they can achieve a synthetic testosterone, they would ideally be able to formulate an inhaled drug that can be taken through an inhaler, similar to other drugs for lung-related diseases.
Delving into these kinds of differences in how the sexes respond to disease is part of a "big push in the field to have a personalized approach to medicine," says Belz. "So you’d have a slightly different approach to males or females to get on top of these diseases."