Male sex hormones may protect the lungs from asthma by boosting nerve connections

The differences in male and female sex hormones are most evident during growth, puberty and reproduction, when they help shape how the body develops and functions. Beyond their more visible effects, these chemical messengers can also influence how certain diseases develop and progress. One such potential example is asthma, a chronic respiratory disease that often begins in childhood. Although it is more common in boys before puberty, this pattern changes during puberty, when asthma symptoms often improve in males while becoming more common and severe in females.

A recent study published in Science Immunology explored whether sex hormones drive these differences and, if so, how male sex hormones mitigate allergic asthma. When exposed to house dust mite allergens, young male mice developed substantially less allergic lung inflammation than females. This protection involved the endocrine–neuroimmune axis, a bidirectional communication network in which the endocrine, nervous and immune systems work together to regulate lung immunity.

Androgens (male sex hormones) dampened allergy-triggered inflammation not by acting directly on the immune response, but by strengthening the sympathetic nerve supply to the lungs. This nerve supply then triggered the release of the neurotransmitter norepinephrine, suppressing type 2 pulmonary inflammation.

A puberty-linked asthma reversal

Asthma can make even simple breathing difficult; inflammation and tightening of the muscles around the airways interfere with breathing, which can result in coughing, wheezing, shortness of breath or chest tightness, with symptoms that come and go over time. Asthma affects people of all ages. In 2023, an estimated 363 million people were affected worldwide, and 442,000 lost their lives to it. Knowing who is more vulnerable can improve treatment strategies and long-term care.

Doctors have long observed a puzzling shift during puberty. While childhood asthma is more common in boys, after puberty, it becomes much more common and severe in adolescent girls and women. Previous studies have shown how sex hormones directly affect immune cells, but scientists understood little about how they affect nonimmune cells in the lungs.

To study how asthma develops during the hormone surges of puberty, the researchers used young mice. Starting at 15 days old, at the onset of puberty, the mice received daily nasal doses of house dust mite (HDM) extract, a common human allergen, for three weeks. The treatment triggered allergic lung inflammation similar to that seen in human asthma.

Although both developed allergies, the young male mice had less lung inflammation and fewer inflammatory immune cells than females.

At 14 days old, just before puberty, researchers removed the testicles in males and ovaries in females to prevent sex hormone production. Without their natural hormones, the males lost this protection and developed much more severe allergic lung inflammation. Injecting testosterone into these hormone-deficient males successfully calmed the inflammation.

Nerves emerge as the key link

They analyzed the nerve centers connected to the lungs using bulk RNA sequencing, which revealed that male hormones switched on genes involved in nerve growth and development.

During puberty, rising male hormones bind to receptors on sympathetic nerves in the lungs, which switch on genes responsible for nerve growth—leading to a much denser, more highly branched network of protective sympathetic nerves developing in male lungs than in females. The developed nerves release norepinephrine, which acts like a brake, telling hyperactive immune cells to stop producing the proteins that trigger inflammation.

Genetically engineered mice whose sympathetic nerves lacked androgen receptors showed poor nerve growth in the lungs, despite having normal hormones elsewhere. When exposed to allergens, they developed severe lung inflammation and heavy mucus production in the airways.

The researchers said their findings exposed the interplay between hormones, the immune system and the nerves carrying signals to and from the lungs, offering clues about asthma's changing course depending on a person's sex and potential new ways to kickstart remission. The next investigative step would be determining whether humans share this pathway and how it evolves from childhood through puberty and into adulthood.

This article was originally published on MedicalXpress Breaking News-and-Events.