Considering Sex and Gender Differences in Respiratory Health

Sex and gender differences need to be taken in account more when researching and treating patients, according to speakers at the European Respiratory Society International Congress 2021.

Although asthma is more prevalent in young boys than girls, after puberty, asthma is not only more prevalent in women, but it’s more severe than it is in men, explained Apostolos Bossios, MD, PhD, associate professor of respiratory medicine at the Karolinska Institute.

Year after year, asthma mortality in women is twice that in men, according to a study in the United States,¹ and similar patterns were seen in Sweden using data from the National Board of Health and Welfare. Data on emergency department (ED) visits across a wide age range in southern California found that in children, the patients were mostly boys (63% vs 37%), but that evened out in adolescence (53% vs 47%) before skewing toward women in adulthood (35% vs 65%).²

Other studies all confirmed that using various clinical markers, women almost always were more likely to have severe asthma, he said.

There are many reasons why women have more severe asthma, Bossios explained. Some of it is simple physiology. Whereas boys have narrower airways than girls, women have smaller lungs and airways compared with men in adulthood. However, changes start in puberty and there are hormonal variations associated with changes in asthma severity and prevalence.

A study³ using mice found that the females had more eosinophils, neutrophils, macrophages, and lymphocytes, and hormones played a role. When the researchers took the estrogen out of female mice, eosinophils, neutrophils, lung function, and more evened out to the levels of male mice. Similarly, when they removed the testosterone from male mice, everything increased like in females.

In humans, testosterone was found to attenuate the number of group 2 innate lymphoid cells (ILC2), which is increased in patients with asthma and particularly in women with asthma.⁴

Other research showed that menstruation and menopause impact asthma. During menstruation, women have increased asthma symptoms, ED visits, hospitalizations, oral steroid use, and intensive care admissions.⁵ This perimenstrual asthma (PMA) was self-reported in 17% of the women surveyed in the study. In addition, more than half (52%) of the PMA group met criteria for severe asthma compared with 30% of the non-PMA group.

A study of French women found new-onset asthma cases after menopause and that women with menopause and obesity were at risk of developing asthma.⁶ However, the results on hormone replacement therapy (HRT), which is common during menopause, are mixed. One study found that women taking HRT had reduced risk of developing asthma,⁷ whereas another study found HRT was associated with new asthma and when the women stopped taking HRT, they also stopped asthma medications.⁸

Overall, the research has shown sex-based dimorphism in asthma and that women have more severe asthma, with estrogen playing a role in inflammation, Bossios concluded. Clinicians and female patients need to be able to discuss this is everyday practice, he said.

In addition to sex, or the biological features of a person, impacting respiratory diseases, gender does as well, said Sofia Belo Ravara, MD, MSc, PhD, of the University of Beira Interior in Portugal. She began her talk by highlighting that although sex and gender are often used interchangeably, they are not the same, although they are related.

Whereas sex impacts the mechanism of diseases, as well as responses to treatment and pharmacological treatment targets, gender is a social construct that has more of an impact on behavior and life experience, she explained.

Gender is a main driver in health inequalities in 3 domains:

• Health determinants: gender has an influence in its own right, as well as through interaction with other social determinants of inequality and vulnerability, such as poverty, occupation, education, nutrition, and participation.
• Behaviors: gender norms and expectations influence exposure to unhealthy products, care seeking, and health protection patterns.
• Health systems and services: gender impacts at the institutional and individual levels through patterns of health service provision and care pathways within services.

Ravara provided tobacco, a main cause of lung cancer and respiratory diseases, as an example. In Portugal, women smoke less than men and gender norms enforce if people smoke and whether they seek care for illnesses arising from tobacco use.

Data from the World Health Organization has shown that tobacco use can be attributed to 63% of respiratory disease deaths for men but only 37% of respiratory deaths for women. However, women face more secondhand exposure to smoke than men, Ravara said.

However, there is a major gap in tobacco research and information and in general, most research is gender blinded in respiratory diseases, she said. One meta-analysis found that there is an inequality among diseases. Cardiology had more investigations in terms of gender and sex, whereas respiratory diseases were less investigated in terms of gender and sex.⁹ In addition, other diseases that are comorbidities of respiratory diseases, such as osteoporosis and depression, are mostly considered female diseases and might be underdiagnosed in men, Ravara added.

The COVID-19 pandemic has highlighted and exacerbated social and health inequalities, in addition to placing a disproportionate burden on women. In general, pandemics are gendered regarding who is affected, who dies, who provides care, who is secured against violence and economic change, and who leads the decisions, she said.

“The time for engendering health systems and gender-affirming health care is now,” Ravara said, adding that more attention needs to be placed on gender differences in health risks, health determinants, health-seeking behavior, and delivery of care.

References

1. Zein JG, Denson JL, Wechsler ME. Asthma over the adult life course: gender and hormonal influences. Clin Chest Med. 2019;40(1):149-161. doi:10.1016/j.ccm.2018.10.009

2. Schatz M, Zeiger RS, Vollmer WM, et al. The controller-to-total asthma medication ratio is associated with patient-centered as well as utilization outcomes. Chest. 2006;130(1):43-50. doi:10.1378/chest.130.1.43

3. Fuseini H, Yung JA, Cephus JY, et al. Testosterone decreases house dust mite-induced type 2 and IL-17A-mediated airway inflammation. J Immunol. 2018;201(7):1843-1854. doi:10.4049/jimmunol.1800293

4. Cephus JY, Stier MT, Fuseini H, et al. Testosterone attenuates group 2 innate lymphoid cell-mediated airway inflammation. Cell Rep. 2017;21(9):2487-2499. doi:10.1016/j.celrep.2017.10.110

5. Rao CK, Moore CG, Bleecker E, et al. Characteristics of perimenstrual asthma and its relation to asthma severity and control: data from the Severe Asthma Research Program. Chest. 2013;143(4):984-992. doi:10.1378/chest.12-0973

6. Matulonga-Diakiese B, Courbon D, Fournier A, et al. Risk of asthma onset after natural and surgical menopause: Results from the French E3N cohort. Maturitas. 2018;118:44-50. doi:10.1016/j.maturitas.2018.10.006

7. Shah SA, Tibble H, Pillinger R, et al. Hormone replacement therapy and asthma onset in menopausal women: National cohort study. J Allergy Clin Immunol. 2021;147(5):1662-1670. doi:10.1016/j.jaci.2020.11.024

8. Hansen ESH, Aasbjerg K, Moeller AL, Gade EJ, Torp-Pedersen C, Backer V. Hormone replacement therapy and development of new asthma. Chest. 2021;160(1):45-52. doi:10.1016/j.chest.2021.01.054

9. Regitz-Zagrosek V. Sex and gender differences in health. EMBO Rep. 2012;13(7):596-603. doi:10.1038/embor.2012.87