In Women, Hormones and Gender Affect Asthma Incidence and Treatment Response

In men and women, the timing and manifestations of asthma have notable differences that have only recently been recognized in research. As research continues to delve into these differences — and especially into how hormonal and other changes occurring during the lifecycle of women affect their asthma incidence and response to treatment — it is possible that asthma treatment in women could look very different in the future than it does today.

Asthma and hormonal changes

Research indicates asthma during early childhood is more prevalent in boys vs girls, with reported rates of 11.9% and 7.5%, respectively, and that this pattern begins to shift around the time of puberty.¹ For adults, the estimated prevalence of asthma is 6.3% in men vs 9.6% in women.¹ Adult women with asthma also experience greater disease severity, more frequent hospitalizations, and worse quality of life compared with men who have asthma.^2,3

Investigations into the association between hormonal changes experienced by women and asthma incidence suggest that sex hormones may play an important role in the pathogenesis of the disease.

In addition to puberty as a critical timepoint in the disease course, the available evidence suggests heightened risks for asthma onset and exacerbation in women around menstruation and pregnancy. Multiple studies have demonstrated an increase in asthma symptoms during the pre- and peri-menstrual period in 20% to 40% of women, and other research has found higher rates of health care utilization, hospitalization, and oral corticosteroid use in pre- and peri-menstrual women compared with women without pre- and peri-menstrual asthma.⁴

Research examining the course of asthma during pregnancy collectively suggests that “approximately one-third of women…experience improvement, one-third show worsening of symptoms, and one-third remain unchanged,” with greater odds of exacerbations during pregnancy in those with severe vs mild asthma.² Women who experience a change in symptom severity during pregnancy tend to return to pre-pregnancy symptom severity after delivery.

The link between asthma and menopause has yet to be clarified. Current research has shown conflicting findings as to whether asthma risk increases or decreases during menopause.² However, 2 recent studies involving women receiving hormone replacement therapy (HRT) during menopause offer further evidence of the link between asthma and hormonal levels in women, with both studies finding that HRT elevates the risk for asthma in women.^5,6 In a 2021 study of 34,533 women with asthma and 345,116 women without asthma, the hazard ratio for new asthma onset was 1.63 (95% CI, 1.55-1.71; P <.001) in women receiving HRT.⁵ Similarly, a 17-year national cohort study found that previous use of HRT was associated with an increased risk of severe exacerbation (incidence rate ratio, 1.24; 95% CI, 1.22-1.26) in a sample of 31,656 perimenopausal/postmenopausal women.⁶

Asthma, sex, and gender

Experts emphasize the need for health care providers to understand the specific and often intersecting effects of sex and gender in respiratory disease, noting that these terms are frequently misused or conflated.^7,8 For example, the potential influence of reproductive events on asthma represents an effect of sex, whereas greater exposure to cooking oil fumes (typically in developing countries) is a risk factor related to gender because women are often responsible for cooking due to gender role expectations.^7,9

According to a review published in February 2022 in the Journal of Asthma and Allergy, further research is needed to elucidate the impact of sex-hormone signaling pathways on asthma pathogenesis and symptoms.² Such research could possibly lead to the discovery of “sex hormone-driven asthma endotypes and novel therapeutic targets, providing the basis for a more personalized asthma management strategy.”²

To glean further insights regarding asthma disparities in women, Pulmonology Advisor interviewed Carolyn D’Ambrosio, MS, MD, FCCP, associate professor of pulmonary medicine at Yale School of Medicine in New Haven, Connecticut, and coauthor of a recent review related to asthma in women,⁷ and Peng Zhang, MD, a pulmonary and critical care physician at Cleveland Clinic in Ohio.

What does evidence suggest about differences in asthma treatment in women vs men, and the reasons for these differences? 

Dr D’Ambrosio: Female patients are frequently underdiagnosed or misdiagnosed and treated with psychopharmaceuticals more often than males. They also have a worse perception of their disease when compared with more objective measures of disease severity and control. Females may respond better to Montelukast, and males (who are nonsmokers) have improved FEV₁ [forced expiratory volume in 1 second] with use of inhaled corticosteroids (ICS) compared with females. ^7,10

Dr Zhang: Although asthma is a heterogeneous disease with considerable gender differences, such knowledge unfortunately has yet to be translated into gender-specific asthma care. Male and female sex hormones modulate the immune system in opposite ways: For both Type 2 (T2) inflammation and non-T2 inflammation, estrogen is largely proinflammatory and androgen anti-inflammatory.¹

Women experience dramatic variations in sex hormone levels during menses, pregnancy, and perimenopause. Additionally, women more frequently have comorbidities including obesity. The interaction between sex hormones, environmental factors (such as occupational exposures and smoking) and comorbidities underlies the observed female-predominance in severe asthma, late-onset asthma with obesity, and steroid-refractory asthma.⁷

Furthermore, women tend to have lower levels of T2 inflammation, clinically gauged indirectly by blood eosinophil count, exhaled nitric oxide, and serum immunoglobulin E (IgE) levels. Yet, the majority of currently available asthma therapies, specifically the ICS and most biologics, target the T2 inflammation pathway. Relatively few studies have evaluated gender-specific therapeutic effectiveness.  

It appears that ICS may be more effective for men. Gender differences were not observed with long-acting β-agonist, tiotropium, or anti-IgE treatment. No studies are available for gender-specific therapeutic effectiveness of anti-IL5 or anti-IL4 biologics.⁴ In summary, the differences between women and men with asthma indicate an unmet need for a tailored, gender-specific approach.  

What are the limitations of applying asthma research conducted in men to the treatment of women? 

Dr D’Ambrosio: Right now, we do not have sufficient data on some of the newer agents with regards to sex differences. A review of the current data showed only 5 of 37 trials on the biologic agents for asthma did a separate analysis for sex, and none looked at gender.¹¹

Dr Zhang: As suggested above, the underlying asthma characteristics between men and women are not entirely identical. Unfortunately, most clinical studies did not carry out gender-specific analyses. Applying these findings without modification to women could potentially lead to over-estimation of treatment effect size and success rate. Another issue is that most asthma clinical trials excluded pregnant women and did not record information on period cycles. As a result, our current understanding is fairly limited in these areas.  

Why is gender-sensitive asthma care an important clinical issue?  

Dr D’Ambrosio: At every stage of the patient’s experience, the clinician needs to be aware of differences in sex and gender for asthma: presenting symptoms, response to therapy including perceived response to therapy, the lack of data on some of the newer agents, and finally, for female sex, the effects of pregnancy and menopause on asthma. 

Asthma affects 3% to 12 % of pregnant women, and maternal and fetal complications can occur if asthma is not well controlled. Approximately one-third of pregnant patients with asthma will experience worsening symptoms.⁷ The preferred agents in pregnancy are budesonide, beclomethasone, and fluticasone propionate. However, treating the asthma appropriately outweighs any risk of the medications. In menopause, the use of hormone replacement therapy can increase the risk for severe asthma exacerbation and increased hospitalizations.⁷

Dr Zhang: Several issues in gender-sensitive asthma care deserve special attention. First, asthma severity for a woman is not static; it is related to variations in sex-hormone levels. Factors that affect sex-hormone levels, either endogenous factors such as pregnancy or exogenous factors such as initiation or discontinuation of oral contraception pills or menopausal hormonal therapies, can also affect asthma disease burden, thus warranting clinical attention.

Second, women tend to have more comorbid conditions such as gastrointestinal reflux disease and potentially less robust response to T2-targeting treatments. Early recognition and aggressive management of these comorbidities are paramount in obtaining and maintaining adequate asthma control.  

What further research is most needed on asthma care in women? 

Dr D’Ambrosio: As a community, the medical profession needs to be educated on sex and gender differences in diseases like asthma and tailor our approach to the patient accordingly. We have almost no data on transgender patients and still a dearth of data on sex differences in some of the newer biologic treatments for asthma. 

Dr Zhang: Mechanistic studies to elucidate the interplay between sex hormones and T2/non-T2 pathways are urgently needed. Knowledge from these studies may lead to tailored, sex- and gender-specific asthma therapies. Clinically, we will need more asthma research that includes sex-specific analysis, as well as dedicated research on special populations including pregnant women with asthma.

References

1. Fuseini H, Newcomb DC. Mechanisms driving gender differences in asthma. Curr Allergy Asthma Rep. 2017;17(3):19. doi:10.1007/s11882-017-0686-1
2. Zhang GQ, Özuygur Ermis SS, Rådinger M, Bossios A, Kankaanranta H, Nwaru B. Sex disparities in asthma development and clinical outcomes: implications for treatment strategies. J Asthma Allergy. 2022;15:231-247. doi:10.2147/JAA.S282667
3. Colombo D, Zagni E, Ferri F, Canonica GW; PROXIMA study centers. Gender differences in asthma perception and its impact on quality of life: a post hoc analysis of the PROXIMA (Patient Reported Outcomes and Xolair^® In the Management of Asthma) study. Allergy Asthma Clin Immunol. 2019;15:65. doi:10.1186/s13223-019-0380-z
4. Chowdhury NU, Guntur VP, Newcomb DC, Wechsler ME. Sex and gender in asthma. Eur Respir Rev. 2021;30(162):210067. doi:10.1183/16000617.0067-2021
5. Nwaru BI, Shah SA, Tibble H, et al. Hormone replacement therapy and risk of severe asthma exacerbation in perimenopausal and postmenopausal women: 17-year national cohort study. J Allergy Clin Immunol Pract. 2021;9(7):2751-2760.e1. doi:10.1016/j.jaip.2021.02.052
6. 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
7. Sodhi A, Pisani M, Glassberg MK, Bourjeily G, D’Ambrosio C. Sex and gender in lung disease and sleep disorders: a state-of-the-art review. Chest. 2022:S0012-3692(22)00438-X. doi:10.1016/j.chest.2022.03.006
8. Jenkins CR, Boulet LP, Lavoie KL, Raherison-Semjen C, Singh D. Personalized treatment of asthma: the importance of sex and gender differences. J Allergy Clin Immunol Pract. 2022;10(4):963-971.e3. doi:10.1016/j.jaip.2022.02.002
9. Juntarawijit Y, Juntarawijit C. Cooking smoke exposure and respiratory symptoms among those responsible for household cooking: a study in Phitsanulok, Thailand. Heliyon. 2019;5(5):e01706. doi:10.1016/j.heliyon.2019.e01706
10. Esposito R, Spaziano G, Giannattasio D, et al. Montelukast improves symptoms and lung function in asthmatic women compared with men. Front Pharmacol. 2019;10:1094. doi:10.3389/fphar.2019.01094
11. Ciudad-Gutiérrez P, Fernández-Rubio B, Guisado-Gil AB. Gender bias in clinical trials of biological agents for severe asthma: a systematic review. PLoS One. 2021;16(9):e0257765. doi:10.1371/journal.pone.0257765