Sex Disparities in Asthma Development and Clinical Outcomes: Implications for Treatment Strategies

Figures & data

Table 1 Summary of Epidemiological Evidence on Sex Hormones and Asthma Onset

Exposure	Epidemiological Evidence
Puberty	A systematic review^Citation51 including six cohort studies with 18,272 women reported that compared to typical menarche (11–13 years), early menarche (< 11 years) was associated with an increased risk of new-onset asthma after puberty. Two MR studies^Citation52,Citation53 found similar results.
Menstruation	A systematic review^Citation51 including three cross-sectional studies reported that compared to regular menstruation, irregular menstruation was associated with increased odds of current asthma. However, because of the cross-sectional design, causal inference is impossible.
Pregnancy	Three cross-sectional studies^Citation56^–^Citation58 investigated association between pregnancy history and asthma odds, but reported inconsistent results. Likewise, causal inference is impossible because of the cross-sectional design.
Menopause	Conflicting evidence exists for menopause and asthma: the UK national cohort study^Citation62 of 353,173 women and the Nurses’ Health Study^Citation59 of 64,237 women reported that postmenopausal women had a decreased risk of new-onset asthma compared to pre- or peri-menopausal women; by contrast, the French E3N cohort study^Citation61 of 67,872 women and the Respiratory Health in Northern Europe study^Citation60 of 2322 women found that compared to premenopausal women, peri- or post-menopausal women had an increased asthma risk.
Hormonal contraceptives	The evidence on hormonal contraceptives and asthma is mixed: the UK national cohort study^Citation64 of 564,896 women and a German community-based cohort study^Citation63 of 1191 women reported that use of hormonal contraceptives was associated with a decreased risk of new-onset asthma compared to non-use, and that longer duration of use was associated with a lower asthma risk than shorter duration^Citation64; however, the Nurses’ Health Study^Citation59 of 36,094 women found that use of hormonal contraceptives was associated with an increased asthma risk.
Menopausal hormone therapy (MHT)	The evidence on MHT and asthma is mixed: an umbrella review^Citation65 including five cohort studies with 163,161 women and a Danish register-based nested case-control study^Citation66 of 379,649 women reported that use of MHT was associated with an increased risk of new-onset asthma compared to non-use; however, the UK national cohort study^Citation62 of 353,173 women found that use of MHT was associated with a decreased asthma risk, and that longer duration of use was associated with a lower asthma risk than shorter duration.
Serum levels of sex hormones	A cross-sectional study^Citation67 reported that an elevated serum level of estradiol was associated with decreased odds of current asthma in both women and men. Three cross-sectional studies^Citation67^–^Citation69 found that an elevated serum level of (free) testosterone was associated with decreased odds of asthma in females and/or males. However, causal inference is impossible because of the cross-sectional design.

Abbreviations: MHT, menopausal hormone therapy; MR, Mendelian randomization.

Table 2 Summary of Epidemiological Evidence on Sex Hormones and Asthma Progression and Clinical Outcomes

Exposure	Epidemiological Evidence
Puberty	The Childhood Asthma Management Program study^Citation71 prospectively tracked 418 children with asthma through childhood and adolescence, and found that asthma symptoms tended to worsen in girls but improve in boys.
Menstruation	Around 10–40% of women with asthma experience cyclical worsening of asthma symptoms during the perimenstrual period, a phenomenon known as perimenstrual asthma (PMA).^Citation72^–^Citation75 The pathophysiological mechanisms of PMA remain poorly understood.
Pregnancy	During pregnancy, approximately one third of women with asthma experience improvement, one third show worsening of symptoms, and one third remain unchanged.^Citation83^–^Citation86 Asthma tends to return to the pre-pregnancy state after delivery.^Citation91^–^Citation93 Some studies^Citation88,Citation90,Citation97,Citation100^–^Citation106 investigated association between fetal gender and maternal asthma, but reported inconsistent results.
Menopause	To our best knowledge, no studies have investigated asthma progression during menopausal transition among women with asthma. Several longitudinal studies^Citation107^–^Citation110 and a MR study^Citation111 looked at the trajectory of lung function during menopausal transition among healthy women, but reported contradictory results.
Hormonal contraceptives	Among asthmatic patients, the UK national cohort study^Citation118 of 83,084 women and the Children’s Health Study^Citation117 of 192 women found that use of hormonal contraceptives was associated with a decreased risk of severe asthma exacerbations or wheezing symptoms compared to non-use. The therapeutic effects of hormonal contraceptives on PMA were reported in several case reports and series,^Citation81,Citation112,Citation113 but not in another case report.^Citation114
Menopausal hormone therapy (MHT)	The UK national cohort study^Citation124 of 31,656 women with asthma found that use of MHT was associated with an increased risk of severe asthma exacerbations compared to non-use, and that longer duration of use was associated with a higher risk of asthma exacerbations than shorter duration. Several uncontrolled before-and-after studies^Citation119^–^Citation121 investigated the effects of MHT on lung function or asthma medication use in women with asthma, but reported conflicting results.
Serum levels of sex hormones	Among asthmatic patients, a cross-sectional study^Citation125 reported that an elevated serum level of estradiol was associated with decreased lung function in girls. Three cross-sectional studies^Citation68,Citation69,Citation125 found that an elevated serum level of (free) testosterone or DHEAS was associated with increased lung function and/or deceased odds of asthma symptoms in females and/or males. However, causal inference is impossible because of the cross-sectional design.

Abbreviations: DHEAS, dehydroepiandrosterone sulfate; MHT, menopausal hormone therapy; MR, Mendelian randomization; PMA, perimenstrual asthma.

Figure 1 Schematic of eosinophilic and neutrophilic airway inflammation in asthma. Summary of sex differences and the role of sex hormone signaling in airway inflammation based on experimental evidence from human cells and animal studies are shown in the box below the schematic.

Notes: Modified from Yung JA, Fuseini H, Newcomb DC. Hormones, sex, and asthma. Ann Allergy Asthma Immunol. 2018;120(5):488–494, © 2018 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.¹³⁰

Abbreviations: CXCL8, C-X-C motif chemokine ligand 8; ER, estrogen receptor; IFN-γ; interferon-γ; IgE, immunoglobulin E; IL, interleukin; ILC, innate lymphoid cell; Mφ, macrophage; NK, natural killer cell; T_H, T helper cell; TSLP, thymic stromal-derived lymphopoietin.

McCleary N, Nwaru BI, Nurmatov UB, Critchley H, Sheikh A. Endogenous and exogenous sex steroid hormones in asthma and allergy in females: a systematic review and meta-analysis. J Allergy Clin Immunol. 2018;141(4):1510–1513. doi:10.1016/j.jaci.2017.11.034

 PubMed Web of Science ®Google Scholar

Minelli C, van der Plaat DA, Leynaert B, et al. Age at puberty and risk of asthma: a Mendelian randomisation study. PLoS Med. 2018;15(8):e1002634. doi:10.1371/journal.pmed.1002634

 PubMed Web of Science ®Google Scholar

Chen YC, Fan HY, Yang C, Lee YL. Early pubertal maturation and risk of childhood asthma: a Mendelian randomization and longitudinal study. Allergy. 2020;75(4):892–900. doi:10.1111/all.14009

 PubMed Web of Science ®Google Scholar

Jenkins MA, Dharmage SC, Flander LB, et al. Parity and decreased use of oral contraceptives as predictors of asthma in young women. Clin Exp Allergy. 2006;36(5):609–613. doi:10.1111/j.1365-2222.2006.02475.x

 PubMed Web of Science ®Google Scholar

Forastiere F, Sunyer J, Farchi S, et al. Number of offspring and maternal allergy. Allergy. 2005;60(4):510–514. doi:10.1111/j.1398-9995.2005.00736.x

 PubMed Web of Science ®Google Scholar

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

 PubMed Web of Science ®Google Scholar

Troisi RJ, Speizer FE, Willett WC, Trichopoulos D, Rosner B. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. A prospective cohort study. Am J Respir Crit Care Med. 1995;152(4 Pt 1):1183–1188. doi:10.1164/ajrccm.152.4.7551368

 PubMed Web of Science ®Google Scholar

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

 PubMed Web of Science ®Google Scholar

Triebner K, Johannessen A, Puggini L, et al. Menopause as a predictor of new-onset asthma: a longitudinal Northern European population study. J Allergy Clin Immunol. 2016;137(1):50–57. doi:10.1016/j.jaci.2015.08.019

 PubMed Web of Science ®Google Scholar

Nwaru BI, Pillinger R, Tibble H, et al. Hormonal contraceptives and onset of asthma in reproductive-age women: population-based cohort study. J Allergy Clin Immunol. 2020;146(2):438–446. doi:10.1016/j.jaci.2020.02.027

 PubMed Web of Science ®Google Scholar

Wei J, Gerlich J, Genuneit J, et al. Hormonal factors and incident asthma and allergic rhinitis during puberty in girls. Ann Allergy Asthma Immunol. 2015;115(1):21–27. doi:10.1016/j.anai.2015.04.019

 PubMed Web of Science ®Google Scholar

Zhang GQ, Chen JL, Luo Y, et al. Menopausal hormone therapy and women’s health: an umbrella review. PLoS Med. 2021;18(8):e1003731. doi:10.1371/journal.pmed.1003731

 PubMed Web of Science ®Google Scholar

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

 PubMed Web of Science ®Google Scholar

Han YY, Forno E, Celedón JC. Sex steroid hormones and asthma in a nationwide study of U.S. adults. Am J Respir Crit Care Med. 2020;201(2):158–166. doi:10.1164/rccm.201905-0996OC

 PubMed Web of Science ®Google Scholar

Bulkhi AA, Shepard KV, Casale TB, Cardet JC. Elevated testosterone is associated with decreased likelihood of current asthma regardless of sex. J Allergy Clin Immunol Pract. 2020;8(9):3029–3035. doi:10.1016/j.jaip.2020.05.022

 PubMed Web of Science ®Google Scholar

Fu L, Freishtat RJ, Gordish-Dressman H, et al. Natural progression of childhood asthma symptoms and strong influence of sex and puberty. Ann Am Thorac Soc. 2014;11(6):939–944. doi:10.1513/AnnalsATS.201402-084OC

 PubMedGoogle Scholar

Vrieze A, Postma DS, Kerstjens HA. Perimenstrual asthma: a syndrome without known cause or cure. J Allergy Clin Immunol. 2003;112(2):271–282. doi:10.1067/mai.2003.1676

 PubMed Web of Science ®Google Scholar

Eid RC, Palumbo ML, Cahill KN. Perimenstrual asthma in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol Pract. 2020;8(2):573–578. doi:10.1016/j.jaip.2019.08.054

 PubMed Web of Science ®Google Scholar

Gluck JC, Gluck P. The effects of pregnancy on asthma: a prospective study. Ann Allergy. 1976;37(3):164–168.

 PubMedGoogle Scholar

Schatz M, Dombrowski MP, Wise R, et al. Asthma morbidity during pregnancy can be predicted by severity classification. J Allergy Clin Immunol. 2003;112(2):283–288. doi:10.1067/mai.2003.1516

 PubMed Web of Science ®Google Scholar

Gluck JC, Gluck PA. The effect of pregnancy on the course of asthma. Immunol Allergy Clin North Am. 2006;26(1):63–80. doi:10.1016/j.iac.2005.10.008

 PubMed Web of Science ®Google Scholar

Shanies HM, Venkataraman MT, Peter T. Reversal of intractable acute severe asthma by first-trimester termination of pregnancy. J Asthma. 1997;34(2):169–172. doi:10.3109/02770909709075662

 PubMed Web of Science ®Google Scholar

Belanger K, Hellenbrand ME, Holford TR, Bracken M. Effect of pregnancy on maternal asthma symptoms and medication use. Obstet Gynecol. 2010;115(3):559–567. doi:10.1097/AOG.0b013e3181d06945

 PubMed Web of Science ®Google Scholar

Bokern M, Robijn A, Jensen ME, et al. Factors associated with asthma exacerbations during pregnancy. J Allergy Clin Immunol Pract. 2021;9:4343–4352.e4. doi:10.1016/j.jaip.2021.07.055

 PubMed Web of Science ®Google Scholar

Murphy VE, Gibson PG, Giles WB, et al. Maternal asthma is associated with reduced female fetal growth. Am J Respir Crit Care Med. 2003;168(11):1317–1323. doi:10.1164/rccm.200303-374OC

 PubMed Web of Science ®Google Scholar

Kwon HL, Belanger K, Holford TR, Bracken MB. Effect of fetal sex on airway lability in pregnant women with asthma. Am J Epidemiol. 2006;163(3):217–221. doi:10.1093/aje/kwj032

 PubMed Web of Science ®Google Scholar

Firoozi F, Ducharme FM, Lemière C, et al. Effect of fetal gender on maternal asthma exacerbations in pregnant asthmatic women. Respir Med. 2009;103(1):144–151. doi:10.1016/j.rmed.2008.07.013

 PubMed Web of Science ®Google Scholar

Campbell B, Davis SR, Abramson MJ, et al. Menopause, lung function and obstructive lung disease outcomes: a systematic review. Climacteric. 2018;21(1):3–12. doi:10.1080/13697137.2017.1392504

 PubMed Web of Science ®Google Scholar

Campbell B, Bui DS, Simpson JA, et al. Early age at natural menopause is related to lower post-bronchodilator lung function. A longitudinal population-based study. Ann Am Thorac Soc. 2020;17(4):429–437. doi:10.1513/AnnalsATS.201902-180OC

 PubMed Web of Science ®Google Scholar

van der Plaat DA, Pereira M, Pesce G, et al. Age at menopause and lung function: a Mendelian randomisation study. Eur Respir J. 2019;54(4):1802421. doi:10.1183/13993003.02421-2018

 PubMed Web of Science ®Google Scholar

Nwaru BI, Tibble H, Shah SA, et al. Hormonal contraception and the risk of severe asthma exacerbation: 17-year population-based cohort study. Thorax. 2021;76(2):109–115. doi:10.1136/thoraxjnl-2020-215540

 PubMed Web of Science ®Google Scholar

Salam MT, Wenten M, Gilliland FD. Endogenous and exogenous sex steroid hormones and asthma and wheeze in young women. J Allergy Clin Immunol. 2006;117(5):1001–1007. doi:10.1016/j.jaci.2006.02.004

 PubMed Web of Science ®Google Scholar

Beynon HL, Garbett ND, Barnes PJ. Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone. Lancet. 1988;332(8607):370–372. doi:10.1016/S0140-6736(88)92837-1

 Google Scholar

Lam SM, Huang SC. Premenstrual asthma: report of a case with hormonal studies. J Microbiol Immunol Infect. 1998;31(3):197–199.

 PubMedGoogle Scholar

Matsuo N, Shimoda T, Matsuse H, Kohno S. A case of menstruation-associated asthma: treatment with oral contraceptives. Chest. 1999;116(1):252–253. doi:10.1378/chest.116.1.252

 PubMed Web of Science ®Google Scholar

Derimanov GS, Oppenheimer J. Exacerbation of premenstrual asthma caused by an oral contraceptive. Ann Allergy Asthma Immunol. 1998;81(3):243–246. doi:10.1016/S1081-1206(10)62820-7

 PubMed Web of Science ®Google Scholar

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. doi:10.1016/j.jaip.2021.02.052

 PubMed Web of Science ®Google Scholar

Kos-Kudła B, Ostrowska Z, Marek B, Ciesielska-Kopacz N, Kajdaniuk D, Kudła M. Effects of hormone replacement therapy on endocrine and spirometric parameters in asthmatic postmenopausal women. Gynecol Endocrinol. 2001;15(4):304–311. doi:10.1080/gye.15.4.304.311

 PubMed Web of Science ®Google Scholar

Hepburn MJ, Dooley DP, Morris MJ. The effects of estrogen replacement therapy on airway function in postmenopausal, asthmatic women. Arch Intern Med. 2001;161(22):2717–2720. doi:10.1001/archinte.161.22.2717

 PubMedGoogle Scholar

DeBoer MD, Phillips BR, Mauger DT, et al. Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma. BMC Pulm Med. 2018;18(1):58. doi:10.1186/s12890-018-0612-x

 PubMed Web of Science ®Google Scholar

Han YY, Yan Q, Yang G, Chen W, Forno E, Celedon JC. Serum free testosterone and asthma, asthma hospitalisations and lung function in British adults. Thorax. 2020;75(10):849–854. doi:10.1136/thoraxjnl-2020-214875

 PubMed Web of Science ®Google Scholar

Yung JA, Fuseini H, Newcomb DC. Hormones, sex, and asthma. Ann Allergy Asthma Immunol. 2018;120(5):488–494. doi:10.1016/j.anai.2018.01.016

 PubMed Web of Science ®Google Scholar